[go: up one dir, main page]

WO2017015659A1 - System and method for the treatment of disease using nanoparticles - Google Patents

System and method for the treatment of disease using nanoparticles Download PDF

Info

Publication number
WO2017015659A1
WO2017015659A1 PCT/US2016/043858 US2016043858W WO2017015659A1 WO 2017015659 A1 WO2017015659 A1 WO 2017015659A1 US 2016043858 W US2016043858 W US 2016043858W WO 2017015659 A1 WO2017015659 A1 WO 2017015659A1
Authority
WO
WIPO (PCT)
Prior art keywords
super
spion
coating
npvd
set forth
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/043858
Other languages
French (fr)
Inventor
Jayanth Venkata Nagendra S. BATCHU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novather Inc
Original Assignee
Novather Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novather Inc filed Critical Novather Inc
Publication of WO2017015659A1 publication Critical patent/WO2017015659A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6425—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/183—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an inorganic material or being composed of an inorganic material entrapping the MRI-active nucleus, e.g. silica core doped with a MRI-active nucleus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds

Definitions

  • This invention relates to the field of drug delivery and more particularly to nanoscopic techniques for drug delivery.
  • Cancer is an abnormality in a cell's internal regulatory mechanisms that results in uncontrolled growth and reproduction of the cell. Normal cells make up tissues, and when these cells lose their ability to behave as a specified, controlled, and coordinated unit, (termed “dedifferentiation"), the defect leads to disarray among the cell population. When this occurs, a tumor begins to propagate.
  • Surgery often is the first step in the treatment of cancer.
  • the objective of surgery varies. Sometimes it is used to remove as much of the evident cancerous tumor as possible, or at least to "debulk” it (remove the major bulk(s) of tumor so that there is less that needs to be treated by other techniques).
  • surgery can also provide some symptomatic relief to the patient. For example, if a surgeon can remove a large portion of an expanding brain tumor, the pressure inside the skull will decrease, leading to improvement in the patient's symptoms.
  • tumors are amenable to surgery. Some may be located in parts of the body that render them impossible to completely excise. Examples of these would include tumors in the brainstem (a part of the brain that controls breathing) or a tumor which has grown in and around a major blood vessel. In these cases, the role of surgery is limited due to the high risk associated with tumor removal.
  • Hodgkin's lymphoma a cancer of the lymph nodes that responds very well to combinations of chemotherapy and radiation therapy. In Hodgkin's lymphoma, surgery is rarely needed to achieve cure, but almost always used to establish a diagnosis (i.e. in the form of a biopsy).
  • Chemotherapy is another common form of cancer treatment. Essentially, it involves the use of medications (usually administered orally or by injection) which specifically attack rapidly dividing cells (such as those found in a tumor) throughout the body. This makes chemotherapy useful in treating cancers that have already metastasized, as well as tumors that have a high chance of spreading through the blood and lymphatic systems but are not evident beyond the primary tumor. Chemotherapy may also be used to enhance the response of localized tumors to surgery and radiation therapy. This is the case, for example, for some cancers of the head and neck.
  • chemotherapeutic agents that are not only better at killing cancer cells, but that also result in fewer side effects for the patient.
  • radiation therapy is another commonly used weapon in the fight against cancer. Ionizing radiation kills cancer by penetrating skin and intervening tissue, and damaging the DNA within the tumor cells.
  • the radiation is delivered in different ways. The most common delivery technique involves directing a beam of radiation at the patient in a highly precise manner, focusing on the tumor. In performing this treatment, a patient lies on a table and the beam source moves around him or her, while transmitting the therapeutic radiation dose in a directed manner. The procedure lasts minutes, but may be performed daily for several weeks (depending on the type of tumor), to achieve a particular total prescribed dose.
  • a radioisotope can be safely used to deliver local radiation for cancer treatment.
  • a typical example of a radioisotope is 1-131 for the treatment of thyroid cancer.
  • brachy therapy Another radiation method sometimes employed, called brachy therapy, involves implanting radioactive pellets (seeds) or wires in the patient's body in the region of the tumor.
  • the implants can be temporary or permanent.
  • the radiation in the seeds decays over a period of days or weeks so that the patient is not rendered radioactive.
  • the entire dose of radiation is usually delivered in a few days, and the patient must remain in the hospital during that time, due to the need for observation and generally in view of his or her heightened radioactivity.
  • radiation is generally delivered to a very targeted area to gain local control over a cancer (as opposed to treating the whole body, as is accomplished using
  • Immunotherapy There are various techniques designed to assist the patient's own immune system fight the cancer, quite separately from radiation or chemotherapy. Oftentimes, to achieve the goal, researchers inject the patient with a specially derived vaccine that strengthens the particular immune response needed to resist the cancer.
  • Monoclonal Antibodies These are antibodies designed to attach to cancerous cells (but not normal cells) by taking advantage of differences between cancerous and noncancerous cells in their antigenic and/or other characteristics.
  • the antibodies can be administered to the patient alone or conjugated to various cytotoxic compounds or in radioactive form, such that the antibody preferentially targets the cancerous cells, thereby delivering the toxic agent or radioactivity to the desired cells.
  • Anti-Angiogenesis Factors As cancer cells rapidly divide and tumors grow, they can soon outgrow their blood supply. To compensate for this, some tumors secrete a substance believed to help induce the growth of blood vessels in their vicinity, thus providing the cancer cells with a vascular source of nutrients. Experimental therapies have been designed to arrest the growth of blood vessels to tumors, thereby depriving them of needed sustenance.
  • Cancer is the product of a series of mutations that ultimately lead to the production of a cancer cell and its excessive proliferation. Cancers can be treated by introducing genes to the cancer cells that will act either to check or stop the cancer's proliferation, turn on the cell's programmed cell mechanisms to destroy the cell, enhance immune recognition of the cell, or express a pro-drug that converts to a toxic metabolite or a cytokine that inhibits tumor growth.
  • Another option for treatment for cancers is to employ nanoparticles that are tailored to be taken-up by the particular organ or tissue. For example, paclitaxel albumin- stabilized nanoparticle formulation for the treatment of metastatic adenocarcinoma of the pancreas.
  • This therapy plus gemcitabine had an improved overall survival and progression- free survival in patients with metastatic adenocarcinoma of the pancreas when compared to the overall survival and progression-free survival in patients treated with gemcitabine alone. This therapy has even been approved by the FDA.
  • This invention overcomes disadvantages of the prior art by providing a super paramagnetic iron oxide nanoparticle (SPION) based drug delivery system, method and associated process(es) that provides a drug delivery system using an interdisciplinary approach combining the fields of biotechnology, physics, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s) (e.g. chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads to the desired target site(s) within a body with minimal or no side effects.
  • therapeutic payload(s) e.g. chemotherapeutic drugs, etc.
  • imaging/diagnostic payloads e.g. chemotherapeutic drugs, etc.
  • These payloads can provide therapeutic affects and/or can be used to diagnose and/or image the target site and can be combined variously in a discrete SPION structure to optimize its operation.
  • the SPION based drug delivery system is provided as a SPION Super Complex.
  • the SPION Super Complexes have a adsorption prevention coating, phagocytosis prevention coating (this coating is present on a SPION Super Complex dependent on the variation of the SPION Super Complex), targeting ligand coating, fusogenic peptide coating (this coating is present on an SPION Super Complex dependent on the variation of the SPION Super Complex), thermal and magnetic mechanisms, therapeutic payload(s) (chemotherapeutic drugs, etc . ), and/or
  • the thermal mechanism is the heat generation mechanism, and this thermal mechanism is activated by the application of the activation magnetic field which is an appropriate magnetic field that can cause the nanoparticle to generate heat.
  • the SPION is spherical in general nature and is manufactured through accepted, published protocols. These manufacturing processes can be used to make SPIONs of various sizes. Once the SPIONs of desired size are obtained, the coatings, therapeutic payload(s) (chemotherapeutic drugs, etc . ), and/or imaging/diagnostic payload(s) can be applied to the SPIONs to turn the SPIONs into SPION Super Complexes. This transformation from a SPION to a SPION Super Complex is called the SPION Super Complex Synthesis. Then, in turn, the SPION Super Complexes can be administered into the body.
  • this invention provides a nanoscopic photovoltaic device (NPVD) based drug delivery system, method and associated process that provides a drug delivery system using an interdisciplinary approach combining the fields of biotechnology, semiconductor physics, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s) (e.g. chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads to the desired target site(s) within a body, with minimal or no side effects.
  • therapeutic payload(s) e.g. chemotherapeutic drugs, etc.
  • imaging/diagnostic payloads e.g. chemotherapeutic drugs, etc.
  • These payloads can provide therapeutic affects and/or can be used to diagnose and/or image the target site and can be combined variously in a discrete NPVD structure to optimize its operation.
  • the NPVD based drug delivery system is provided as an NPVD Super Complex.
  • the NPVD Super Complexes have a protein adsorption prevention coating, phagocytosis prevention coating (this coating is present on an NPVD Super Complex dependent on the variation of the NPVD Super Complex), targeting ligand coating, pore locker coating, fusogenic peptide coating, photovoltaic mechanisms, therapeutic payload(s) (chemotherapeutic drugs, etc . ), and/or imaging/diagnostic payloads.
  • the photovoltaic mechanism is the activated drug release mechanism
  • Fig. 1 is an external view showing a bare (coating-free) super paramagnetic iron oxide nanoparticle (SPION);
  • Fig. 2 is a cross sectional view showing the main layers of a SPION coated with a adsorption prevention or a zwitterionic coating;
  • FIG. 3 is a cross sectional view showing the main layers of a SPION coated with a fusogenic peptide coating and a adsorption prevention or a zwitterionic coating;
  • FIG. 4 is a cross sectional view showing the main layers of a SPION coated with a targeting ligand coating and a adsorption prevention or a zwitterionic coating;
  • Fig. 5 is a cross-sectional view showing the main layers of a SPION Super
  • Fig. 6 is an external view showing a SPION Super Complex variation in which the SPION is coated with a fusogenic peptide coating, targeting ligand coating, and adsorption prevention or zwitterionic coating;
  • Fig. 7 is a cross sectional view of a blood vessel with SPION Super
  • Fig. 8 is a diagram showing the SPION Super Complexes before they move from the blood vessel to the tumor region;
  • FIG. 9 is a top view of a potential targeting ligand initiated receptor-mediated endocytosis of a SPION Super Complex or a potential targeting ligand initiated receptor- endocytosis of a SPION Super Complex;
  • Fig. 10 is a flowchart briefly describing the general manufacturing processes of a SPION Super Complex variation
  • Fig. 11 is a side perspective view showing a bare (coating-free) nanoscopic photovoltaic device (NPVD) according to a further embodiment
  • Fig. 12 is tilted side perspective view showing a bare NPVD from a different angle
  • Fig. 13 is a tilted side perspective view showing a NPVD Super Complex
  • Fig. 14 is a tilted side perspective view showing a variation of a NPVD Super
  • Fig. 15 is a cross-sectional view of a blood vessel with NPVD Super
  • Fig. 16 is a diagram showing the NPVD Super Complexes before they move from the blood vessel to the tumor region;
  • Fig. 17 is a top view of aptamer initiated receptor-mediated endocytosis of an
  • Fig. 18 is a flowchart briefly describing the manufacturing processes of the
  • Fig. 19 is a flowchart briefly describing the manufacturing processes of the
  • Fig. 20 is a flowchart briefly describing the manufacturing processes of the
  • Fig. 1 depicts a bare super paramagnetic iron oxide nanoparticle (SPION) without any coatings or chemotherapeutic drugs.
  • part 102 is the SPION without any coatings.
  • the SPION can be created through accepted, published protocols.
  • Therapeutic payload(s) (chemotherapeutic drugs, etc... ), and/or imaging/diagnostic payloads can be attached to the surface of the bare SPION.
  • the drugs can be attached using conventional chemistries.
  • the SPION itself can be used for therapeutic purposes such as treatment with hyperthermia and imaging with imaging techniques such as magnetic resonance imaging. Other geometries and edge details are expressly contemplated in alternate embodiments.
  • Fig. 2 shows a SPION with an adsorption prevention or zwitterionic coating.
  • This coating can be applied to the surface of the SPION through various applications of chemistry such as ligand exchange in a manner known to those of skill.
  • Compound 202 in Fig. 2 is the adsorption prevention or zwitterionic coating. This coating can allow for longer blood circulation times and the prevention of proteins and other undesired materials to adsorb to the surface of the nanoparticle.
  • Part 204 in Fig. 2 describes the SPION.
  • Fig. 3 shows a SPION with a fusogenic peptide coating and an adsorption prevention or zwitterionic coating. These coatings are applied to the surface of the SPION and other coatings through various applications of chemistry such as ligand exchange, nucleophilic substitution, lewis base addition, Michael addition, and maleimide-thiol chemistry in a manner known to those of skill. SPIONs may or may not have a phagocytosis prevention coating such as a CD47 coating. SPIONs may or may not have a fusogenic peptide coating.
  • Part 302 in Fig. 3 is the adsorption prevention or zwitterionic coating.
  • Part 304 in Fig. 3 describes the SPION.
  • Part 306 in Fig. 3 is the fusogenic peptide.
  • Compound 402 in Fig. 4 is the adsorption prevention or zwitterionic coating.
  • Compound 404 in Fig. 4 describes the SPION.
  • Compound 406 in Fig. 4 is the targeting ligand coating. This targeting ligand allows only the target cells in the body to internalize the SPION Super Complexes. This targeting ligand may use receptor mediated endocytosis to allow the target cells to internalize the SPION Super Complexes.
  • Fig. 5 describes a cross-section of an alternate embodiment of the SPION Super Complex.
  • a fusogenic peptide coating or a phagocytosis prevention coating may or may not be present on the SPION Super Complex.
  • Compound 502 is the in Fig. 5 is the adsorption prevention or zwitterionic coating.
  • Compound 504 in Fig. 5 describes the SPION.
  • Compound 506 in Fig. 5 is the fusogenic peptide that can potentially break the endosome and exposes the SPION Super Complex to the cytoplasm of the target cell after potential internalization.
  • compound 508 in Fig. 5 is the targeting ligand coating.
  • Figure 6 is an external view of an alternate embodiment of the SPION Super
  • a fusogenic peptide coating or a phagocytosis prevention coating may or may not be present on the SPION Super Complex.
  • Compound 602 in Fig. 6 is the adsorption prevention or zwitterionic coating.
  • Compound 604 in Fig. 6 is the fusogenic peptide coating.
  • Compound 606 in Fig. 6 is depicted as the targeting ligand coating.
  • Figs. 7 through 9 describe the general process of therapy using SPION Super
  • FIG. 7 shows the SPION Super Complexes in the blood stream after the administration of the treatment.
  • Particle 702 in Fig. 7 depicts an alternate embodiment of the SPION Super Complex.
  • Fig. 8 is a depiction of SPION Super Complexes before the SPION Super
  • Particle 802 in Fig. 8 depicts a variation of the SPION Super Complex.
  • Fig. 9 depicts and example of SPION Super Complexes undergoing receptor mediated endocytosis.
  • Receptor mediated endocytosis is one of the potential ways of internalization for the SPION Super Complex.
  • the receptor mediated endocytosis can be the result of the SPION Super Complex's targeting ligand coating.
  • SPION Super Complexes 902 in Fig. 9 show various SPION Super Complexes undergoing receptor-mediated endocytosis.
  • a tile is a section of the figure.
  • Tile 9a shows SPION Super Complexes 902 in the beginning of the endocytosis process.
  • Tile 9b shows SPION Super Complexes 902 in the middle of the endocytosis process.
  • Tile 9c shows the SPION Super Complexes 902 almost finished with the endocytosis process.
  • the drugs being delivered can be released from the SPION Super Complexes, the heat generation mechanism of the SPION Super Complex such as hyperthermia to be removed can be activated, and the fusogenic peptide's function can be activated.
  • Fig. 10 is a flowchart describing the general SPION Super Complex Synthesis
  • the SPION Super Complex may or may not have a phagocytosis prevention coating such as a CD47 coating.
  • the SPION Super Complex may or may not have a fusogenic peptide coating.
  • Step 1002 is the representing the growth of SPIONs or obtaining the SPIONs from other sources.
  • Step 1004 is the application of the adsorption prevention or zwitterionic coating.
  • Step 1006 is the application of either the fusogenic peptide (optional) or the targeting ligand coating.
  • the fusogenic peptide application is optional and can be present on other variations of the SPION Super Complex.
  • DNA origami can be used to apply either the optional fusogenic peptide coating or the targeting ligand coating because a DNA origami shell can be created around the SPION with adsorption prevention or zwitterion coating to expose only a particular region for binding by either the optional fusogenic peptide or targeting ligand.
  • Step 1008 is a step that is carried out depending on the type of SPION Super Complex desired. In step 1008, if the fusogenic peptide coating was applied in step 1006, the targeting ligand coating will be applied and the targeting ligand can be applied in a manner using DNA origami similar to the way either the optional fusogenic peptide coating or targeting ligand coating can be applied as described in step 1006.
  • step 1008 if the targeting ligand coating has been applied in step 1006, the fusogenic peptide can be applied if required as it is an optional choice and the potential application of the fusogenic peptide ligand can be applied in a manner using DNA origami similar to the way either the optional fusogenic peptide coating or targeting ligand coating can be applied as described in step 1006.
  • Step 1010 is the potential application of the phagocytosis prevention coating such as the CD47 coating, and the phagocytosis prevention coating such as the CD47 coating can be applied in a manner using DNA origami similar to the way either the optional fusogenic peptide coating or targeting ligand coating can be applied as described in step 1006.
  • Step 1012 is the removal of any potentially unnecessary bonds or interactions, or adding any other desirable coatings or bonds as desired using or not using DNA origami.
  • Step 1014 the SPION Super Complexes can be stored. Overall, multiple chemical processes allow for the production of desired sized nanoparticles.
  • This SPION based drug delivery system or invention overcomes many of the disadvantages of the prior art by using an interdisciplinary approach combining the fields of biotechnology, physics, chemistry, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects.
  • the drug delivery vehicle capable of selectively delivering the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects to treat cancer and other diseases is the SPION Super Complex.
  • the SPION Super Complexes can have a adsorption prevention coating, phagocytosis prevention coating (this coating is present depending on the variation of the SPION Super Complex being synthesized), targeting ligand coating, fusogenic peptide coating (this coating is present depending on the variation of the SPION Super Complex being synthesized), therapeutic payload(s), and/or imaging/diagnostic payload(s), and heat and magnetism based
  • the bonds that bind these coatings to the SPIONs are sufficiently and appropriately strong. This unique and never before used coatings system provides powerful advantages to this new drug delivery system.
  • the adsorption prevention or zwitterionic coating can be a cysteine coating.
  • the adsorption prevention or zwitterionic coating can help prevent the adsorption of proteins to the surface of the SPION Super Complexes due to its zwitterionic charge.
  • a protein corona may not develop on the surface of the SPION Super Complexes. This prevention of the formation of the protein corona will increase the effectivity of SPION complex internalization into tumor cells and decrease the chance of capture by white blood cells present in the body.
  • the adsorption prevention or zwitterionic coating can significantly boost the efficacy of the drug delivery system as a whole.
  • the optional phagocytosis prevention coating (e.g. CD47 coating) on the SPION Super Complexes can prevent phagocytosis of the SPION Super Complexes by white blood cells if any interactions between white blood cells and SPION Super Complexes take place.
  • the heat generation mechanism is activated by applying the activation magnetic field to the SPION Super Complex. When a SPION Super Complex is in the presence of the activation magnetic field, the heat qualities of the SPION Super Complex causes a change in its temperature (an increase in temperature) resulting in the heating of the SPION.
  • the targeting ligand coating enables the SPION Super Complex to be selectively internalized by the tumor cells in various embodiments. This targeting ligand coating can be attached to the SPION or the variations of the SPION Super Complex. The targeting ligand coating can be degraded in the blood stream.
  • This targeting ligand coating present on the SPION Super Complex is such that the SPION Super Complex is small enough for renal filtration and can be exited from the body through renal filtration after it may exit the target cell or spend an appropriate amount of time in the blood/lymph system.
  • the fusogenic peptide coating can allow for endosomal escape of the SPION Super Complex after the SPION Super Complex gains entry into the cell and forms the resulting endosome inside the target cell. This endosomal escape will allow for the therapeutic payload(s) (chemotherapeutic drugs, etc ..
  • the SPION Super Complex can be transported by the SPION Super Complex to be released into the cytoplasm of the target cell if desired and the SPION can be exposed to the activation magnetic field at this time as well to heat the cell.
  • Heat can be generated by the SPION due to the properties of the SPION and thus the SPION portion of a SPION Super Complex can be considered to be part of the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s).
  • the activation magnetic field application will not negatively affect the bonds between the SPION and its coatings and various payloads.
  • the endosomal escape can also allow for the exocytosis of the SPION Super Complex. Therefore, the therapeutic payload(s), and/or imaging/diagnostic payload(s) are selectively and exclusively released/activated in the tumor cells.
  • This coating system is expected to significantly reduce side effects and dramatically increase the overall effectiveness of the drug delivery system.
  • the physical dimensions of the SPION is spherical with smooth/semi-rounded edges and a smooth/semi-rounded top and bottom in general nature.
  • the general manufacturing process of the SPION Super Complex is multistep and called the SPION Super Complex Synthesis Process. The first step is to grow or obtain the SPIONs. Next, the adsorption prevention or zwitterionic coating is applied. Then an optional fusogenic peptide can be applied or the targeting ligand coating is applied.
  • DNA origami can be used to apply either the optional fusogenic peptide coating or the targeting ligand coating because a DNA origami shell can be created around the SPION with adsorption prevention or zwitterion coating to expose only a particular region for binding by either the optional fusogenic peptide or targeting ligand.
  • the optional fusogenic peptide can be applied using DNA origami if the targeting ligand coating has been applied in the previous step, and the targeting ligand can be applied using DNA origami if the optional fusogenic peptide has been applied in the previous step (the fusogenic peptide coating or the targeting ligand coating can be applied using DNA origami because a DNA origami shell can be created around the SPION with adsorption prevention or zwitterionic coating to expose only a particular region for binding by either the optional fusogenic peptide or targeting ligand). Then the optional phagocytosis prevention coating such as the CD47 coating can be applied.
  • This optional phagocytosis prevention coating such as the CD47 coating can be applied using the DNA origami because a DNA origami shell can be created around the SPION with any level or any amount of coatings to expose only a particular region for binding. Then any potentially unnecessary bonds or interactions will be removed, or any other desirable coatings or bonds are added if required using or not using DNA origami.
  • the SPION Super Complexes can be stored. This is potentially how the SPIONs can be turned into SPION Super Complexes. This turning of the SPIONs into SPION Super Complexes can be called as the SPION Super Complex Synthesis process. Other variations of the SPION Super Complexes can be made using variations of this process.
  • This drug delivery system can be administered through IV infusion, injection, through the tactical insertion mechanism, or by other means.
  • the tactical insertion mechanism is the process of releasing the SPION Super Complexes from a catheter near the target site and this catheter used to release/deploy the SPION Super Complexes will be tipped with a remotely controllable activation magnetic field source. In all of these cases, the heat properties or the heat generation mechanism will be activated though applying the activation magnetic field.
  • the treatment scheme is that the SPION Super Complexes are administered into the bloodstream by a variety of modalities, including injection, infusion, oral ingestion, suppository, etc., that should be clear to those of skill.
  • These SPION Super Complexes are represented by particle 702 in Fig. 7.
  • SPION based drug delivery systems can be extended into the field of diagnosis and imaging. Diagnostic and imaging compounds can be added to the SPION Super Complexes to achieve these functions. These diagnostic and imaging compounds can be released as part of the overall of the therapeutic payload(s) and around the time of heat activation. Thus these diagnostic and imaging compounds also aid in diagnosis and imaging.
  • Figs. 11 and 12 depict a bare NPVD, without any coatings or chemotherapeutic drugs.
  • part 1102 is the smooth edged titanium contact layer and in Fig. 12, part 1202 is the smooth edged titanium contact layer.
  • the bare NPVD can be created through the NPVD Synthesis Process.
  • a pore section contains a number of pores.
  • Pore Section 1104 in Fig. 11 and Pore Section 1204 in Fig. 12 are the silica mesopores. In construction, the silica mesopores are grown on top of the single- crystalline silicon ⁇ 111> and the titanium contact layer is grown on top of the silica mesopores.
  • the chemotherapeutic drugs are stored in these silica mesopores.
  • the drugs can be inserted using conventional deposition techniques— for example by mixing the drugs with the nanoparticles.
  • Part 1106 from Fig. 11 and part 1206 from Fig. 12 are made out of single-crystalline silicon ⁇ 111>.
  • Nanoimprinting lithography and reactive ion etching are used to create the boxlike structure with (in this embodiment) smooth/semi-rounded edges and a smooth/semi-rounded top and bottom depicted by part 1106 in Fig. 11 and part 1206 of Fig. 12.
  • Other geometries and edge details are expressly contemplated in alternate embodiments.
  • Fig. 13 shows a NPVD with payloads and protective coatings.
  • An NPVD with payload(s) and protective coating(s) is also known as a NPVD Super Complex. These coatings are applied to the surface of the NPVD through various applications of chemistry such as grafting using silane coupling agents, nucleophilic substitution, Lewis base addition, Michael addition, and maleimide-thiol chemistry in a manner known to those of skill.
  • Part 1302 in Fig. 13 is the titanium contact layer.
  • Pores 1304 in Fig. 13 describes the silica mesopores, which are where the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s) are stored.
  • Part 1306 in Fig. 13 is the single-crystalline silicon ⁇ 111>.
  • Compound 1308 in Fig. 13 is the protein adsorption prevention coating.
  • Compound 1310 in Fig. 13 is the phagocytosis prevention protein coating.
  • Compound 1312 in Fig. 13 is the pore locker coating. This pore locker coating prevents the payload(s) (chemotherapeutic drug, etc.) stored in the silica mesopores from exiting the mesopores until the pore locker coating is removed in the tumor cell in addition to preventing any interactions with anything from the environment.
  • Compound 1314 in Fig. 13 is the aptamer based targeting ligand coating.
  • This aptamer targeting ligand allows only the target cells in the body to internalize the NPVD Super Complexes.
  • This aptamer targeting ligand uses receptor mediated endocytosis to allow the target cells to internalize the NPVD Super Complexes.
  • This aptamer based targeting ligand is coated on top of the pore locker coating.
  • Compound 1316 in Fig. 13 is the fusogenic peptide that breaks the endosome and exposes the NPVD Super Complex to the cytoplasm of the target cell after internalization by receptor mediated endocytosis.
  • Fig. 14 shows a NPVD with payloads and protective coatings.
  • An NPVD with payload(s) and protective coating(s) is also known as a NPVD Super Complex. These coatings are applied to the surface of the NPVD through various applications of chemistry such as grafting using silane coupling agents, nucleophilic substitution, lewis base addition, Michael addition, and maleimide-thiol chemistry in a manner known to those of skill.
  • NPVD Super Complexes may or may not have a phagocytosis prevention coating or a CD47 coating.
  • Part 1402 in Fig. 14 is the titanium contact layer. Pores 1404 in Fig.
  • silica mesopores which are where the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s) are stored.
  • Part 1406 in Fig. 14 is the single-crystalline silicon ⁇ 111>.
  • Compound 1408 in Fig. 14 is the protein adsorption prevention coating.
  • Compound 1410 in Fig. 14 is the pore locker coating. This pore locker coating prevents the payload(s) (chemotherapeutic drug, etc.) stored in the silica mesopores from exiting the mesopores until the pore locker coating is removed in the tumor cell in addition to preventing any interactions with anything from the environment.
  • This aptamer based targeting ligand is the aptamer based targeting ligand coating. This aptamer targeting ligand allows only the target cells in the body to internalize the NPVD Super Complexes. This aptamer targeting ligand uses receptor mediated endocytosis to allow the target cells to internalize the NPVD Super Complexes. This aptamer based targeting ligand is coated on top of the pore locker coating. Compound 1414 in Fig. 14 is the fusogenic peptide that breaks the endosome and exposes the NPVD Super Complex to the cytoplasm of the target cell after internalization by receptor mediated endocytosis.
  • Figs. 15 through 17 describe the process of therapy using the NPVD Super
  • Fig. 15 shows the NPVD Super Complexes in the blood stream after the administration of the treatment.
  • Widget 1502 in Fig. 15 depicts of a NPVD Super Complex.
  • Fig. 16 is a depiction of an NPVD Super Complexes before they move into the tumor cell region. Widget 1602 in Fig. 16 depicts a NPVD Super Complex.
  • Fig. 17 is a picture of NPVD Super Complexes undergoing receptor mediated endocytosis.
  • the receptor mediated endocytosis is the result of the NPVD Super Complex's aptamer coating.
  • NPVD Super Complexes 1702 in Fig. 17 shows various NPVD Super Complexes undergoing receptor-mediated endocytosis.
  • a tile is a section of the figure.
  • Tile 17a shows NPVD Super Complexes in the beginning of the endocytosis process.
  • Tile 17b shows NPVD Super Complexes in the middle of the endocytosis process.
  • Tile 17c shows the NPVD Super Complexes almost finished with the endocytosis process. After the endocytosis of the NPVD Super Complexes, the drugs being delivered will be released from the NPVD Super Complexes and the Fusogenic peptide's function will activate.
  • Fig. 18 is a flowchart describing the NPVD synthesis process (Steps 1810 - 1870) and the NPVD Super Complex synthesis process (Steps 1880 - 1890).
  • Step 1810 describes the creation of the MCM-41 mesoporous silica nanoparticles with 2.5 nm pore size on the single-crystalline silicon ⁇ 111> that serve as the drug bay where the chemotherapeutic drugs and other payload compounds being sequestered.
  • Step 1820 reduces the thickness of the MCM-41 mesoporous silica nanoparticles film with 2.5 nm pore size to approximately 2.5 nm in thickness. This allows for the small size of the NPVD.
  • Step 1830 refers to the application of the 1 nm titanium layer on the surface of the approximately 2.5 nm thick MCM-41 mesoporous silica film using sputtering techniques.
  • nanoimprinting lithography will be used to apply smooth/semi-rounded prism shaped resists with the width of 5 nm and length of 6 nm and height of 10 nm.
  • reactive ion etching or deep reactive ion etching will be used to create trenches approximately 16 nm deep as represented by Step 1850.
  • the resists will be removed.
  • Step 1870 the single-crystalline silicon ⁇ 111> with the MCM-41 mesoporous silica will be flipped and nanoimprinting lithography techniques will be used to apply smooth/semi-rounded prism shaped resists and reactive ion etching or deep reactive ion etching will be used to create a smooth/semi-rounded bottom in a manner similar to the one described previously.
  • Step 1880 reactive ion etching or deep reactive ion etching will be used to isolate the ⁇ 6 nm tall NPVDs.
  • the coatings, the therapeutic payload(s), and/or imaging/diagnostic payload(s) will be applied to the NPVDs to turn the NPVDs into NPVD Super Complexes.
  • the NPVD Super Complexes will be stored.
  • nanoimprinting lithography techniques and reactive ion etching allow for the production of small sized nanoparticles.
  • Fig. 19 is a flowchart describing the NPVD Super Complex Synthesis Process
  • Step 1910 describes the creation of the MCM-41 mesoporous silica nanoparticles with 2.5 nm pore size on the single-crystalline silicon ⁇ 111> that serve as the drug bay where the chemotherapeutic drugs and other payload compounds being sequestered.
  • Step 1912 reduces the thickness of the MCM-41 mesoporous silica nanoparticles film with 2.5 nm pore size to approximately 2.5 nm in thickness. This allows for the small size of the NPVD.
  • Step 1914 refers to the application of the 1 nm titanium layer on the surface of the approximately 2.5 nm thick MCM-41 mesoporous silica film using sputtering techniques.
  • Step 1916 nanoimprinting lithography will be used to apply smooth/semi-rounded prism shaped on a resist line.
  • reactive ion etching or deep reactive ion etching will be used to only leave a repeating pattern of smooth/semi-rounded prism shaped resists (protecting the NPVDs) next to a trench that is as deep as the mesoporous silica material layer as represented by Step 1918.
  • Step 1920 the sides of the trenches will be coated with a silane grafting tool in order to coat the external sides of the pore walls with cysteine.
  • Step 1922 a stiff resist will be applied to shield the side (external wall coating) from reactive ion etching.
  • step 1924 reactive ion etching or deep reactive ion etching will be used to gain access to the pore entrances and achieve the contact layer morphology.
  • step 1926 a part of the pore locker coating is grafted on the pore entrances using a silane grafting tool.
  • step 1928 the NPVD plate is flipped over and nanoimprinting lithography is used to apply smooth/semi-rounded prism like shaped resists. Then in step 1930, reactive ion etching is used to achieve the desired n-type morphology and isolate the NPVD Super Complexes.
  • step 1932 the surfactant inside the pores is extracted and the therapeutic payload(s) (e.g. chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads will be placed into the mesopores after potential modification of the interior of the pore walls.
  • therapeutic payload(s) e.g. chemotherapeutic drugs, etc.
  • imaging/diagnostic payloads will be placed into the mesopores after potential modification of the interior of the pore walls.
  • step 1934 the pore locker coating will be finished by using a substrate with removable tethers on another part of the pore locker coating which will be introduced to loaded NPVDs which will result in the coating of one side of the loaded NPVD and then this substrate with one side of the loaded NPVD capped will be mixed with another part of the pore locker coating attached to an aptamer. Then as represented by step 1936, the tethers and any unnecessary bonds will be removed. Finally, as indicated by Step 1938, The NPVD
  • Fig. 20 is a flowchart describing the NPVD Super Complex Synthesis Process
  • Step 2010 describes the creation of the MCM-41 mesoporous silica nanoparticles with 2.5 nm pore size on the single-crystalline silicon ⁇ 111> that serve as the drug bay where the chemotherapeutic drugs and other payload compounds being sequestered.
  • Step 2012 reduces the thickness of the MCM-41 mesoporous silica nanoparticles film with 2.5 nm pore size to approximately 2.5 nm in thickness. This allows for the small size of the NPVD.
  • Step 2014 refers to the application of the 1 nm titanium layer on the surface of the approximately 2.5 nm thick MCM-41 mesoporous silica film using sputtering techniques.
  • Step 2016, nanoimprinting lithography will be used to apply smooth/semi -rounded prism - rectangular prism - smooth/semi-rounded prism - rectangular prism pattern on a resist line with the rectangular prisms being twice as thick as the smooth/semi-rounded prism's thickness.
  • Step 1020 reactive ion etching or deep reactive ion etching will be used to only leave a repeating pattern of rectangular prism shaped resists next to a trench that is as deep as the mesoporous silica material layer as represented by Step 2018.
  • Step 1020 after potentially introducing a proton source, the sides of the trenches will be coated with a silane grafting tool in order to coat the external sides of the pore walls with cysteine.
  • Step 2022 the whole substrate will be flipped.
  • Step 2024 nanoimprinting lithography is used to apply fern like shaped resists with the leaves of the fern being smooth/semi-rounded prism like and twice as thick as the main stem. There are 2 main stems in this type of resist.
  • step 2026 reactive ion etching is used to achieve the desired n-type morphology and isolate the NPVD Super Complexes and to gain access to the pore entrances and achieve the n-type layer morphology.
  • step 2028 after potentially introducing a proton source, a part of the pore locker coating is grafted on the pore entrances using a silane grafting tool.
  • step 2030 the surfactant inside the pores will be extracted and the mesopores will be loaded with therapeutic payload(s) (e.g.
  • the pore locker coating will be finished by using a substrate with removable tethers on another part of the pore locker coating which will be introduced to loaded NPVDs which will result in the capping of one side of the loaded NPVD and then this substrate with one side of the loaded NPVD capped will be mixed with another part of the pore locker coating attached to an aptamer.
  • the tethers and any unnecessary bonds will be removed.
  • the NPVD Super Complexes will be stored. Overall, nanoimprinting lithography techniques and reactive ion etching allow for the production of small sized nanoparticles.
  • This NPVD based drug delivery system or invention overcomes many of the disadvantages of the prior art by using an interdisciplinary approach combining the fields of biotechnology, semiconductor physics, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects.
  • the drug delivery vehicle capable of selectively delivering the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects to treat cancer are NPVD Super Complexes.
  • the NPVD Super Complexes can have a protein adsorption prevention coating, phagocytosis prevention coating (this coating is present depending on the variation of the NPVD Super Complex being synthesized), targeting ligand coating, pore locker coating, fusogenic peptide coating, therapeutic payload(s), and/or imaging/diagnostic payload(s), and photovoltaic mechanisms.
  • the bonds that bind these coatings to the NPVD complexes and super coating structures are sufficiently strong (except that of the pore locker and the fusogenic peptide).
  • the bonds are illustratively less significantly affected by the body and tumor cells except the bonds of the pore locker and the fusogenic peptide.
  • This unique and never before used coatings system provides powerful advantages to this new drug delivery system.
  • the protein adsorption prevention coating can be a cysteine coating.
  • the cysteine coating can prevent the adsorption of proteins to the surface of the NPVD Super Complexes due to its zwitterionic charge. Thus, a protein corona will not develop on the surface of the NPVD Super Complexes.
  • the phagocytosis prevention coating (e.g. CD47 coating) on the NPVD Super Complexes prevents phagocytosis of the NPVD Super Complexes by white blood cells if any interactions between white blood cells and NPVD Super Complexes take place.
  • the pore locker coating is a coating that coats the openings of the pores of the NPVDs and can be removed in the tumor cell.
  • the pore locker coating is a pH based nanovalve coating and will only be activated once the pH is at the desired level. Once activated, the
  • the activated drug release mechanism is the result of shining the activation radiation (near infrared wavelength of 650 - 900 nm) on the NPVD Super Complex.
  • the photovoltaic qualities of the NPVD Super Complex causes a change in its charge resulting in the expulsion of the positively charged therapeutic payload(s), and/or imaging/diagnostic payload(s) from the mesopores containing the positively charged therapeutic payload(s), and/or imaging/diagnostic payload(s).
  • the NPVD Super Complex will store the therapeutic payload(s), and/or imaging/diagnostic payload(s) in its mesopores. Therefore, the therapeutic payload(s), and/or imaging/diagnostic payload(s) are selectively and exclusively released in the tumor cells.
  • the targeting ligand coating e.g. aptamer coating
  • This aptamer targeting ligand coating is attached to the pore locker coating. This attachment means that once the NPVD Super Complex's pore locker coating is activated, it is small enough for renal filtration and can be exited from the body through renal filtration after it may undergo exocytosis from the target cell.
  • the fusogenic peptide coating allows for endosomal escape of the NPVD Super Complex after the NPVD Super Complex undergoes receptor mediated endocytosis and forms the resulting endosome inside the target cell.
  • This endosomal escape will allow for the therapeutic payload(s) (chemotherapeutic drugs, etc .. ) and/or imaging/diagnostic payload(s) being transported by the NPVD Super Complex to be released into the cytoplasm of the target cell.
  • the endosomal escape can also allow for the exocytosis of the NPVD Super Complex.
  • This coating system is expected to significantly reduce side effects and dramatically increase the overall effectiveness of the drug delivery system.
  • the physical dimensions of the NPVD is boxlike with smooth/semi-rounded edges and a smooth/semi-rounded top and bottom in general nature.
  • the NPVD has a height of approximately ⁇ 6 nm, width of 5 nm and length of 6 nm.
  • the overall structure of the NPVD is mesopores(s) (p-type layer) sandwiched between a layer of titanium (contact layer) and a layer of single-crystalline silicon ⁇ 111> (n-type layer). Different combinations of p-type, n- type, and contact layers may be used.
  • the titanium layer will act as a contact.
  • the manufacturing process of the NPVD is multistep and called the NPVD Synthesis Process.
  • the first step is to grow the MCM-41 variation of mesoporous silica nanoparticles with approximately 2.5 nm pore size on single-crystalline silicon ⁇ 111>.
  • the second step is to use reactive ion etching to reduce the MCM-41 variation of mesoporous silica nanoparticles to approximately 2.5 nm.
  • the next step is to use sputtering techniques to apply a layer of titanium 1 nm thick on top of the MCM-41 variation of mesoporous silica nanoparticles with approximately 2.5 nm pore size.
  • nanoimprinting lithography will be used to apply smooth/semi-rounded prism shaped resists with the width of 5 nm and length of 6 nm and height of 10 nm. Then, reactive ion etching or deep reactive ion etching will be used to create trenches 16 nm deep. After that has finished, the resists will be removed. Then, the single-crystalline silicon ⁇ 111> will be flipped and nanoimprinting lithography techniques will be used to create a smooth/semi-rounded bottom in a manner similar to the one described previously. Then, reactive ion etching or deep reactive ion etching will be used to isolate the ⁇ 6 nm tall NPVDs.
  • the coatings and the therapeutic payload(s), and/or imaging/diagnostic payload(s) will be applied to the NPVDs to turn the NPVDs into NPVD Super Complexes.
  • This turning of the NPVDs into NPVD Super Complexes can be called as the NPVD Super Complex Synthesis process.
  • NPVDs and associated complexes can also be made through the NPVD Super Complex Synthesis Variation 1 and NPVD Super Complex Synthesis Variation 2 described previously.
  • This drug delivery system can be administered through IV infusion, injection, or through the tactical insertion mechanism.
  • the tactical insertion mechanism is the process of releasing the NPVD Super Complexes from a catheter near the target site and this catheter used to release/deploy the NPVD Super Complexes will be tipped with a remotely controllable activation radiation source. In all of these cases, the therapeutic payload will only be released though the activated drug release mechanism.
  • the treatment scheme is that the NPVD Super Complexes are injected into the bloodstream either by infusion or by injection. These NPVD Super Complexes are represented by widget 1502 in Fig. 15. Then these NPVD Super Complexes move from the blood vessels to the tumor cells as shown in Fig.
  • NPVD Super Complex 1602 in Fig. 16 undergo receptor mediated endocytosis as a result of the aptamer coating.
  • the initial part of the receptor mediated endocytosis is depicted by tile 17a in Fig. 17.
  • the intermediate part receptor mediated endocytosis is represented by tile 17b.
  • the final part of receptor mediated endocytosis is described in tile 17c of Fig. 17.
  • NPVD Synthesis Process and NPVD mechanisms are in progress. The exact details will be fumished at a later stage. Additionally, the NPVD based drug delivery systems can be extended into the field of diagnosis and imaging. Diagnostic and imaging compounds can be added to the NPVD Super Complexes to achieve these functions. These diagnostic and imaging compounds can be released as part of the overall of the therapeutic payload(s) and thus also aid in diagnosis and imaging.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nanotechnology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Radiology & Medical Imaging (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Ceramic Engineering (AREA)
  • Dermatology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

This invention provides SPIONs. The SPIONs can be coated as appropriately required for the disease—in the case of cancer treatment, (SPION Super Complex synthesis process) SPION Super Complexes will be the resulting coating-SPION structure. The SPION Super Complexes can also be formed through variations of the SPION Super Complex synthesis process. The NPVD synthesis process uses a combination of nanoimprinting lithography and reactive ion etching to create and isolate the NPVDs. Then the NPVDs can be coated as appropriate for the disease—in the case of cancer treatment, (NPVD Super Complex synthesis process) NPVD Super Complexes will be the resulting coating-NPVD structure. The NPVD Super Complexes can also be formed through the NPVD Super Complex Synthesis Process according to various techniques.

Description

SYSTEM AND METHOD FOR THE TREATMENT OF DISEASE
USING NANOP ARTICLES
FIELD OF THE INVENTION
[0001] This invention relates to the field of drug delivery and more particularly to nanoscopic techniques for drug delivery.
BACKGROUND OF THE INVENTION
[0002] Cancer is an abnormality in a cell's internal regulatory mechanisms that results in uncontrolled growth and reproduction of the cell. Normal cells make up tissues, and when these cells lose their ability to behave as a specified, controlled, and coordinated unit, (termed "dedifferentiation"), the defect leads to disarray among the cell population. When this occurs, a tumor begins to propagate.
[0003] In addressing a cancerous condition, the essence of many medical treatments and procedures involves the removal or destruction of the tumor tissue. Examples of significant types of treatments include the surgical removal of cancerous growths and the destruction of metastatic tumors through chemotherapy and/or radiation therapy.
[0004] Surgery often is the first step in the treatment of cancer. The objective of surgery varies. Sometimes it is used to remove as much of the evident cancerous tumor as possible, or at least to "debulk" it (remove the major bulk(s) of tumor so that there is less that needs to be treated by other techniques). Depending on the type of cancer and its location, surgery can also provide some symptomatic relief to the patient. For example, if a surgeon can remove a large portion of an expanding brain tumor, the pressure inside the skull will decrease, leading to improvement in the patient's symptoms.
[0005] However, not all tumors are amenable to surgery. Some may be located in parts of the body that render them impossible to completely excise. Examples of these would include tumors in the brainstem (a part of the brain that controls breathing) or a tumor which has grown in and around a major blood vessel. In these cases, the role of surgery is limited due to the high risk associated with tumor removal.
[0006] In some cases, surgery is not employed to debulk a tumor because it is simply not necessary. An example is Hodgkin's lymphoma, a cancer of the lymph nodes that responds very well to combinations of chemotherapy and radiation therapy. In Hodgkin's lymphoma, surgery is rarely needed to achieve cure, but almost always used to establish a diagnosis (i.e. in the form of a biopsy).
[0007] Chemotherapy is another common form of cancer treatment. Essentially, it involves the use of medications (usually administered orally or by injection) which specifically attack rapidly dividing cells (such as those found in a tumor) throughout the body. This makes chemotherapy useful in treating cancers that have already metastasized, as well as tumors that have a high chance of spreading through the blood and lymphatic systems but are not evident beyond the primary tumor. Chemotherapy may also be used to enhance the response of localized tumors to surgery and radiation therapy. This is the case, for example, for some cancers of the head and neck.
[0008] Unfortunately, other cells in the human body that also normally divide rapidly
(such as the lining of the stomach and hair) also are affected by chemotherapy. For this reason, many chemotherapy agents induce undesirable side effects such as nausea, vomiting, anemia, hair loss or other symptoms. These side effects are temporary, and there exist medications that can help alleviate many of these side effects. As knowledge in the medical arts has continued to grow, researchers have devised newer chemotherapeutic agents that are not only better at killing cancer cells, but that also result in fewer side effects for the patient.
[0009] As also discussed generally above, radiation therapy is another commonly used weapon in the fight against cancer. Ionizing radiation kills cancer by penetrating skin and intervening tissue, and damaging the DNA within the tumor cells. The radiation is delivered in different ways. The most common delivery technique involves directing a beam of radiation at the patient in a highly precise manner, focusing on the tumor. In performing this treatment, a patient lies on a table and the beam source moves around him or her, while transmitting the therapeutic radiation dose in a directed manner. The procedure lasts minutes, but may be performed daily for several weeks (depending on the type of tumor), to achieve a particular total prescribed dose. A radioisotope can be safely used to deliver local radiation for cancer treatment. A typical example of a radioisotope is 1-131 for the treatment of thyroid cancer.
[0010] Another radiation method sometimes employed, called brachy therapy, involves implanting radioactive pellets (seeds) or wires in the patient's body in the region of the tumor. The implants can be temporary or permanent. For permanent implants, the radiation in the seeds decays over a period of days or weeks so that the patient is not rendered radioactive. For temporary implants, the entire dose of radiation is usually delivered in a few days, and the patient must remain in the hospital during that time, due to the need for observation and generally in view of his or her heightened radioactivity. For both types of brachy therapy, radiation is generally delivered to a very targeted area to gain local control over a cancer (as opposed to treating the whole body, as is accomplished using
chemotherapy).
[0011] A number of other cancer therapies exist. Examples of such treatments include immunotherapy, monoclonal antibodies, anti-angiogenesis factors and gene therapy. A brief description of each of these relatively new treatment regimens is as follows:
[0012] Immunotherapy: There are various techniques designed to assist the patient's own immune system fight the cancer, quite separately from radiation or chemotherapy. Oftentimes, to achieve the goal, researchers inject the patient with a specially derived vaccine that strengthens the particular immune response needed to resist the cancer.
[0013] Monoclonal Antibodies: These are antibodies designed to attach to cancerous cells (but not normal cells) by taking advantage of differences between cancerous and noncancerous cells in their antigenic and/or other characteristics. The antibodies can be administered to the patient alone or conjugated to various cytotoxic compounds or in radioactive form, such that the antibody preferentially targets the cancerous cells, thereby delivering the toxic agent or radioactivity to the desired cells.
[0014] Anti-Angiogenesis Factors: As cancer cells rapidly divide and tumors grow, they can soon outgrow their blood supply. To compensate for this, some tumors secrete a substance believed to help induce the growth of blood vessels in their vicinity, thus providing the cancer cells with a vascular source of nutrients. Experimental therapies have been designed to arrest the growth of blood vessels to tumors, thereby depriving them of needed sustenance.
[0015] Gene Therapy: Cancer is the product of a series of mutations that ultimately lead to the production of a cancer cell and its excessive proliferation. Cancers can be treated by introducing genes to the cancer cells that will act either to check or stop the cancer's proliferation, turn on the cell's programmed cell mechanisms to destroy the cell, enhance immune recognition of the cell, or express a pro-drug that converts to a toxic metabolite or a cytokine that inhibits tumor growth. [0016] Another option for treatment for cancers is to employ nanoparticles that are tailored to be taken-up by the particular organ or tissue. For example, paclitaxel albumin- stabilized nanoparticle formulation for the treatment of metastatic adenocarcinoma of the pancreas. This therapy plus gemcitabine had an improved overall survival and progression- free survival in patients with metastatic adenocarcinoma of the pancreas when compared to the overall survival and progression-free survival in patients treated with gemcitabine alone. This therapy has even been approved by the FDA.
[0017] It is therefore desirable to provide a new therapy employing nanoparticles to transport chemotherapeutic drugs and/or other therapeutic payloads to tumors. This therapy would be significantly more effective if it produces mainly local effects and minimal or no systemic toxicity, or minimal or no overall side effects. This approach should also potentially be applicable to treat or cure a wide variety of diseases involving organs and tissues in addition to cancer.
SUMMARY OF THE INVENTION
[0018] This invention overcomes disadvantages of the prior art by providing a super paramagnetic iron oxide nanoparticle (SPION) based drug delivery system, method and associated process(es) that provides a drug delivery system using an interdisciplinary approach combining the fields of biotechnology, physics, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s) (e.g. chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads to the desired target site(s) within a body with minimal or no side effects. These payloads can provide therapeutic affects and/or can be used to diagnose and/or image the target site and can be combined variously in a discrete SPION structure to optimize its operation. In the case of cancer treatment, the SPION based drug delivery system is provided as a SPION Super Complex. The SPION Super Complexes have a adsorption prevention coating, phagocytosis prevention coating (this coating is present on a SPION Super Complex dependent on the variation of the SPION Super Complex), targeting ligand coating, fusogenic peptide coating (this coating is present on an SPION Super Complex dependent on the variation of the SPION Super Complex), thermal and magnetic mechanisms, therapeutic payload(s) (chemotherapeutic drugs, etc . ), and/or
imaging/diagnostic payloads. Illustratively, the thermal mechanism is the heat generation mechanism, and this thermal mechanism is activated by the application of the activation magnetic field which is an appropriate magnetic field that can cause the nanoparticle to generate heat.
[0019] In an illustrative embodiment, the SPION is spherical in general nature and is manufactured through accepted, published protocols. These manufacturing processes can be used to make SPIONs of various sizes. Once the SPIONs of desired size are obtained, the coatings, therapeutic payload(s) (chemotherapeutic drugs, etc . ), and/or imaging/diagnostic payload(s) can be applied to the SPIONs to turn the SPIONs into SPION Super Complexes. This transformation from a SPION to a SPION Super Complex is called the SPION Super Complex Synthesis. Then, in turn, the SPION Super Complexes can be administered into the body.
[0020] According to a further embodiment, this invention provides a nanoscopic photovoltaic device (NPVD) based drug delivery system, method and associated process that provides a drug delivery system using an interdisciplinary approach combining the fields of biotechnology, semiconductor physics, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s) (e.g. chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads to the desired target site(s) within a body, with minimal or no side effects. These payloads can provide therapeutic affects and/or can be used to diagnose and/or image the target site and can be combined variously in a discrete NPVD structure to optimize its operation. In the case of cancer treatment, the NPVD based drug delivery system is provided as an NPVD Super Complex. The NPVD Super Complexes have a protein adsorption prevention coating, phagocytosis prevention coating (this coating is present on an NPVD Super Complex dependent on the variation of the NPVD Super Complex), targeting ligand coating, pore locker coating, fusogenic peptide coating, photovoltaic mechanisms, therapeutic payload(s) (chemotherapeutic drugs, etc . ), and/or imaging/diagnostic payloads. Illustratively, the photovoltaic mechanism is the activated drug release mechanism
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The invention description below refers to the accompanying drawings, of which:
[0022] Fig. 1 is an external view showing a bare (coating-free) super paramagnetic iron oxide nanoparticle (SPION); [0023] Fig. 2 is a cross sectional view showing the main layers of a SPION coated with a adsorption prevention or a zwitterionic coating;
[0024] Fig. 3 is a cross sectional view showing the main layers of a SPION coated with a fusogenic peptide coating and a adsorption prevention or a zwitterionic coating;
[0025] Fig. 4 is a cross sectional view showing the main layers of a SPION coated with a targeting ligand coating and a adsorption prevention or a zwitterionic coating;
[0026] Fig. 5 is a cross-sectional view showing the main layers of a SPION Super
Complex variation in which the SPION is coated with a fusogenic peptide coating, targeting ligand coating, and adsorption prevention or zwitterionic coating;
[0027] Fig. 6 is an external view showing a SPION Super Complex variation in which the SPION is coated with a fusogenic peptide coating, targeting ligand coating, and adsorption prevention or zwitterionic coating;
[0028] Fig. 7 is a cross sectional view of a blood vessel with SPION Super
Complexes;
[0029] Fig. 8 is a diagram showing the SPION Super Complexes before they move from the blood vessel to the tumor region;
[0030] Fig. 9 is a top view of a potential targeting ligand initiated receptor-mediated endocytosis of a SPION Super Complex or a potential targeting ligand initiated receptor- endocytosis of a SPION Super Complex; and
[0031] Fig. 10 is a flowchart briefly describing the general manufacturing processes of a SPION Super Complex variation;
[0032] Fig. 11 is a side perspective view showing a bare (coating-free) nanoscopic photovoltaic device (NPVD) according to a further embodiment;
[0033] Fig. 12 is tilted side perspective view showing a bare NPVD from a different angle;
[0034] Fig. 13 is a tilted side perspective view showing a NPVD Super Complex;
[0035] Fig. 14 is a tilted side perspective view showing a variation of a NPVD Super
Complex;
[0036] Fig. 15 is a cross-sectional view of a blood vessel with NPVD Super
Complexes;
[0037] Fig. 16 is a diagram showing the NPVD Super Complexes before they move from the blood vessel to the tumor region; [0038] Fig. 17 is a top view of aptamer initiated receptor-mediated endocytosis of an
NPVD Super Complex;
[0039] Fig. 18 is a flowchart briefly describing the manufacturing processes of the
NPVDs and NPVD Super Complexes;
[0040] Fig. 19 is a flowchart briefly describing the manufacturing processes of the
NPVDs and NPVD Super Complexes through the NPVD Super Complex Synthesis Process Variation 1 ; and
[0041] Fig. 20 is a flowchart briefly describing the manufacturing processes of the
NPVDs and NPVD Super Complexes through the NPVD Super Complex Synthesis Process Variation 2.
DETAILED DESCRIPTION
[0042] I. SPION
[0043] Fig. 1 depicts a bare super paramagnetic iron oxide nanoparticle (SPION) without any coatings or chemotherapeutic drugs. In Fig. 1, part 102 is the SPION without any coatings. The SPION can be created through accepted, published protocols. Therapeutic payload(s) (chemotherapeutic drugs, etc... ), and/or imaging/diagnostic payloads can be attached to the surface of the bare SPION. The drugs can be attached using conventional chemistries. The SPION itself can be used for therapeutic purposes such as treatment with hyperthermia and imaging with imaging techniques such as magnetic resonance imaging. Other geometries and edge details are expressly contemplated in alternate embodiments.
[0044] Fig. 2 shows a SPION with an adsorption prevention or zwitterionic coating.
This coating can be applied to the surface of the SPION through various applications of chemistry such as ligand exchange in a manner known to those of skill. Compound 202 in Fig. 2 is the adsorption prevention or zwitterionic coating. This coating can allow for longer blood circulation times and the prevention of proteins and other undesired materials to adsorb to the surface of the nanoparticle. Part 204 in Fig. 2 describes the SPION.
[0045] Fig. 3 shows a SPION with a fusogenic peptide coating and an adsorption prevention or zwitterionic coating. These coatings are applied to the surface of the SPION and other coatings through various applications of chemistry such as ligand exchange, nucleophilic substitution, lewis base addition, Michael addition, and maleimide-thiol chemistry in a manner known to those of skill. SPIONs may or may not have a phagocytosis prevention coating such as a CD47 coating. SPIONs may or may not have a fusogenic peptide coating. Part 302 in Fig. 3 is the adsorption prevention or zwitterionic coating. Part 304 in Fig. 3 describes the SPION. Part 306 in Fig. 3 is the fusogenic peptide.
[0046] Compound 402 in Fig. 4 is the adsorption prevention or zwitterionic coating. Compound 404 in Fig. 4 describes the SPION. Compound 406 in Fig. 4 is the targeting ligand coating. This targeting ligand allows only the target cells in the body to internalize the SPION Super Complexes. This targeting ligand may use receptor mediated endocytosis to allow the target cells to internalize the SPION Super Complexes.
[0047] Fig. 5 describes a cross-section of an alternate embodiment of the SPION Super Complex. A fusogenic peptide coating or a phagocytosis prevention coating may or may not be present on the SPION Super Complex. Compound 502 is the in Fig. 5 is the adsorption prevention or zwitterionic coating. Compound 504 in Fig. 5 describes the SPION. Compound 506 in Fig. 5 is the fusogenic peptide that can potentially break the endosome and exposes the SPION Super Complex to the cytoplasm of the target cell after potential internalization. As depicted, compound 508 in Fig. 5 is the targeting ligand coating.
[0048] Figure 6 is an external view of an alternate embodiment of the SPION Super
Complex. A fusogenic peptide coating or a phagocytosis prevention coating may or may not be present on the SPION Super Complex. Compound 602 in Fig. 6 is the adsorption prevention or zwitterionic coating. Compound 604 in Fig. 6 is the fusogenic peptide coating. Compound 606 in Fig. 6 is depicted as the targeting ligand coating.
[0049] Figs. 7 through 9 describe the general process of therapy using SPION Super
Complexes. Fig. 7 shows the SPION Super Complexes in the blood stream after the administration of the treatment. Particle 702 in Fig. 7 depicts an alternate embodiment of the SPION Super Complex.
[0050] Fig. 8 is a depiction of SPION Super Complexes before the SPION Super
Complexes move into the tumor cell(s) region. Particle 802 in Fig. 8 depicts a variation of the SPION Super Complex.
[0051] Fig. 9 depicts and example of SPION Super Complexes undergoing receptor mediated endocytosis. Receptor mediated endocytosis is one of the potential ways of internalization for the SPION Super Complex. The receptor mediated endocytosis can be the result of the SPION Super Complex's targeting ligand coating. SPION Super Complexes 902 in Fig. 9 show various SPION Super Complexes undergoing receptor-mediated endocytosis. A tile is a section of the figure. Tile 9a shows SPION Super Complexes 902 in the beginning of the endocytosis process. Tile 9b shows SPION Super Complexes 902 in the middle of the endocytosis process. Tile 9c shows the SPION Super Complexes 902 almost finished with the endocytosis process. After the endocytosis of the SPION Super Complexes, the drugs being delivered can be released from the SPION Super Complexes, the heat generation mechanism of the SPION Super Complex such as hyperthermia to be removed can be activated, and the fusogenic peptide's function can be activated.
[0052] Fig. 10 is a flowchart describing the general SPION Super Complex Synthesis
Process. The SPION Super Complex may or may not have a phagocytosis prevention coating such as a CD47 coating. The SPION Super Complex may or may not have a fusogenic peptide coating. Step 1002 is the representing the growth of SPIONs or obtaining the SPIONs from other sources. Step 1004 is the application of the adsorption prevention or zwitterionic coating. Step 1006 is the application of either the fusogenic peptide (optional) or the targeting ligand coating. The fusogenic peptide application is optional and can be present on other variations of the SPION Super Complex. DNA origami can be used to apply either the optional fusogenic peptide coating or the targeting ligand coating because a DNA origami shell can be created around the SPION with adsorption prevention or zwitterion coating to expose only a particular region for binding by either the optional fusogenic peptide or targeting ligand. Step 1008 is a step that is carried out depending on the type of SPION Super Complex desired. In step 1008, if the fusogenic peptide coating was applied in step 1006, the targeting ligand coating will be applied and the targeting ligand can be applied in a manner using DNA origami similar to the way either the optional fusogenic peptide coating or targeting ligand coating can be applied as described in step 1006. Also, in step 1008, if the targeting ligand coating has been applied in step 1006, the fusogenic peptide can be applied if required as it is an optional choice and the potential application of the fusogenic peptide ligand can be applied in a manner using DNA origami similar to the way either the optional fusogenic peptide coating or targeting ligand coating can be applied as described in step 1006. Step 1010 is the potential application of the phagocytosis prevention coating such as the CD47 coating, and the phagocytosis prevention coating such as the CD47 coating can be applied in a manner using DNA origami similar to the way either the optional fusogenic peptide coating or targeting ligand coating can be applied as described in step 1006. Step 1012 is the removal of any potentially unnecessary bonds or interactions, or adding any other desirable coatings or bonds as desired using or not using DNA origami. Finally, as indicated by Step 1014, the SPION Super Complexes can be stored. Overall, multiple chemical processes allow for the production of desired sized nanoparticles.
[0053] This SPION based drug delivery system or invention overcomes many of the disadvantages of the prior art by using an interdisciplinary approach combining the fields of biotechnology, physics, chemistry, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects.
[0054] The drug delivery vehicle capable of selectively delivering the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects to treat cancer and other diseases is the SPION Super Complex. The SPION Super Complexes can have a adsorption prevention coating, phagocytosis prevention coating (this coating is present depending on the variation of the SPION Super Complex being synthesized), targeting ligand coating, fusogenic peptide coating (this coating is present depending on the variation of the SPION Super Complex being synthesized), therapeutic payload(s), and/or imaging/diagnostic payload(s), and heat and magnetism based
mechanisms. The bonds that bind these coatings to the SPIONs are sufficiently and appropriately strong. This unique and never before used coatings system provides powerful advantages to this new drug delivery system. The adsorption prevention or zwitterionic coating can be a cysteine coating. The adsorption prevention or zwitterionic coating can help prevent the adsorption of proteins to the surface of the SPION Super Complexes due to its zwitterionic charge. Thus, a protein corona may not develop on the surface of the SPION Super Complexes. This prevention of the formation of the protein corona will increase the effectivity of SPION complex internalization into tumor cells and decrease the chance of capture by white blood cells present in the body. Therefore, the adsorption prevention or zwitterionic coating can significantly boost the efficacy of the drug delivery system as a whole. The optional phagocytosis prevention coating (e.g. CD47 coating) on the SPION Super Complexes can prevent phagocytosis of the SPION Super Complexes by white blood cells if any interactions between white blood cells and SPION Super Complexes take place. However, not all SPION Super Complex variations have the phagocytosis prevention coating. The heat generation mechanism is activated by applying the activation magnetic field to the SPION Super Complex. When a SPION Super Complex is in the presence of the activation magnetic field, the heat qualities of the SPION Super Complex causes a change in its temperature (an increase in temperature) resulting in the heating of the SPION. This heat can destroy the target cells. MRI and other diagnostic techniques can be used to detect the location of the SPION Super Complexes also. Without the presence of activation magnetic field, the SPION Super Complex will not be heated. Without MRI techniques, the SPION Super Complex may not be visible when viewed. The targeting ligand coating enables the SPION Super Complex to be selectively internalized by the tumor cells in various embodiments. This targeting ligand coating can be attached to the SPION or the variations of the SPION Super Complex. The targeting ligand coating can be degraded in the blood stream. This targeting ligand coating present on the SPION Super Complex is such that the SPION Super Complex is small enough for renal filtration and can be exited from the body through renal filtration after it may exit the target cell or spend an appropriate amount of time in the blood/lymph system. The fusogenic peptide coating can allow for endosomal escape of the SPION Super Complex after the SPION Super Complex gains entry into the cell and forms the resulting endosome inside the target cell. This endosomal escape will allow for the therapeutic payload(s) (chemotherapeutic drugs, etc .. ) and/or imaging/diagnostic payload(s) being transported by the SPION Super Complex to be released into the cytoplasm of the target cell if desired and the SPION can be exposed to the activation magnetic field at this time as well to heat the cell. Heat can be generated by the SPION due to the properties of the SPION and thus the SPION portion of a SPION Super Complex can be considered to be part of the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s). The activation magnetic field application will not negatively affect the bonds between the SPION and its coatings and various payloads. The endosomal escape can also allow for the exocytosis of the SPION Super Complex. Therefore, the therapeutic payload(s), and/or imaging/diagnostic payload(s) are selectively and exclusively released/activated in the tumor cells. This coating system is expected to significantly reduce side effects and dramatically increase the overall effectiveness of the drug delivery system.
[0055] In an illustrative embodiment, and by way of non-limiting example, the physical dimensions of the SPION, the SPION is spherical with smooth/semi-rounded edges and a smooth/semi-rounded top and bottom in general nature. The general manufacturing process of the SPION Super Complex is multistep and called the SPION Super Complex Synthesis Process. The first step is to grow or obtain the SPIONs. Next, the adsorption prevention or zwitterionic coating is applied. Then an optional fusogenic peptide can be applied or the targeting ligand coating is applied. DNA origami can be used to apply either the optional fusogenic peptide coating or the targeting ligand coating because a DNA origami shell can be created around the SPION with adsorption prevention or zwitterion coating to expose only a particular region for binding by either the optional fusogenic peptide or targeting ligand. Then the optional fusogenic peptide can be applied using DNA origami if the targeting ligand coating has been applied in the previous step, and the targeting ligand can be applied using DNA origami if the optional fusogenic peptide has been applied in the previous step (the fusogenic peptide coating or the targeting ligand coating can be applied using DNA origami because a DNA origami shell can be created around the SPION with adsorption prevention or zwitterionic coating to expose only a particular region for binding by either the optional fusogenic peptide or targeting ligand). Then the optional phagocytosis prevention coating such as the CD47 coating can be applied. This optional phagocytosis prevention coating such as the CD47 coating can be applied using the DNA origami because a DNA origami shell can be created around the SPION with any level or any amount of coatings to expose only a particular region for binding. Then any potentially unnecessary bonds or interactions will be removed, or any other desirable coatings or bonds are added if required using or not using DNA origami. Finally, the SPION Super Complexes can be stored. This is potentially how the SPIONs can be turned into SPION Super Complexes. This turning of the SPIONs into SPION Super Complexes can be called as the SPION Super Complex Synthesis process. Other variations of the SPION Super Complexes can be made using variations of this process.
[0056] This drug delivery system can be administered through IV infusion, injection, through the tactical insertion mechanism, or by other means. The tactical insertion mechanism is the process of releasing the SPION Super Complexes from a catheter near the target site and this catheter used to release/deploy the SPION Super Complexes will be tipped with a remotely controllable activation magnetic field source. In all of these cases, the heat properties or the heat generation mechanism will be activated though applying the activation magnetic field. The treatment scheme is that the SPION Super Complexes are administered into the bloodstream by a variety of modalities, including injection, infusion, oral ingestion, suppository, etc., that should be clear to those of skill. These SPION Super Complexes are represented by particle 702 in Fig. 7. Then these SPION Super Complexes move from the blood vessels to the tumor cells as shown in Fig. 8 by the red arrow. Once close enough to the tumor cells, the SPION Super Complexes can gain entry into the cell. One potential way the SPION Super Complexes (represented by SPION Super Complex 902 in Fig. 9) can gain entry into the cell is that they could undergo receptor mediated endocytosis as a result of the targeting ligand coating. The initial part of the receptor mediated endocytosis is depicted by tile 9a in Fig. 9. The intermediate part receptor mediated endocytosis is represented by tile 9b. The final part of receptor mediated endocytosis is described in tile 9c of Fig. 9.
[0057] The development/implementation of the SPION Super Complex Synthesis
Process and SPION properties/mechanisms are in progress. The exact details will be furnished at a later stage. Additionally, the SPION based drug delivery systems can be extended into the field of diagnosis and imaging. Diagnostic and imaging compounds can be added to the SPION Super Complexes to achieve these functions. These diagnostic and imaging compounds can be released as part of the overall of the therapeutic payload(s) and around the time of heat activation. Thus these diagnostic and imaging compounds also aid in diagnosis and imaging.
[0058] II. NPVD
[0059] According to a further embodiment, Figs. 11 and 12 depict a bare NPVD, without any coatings or chemotherapeutic drugs. In Fig. 11, part 1102 is the smooth edged titanium contact layer and in Fig. 12, part 1202 is the smooth edged titanium contact layer. The bare NPVD can be created through the NPVD Synthesis Process. A pore section contains a number of pores. Pore Section 1104 in Fig. 11 and Pore Section 1204 in Fig. 12 are the silica mesopores. In construction, the silica mesopores are grown on top of the single- crystalline silicon <111> and the titanium contact layer is grown on top of the silica mesopores. This can be accomplished using construction techniques known to those of skill and using conventional equipment described further below. The chemotherapeutic drugs are stored in these silica mesopores. The drugs can be inserted using conventional deposition techniques— for example by mixing the drugs with the nanoparticles. Part 1106 from Fig. 11 and part 1206 from Fig. 12 are made out of single-crystalline silicon <111>. Nanoimprinting lithography and reactive ion etching are used to create the boxlike structure with (in this embodiment) smooth/semi-rounded edges and a smooth/semi-rounded top and bottom depicted by part 1106 in Fig. 11 and part 1206 of Fig. 12. Other geometries and edge details are expressly contemplated in alternate embodiments. [0060] Fig. 13 shows a NPVD with payloads and protective coatings. An NPVD with payload(s) and protective coating(s) is also known as a NPVD Super Complex. These coatings are applied to the surface of the NPVD through various applications of chemistry such as grafting using silane coupling agents, nucleophilic substitution, Lewis base addition, Michael addition, and maleimide-thiol chemistry in a manner known to those of skill. Part 1302 in Fig. 13 is the titanium contact layer. Pores 1304 in Fig. 13 describes the silica mesopores, which are where the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s) are stored. Part 1306 in Fig. 13 is the single-crystalline silicon <111>. Compound 1308 in Fig. 13 is the protein adsorption prevention coating. Compound 1310 in Fig. 13 is the phagocytosis prevention protein coating. Compound 1312 in Fig. 13 is the pore locker coating. This pore locker coating prevents the payload(s) (chemotherapeutic drug, etc.) stored in the silica mesopores from exiting the mesopores until the pore locker coating is removed in the tumor cell in addition to preventing any interactions with anything from the environment. Compound 1314 in Fig. 13 is the aptamer based targeting ligand coating. This aptamer targeting ligand allows only the target cells in the body to internalize the NPVD Super Complexes. This aptamer targeting ligand uses receptor mediated endocytosis to allow the target cells to internalize the NPVD Super Complexes. This aptamer based targeting ligand is coated on top of the pore locker coating. Compound 1316 in Fig. 13 is the fusogenic peptide that breaks the endosome and exposes the NPVD Super Complex to the cytoplasm of the target cell after internalization by receptor mediated endocytosis.
[0061] Fig. 14 shows a NPVD with payloads and protective coatings. An NPVD with payload(s) and protective coating(s) is also known as a NPVD Super Complex. These coatings are applied to the surface of the NPVD through various applications of chemistry such as grafting using silane coupling agents, nucleophilic substitution, lewis base addition, Michael addition, and maleimide-thiol chemistry in a manner known to those of skill. NPVD Super Complexes may or may not have a phagocytosis prevention coating or a CD47 coating. Part 1402 in Fig. 14 is the titanium contact layer. Pores 1404 in Fig. 14 describes the silica mesopores, which are where the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s) are stored. Part 1406 in Fig. 14 is the single-crystalline silicon <111>. Compound 1408 in Fig. 14 is the protein adsorption prevention coating. Compound 1410 in Fig. 14 is the pore locker coating. This pore locker coating prevents the payload(s) (chemotherapeutic drug, etc.) stored in the silica mesopores from exiting the mesopores until the pore locker coating is removed in the tumor cell in addition to preventing any interactions with anything from the environment. Compound 1412 in Fig. 14 is the aptamer based targeting ligand coating. This aptamer targeting ligand allows only the target cells in the body to internalize the NPVD Super Complexes. This aptamer targeting ligand uses receptor mediated endocytosis to allow the target cells to internalize the NPVD Super Complexes. This aptamer based targeting ligand is coated on top of the pore locker coating. Compound 1414 in Fig. 14 is the fusogenic peptide that breaks the endosome and exposes the NPVD Super Complex to the cytoplasm of the target cell after internalization by receptor mediated endocytosis.
[0062] Figs. 15 through 17 describe the process of therapy using the NPVD Super
Complexes. Fig. 15 shows the NPVD Super Complexes in the blood stream after the administration of the treatment. Widget 1502 in Fig. 15 depicts of a NPVD Super Complex.
[0063] Fig. 16 is a depiction of an NPVD Super Complexes before they move into the tumor cell region. Widget 1602 in Fig. 16 depicts a NPVD Super Complex.
[0064] Fig. 17 is a picture of NPVD Super Complexes undergoing receptor mediated endocytosis. The receptor mediated endocytosis is the result of the NPVD Super Complex's aptamer coating. NPVD Super Complexes 1702 in Fig. 17 shows various NPVD Super Complexes undergoing receptor-mediated endocytosis. A tile is a section of the figure. Tile 17a shows NPVD Super Complexes in the beginning of the endocytosis process. Tile 17b shows NPVD Super Complexes in the middle of the endocytosis process. Tile 17c shows the NPVD Super Complexes almost finished with the endocytosis process. After the endocytosis of the NPVD Super Complexes, the drugs being delivered will be released from the NPVD Super Complexes and the Fusogenic peptide's function will activate.
[0065] Fig. 18 is a flowchart describing the NPVD synthesis process (Steps 1810 - 1870) and the NPVD Super Complex synthesis process (Steps 1880 - 1890). Step 1810 describes the creation of the MCM-41 mesoporous silica nanoparticles with 2.5 nm pore size on the single-crystalline silicon <111> that serve as the drug bay where the chemotherapeutic drugs and other payload compounds being sequestered. Step 1820 reduces the thickness of the MCM-41 mesoporous silica nanoparticles film with 2.5 nm pore size to approximately 2.5 nm in thickness. This allows for the small size of the NPVD. Step 1830 refers to the application of the 1 nm titanium layer on the surface of the approximately 2.5 nm thick MCM-41 mesoporous silica film using sputtering techniques. In the next step as represented by Step 1840, nanoimprinting lithography will be used to apply smooth/semi-rounded prism shaped resists with the width of 5 nm and length of 6 nm and height of 10 nm. Then reactive ion etching or deep reactive ion etching will be used to create trenches approximately 16 nm deep as represented by Step 1850. Then, as indicated by Step 1860, the resists will be removed. Then, as represented by Step 1870, the single-crystalline silicon <111> with the MCM-41 mesoporous silica will be flipped and nanoimprinting lithography techniques will be used to apply smooth/semi-rounded prism shaped resists and reactive ion etching or deep reactive ion etching will be used to create a smooth/semi-rounded bottom in a manner similar to the one described previously. Then, as represented by Step 1880, reactive ion etching or deep reactive ion etching will be used to isolate the ~6 nm tall NPVDs. Then, as indicated by Step 890, the coatings, the therapeutic payload(s), and/or imaging/diagnostic payload(s) will be applied to the NPVDs to turn the NPVDs into NPVD Super Complexes. Then, as indicated by Step 1899, The NPVD Super Complexes will be stored. Overall, nanoimprinting lithography techniques and reactive ion etching allow for the production of small sized nanoparticles.
[0066] Fig. 19 is a flowchart describing the NPVD Super Complex Synthesis Process
Variation 1. This NPVD Super Complex variation may or may not have a CD47 coating or a phagocytosis prevention coating. Step 1910 describes the creation of the MCM-41 mesoporous silica nanoparticles with 2.5 nm pore size on the single-crystalline silicon <111> that serve as the drug bay where the chemotherapeutic drugs and other payload compounds being sequestered. Step 1912 reduces the thickness of the MCM-41 mesoporous silica nanoparticles film with 2.5 nm pore size to approximately 2.5 nm in thickness. This allows for the small size of the NPVD. Step 1914 refers to the application of the 1 nm titanium layer on the surface of the approximately 2.5 nm thick MCM-41 mesoporous silica film using sputtering techniques. In the next step as represented by Step 1916, nanoimprinting lithography will be used to apply smooth/semi-rounded prism shaped on a resist line. Then reactive ion etching or deep reactive ion etching will be used to only leave a repeating pattern of smooth/semi-rounded prism shaped resists (protecting the NPVDs) next to a trench that is as deep as the mesoporous silica material layer as represented by Step 1918. Then, as indicated by Step 1920, the sides of the trenches will be coated with a silane grafting tool in order to coat the external sides of the pore walls with cysteine. Then, as represented by Step 1922, a stiff resist will be applied to shield the side (external wall coating) from reactive ion etching. Then, as represented by step 1924, reactive ion etching or deep reactive ion etching will be used to gain access to the pore entrances and achieve the contact layer morphology. Then as represented by step 1926, a part of the pore locker coating is grafted on the pore entrances using a silane grafting tool. In step 1928, the NPVD plate is flipped over and nanoimprinting lithography is used to apply smooth/semi-rounded prism like shaped resists. Then in step 1930, reactive ion etching is used to achieve the desired n-type morphology and isolate the NPVD Super Complexes. In step 1932, the surfactant inside the pores is extracted and the therapeutic payload(s) (e.g. chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads will be placed into the mesopores after potential modification of the interior of the pore walls. Then in step 1934, the pore locker coating will be finished by using a substrate with removable tethers on another part of the pore locker coating which will be introduced to loaded NPVDs which will result in the coating of one side of the loaded NPVD and then this substrate with one side of the loaded NPVD capped will be mixed with another part of the pore locker coating attached to an aptamer. Then as represented by step 1936, the tethers and any unnecessary bonds will be removed. Finally, as indicated by Step 1938, The NPVD
Super Complexes will be stored. Overall, nanoimprinting lithography techniques and reactive ion etching allow for the production of small sized nanoparticles.
[0067] Fig. 20 is a flowchart describing the NPVD Super Complex Synthesis Process
Variation 2. This NPVD Super Complex variation may or may not have a CD47 coating or a phagocytosis prevention coating. Step 2010 describes the creation of the MCM-41 mesoporous silica nanoparticles with 2.5 nm pore size on the single-crystalline silicon <111> that serve as the drug bay where the chemotherapeutic drugs and other payload compounds being sequestered. Step 2012 reduces the thickness of the MCM-41 mesoporous silica nanoparticles film with 2.5 nm pore size to approximately 2.5 nm in thickness. This allows for the small size of the NPVD. Step 2014 refers to the application of the 1 nm titanium layer on the surface of the approximately 2.5 nm thick MCM-41 mesoporous silica film using sputtering techniques. In the next step as represented by Step 2016, nanoimprinting lithography will be used to apply smooth/semi -rounded prism - rectangular prism - smooth/semi-rounded prism - rectangular prism pattern on a resist line with the rectangular prisms being twice as thick as the smooth/semi-rounded prism's thickness. Then reactive ion etching or deep reactive ion etching will be used to only leave a repeating pattern of rectangular prism shaped resists next to a trench that is as deep as the mesoporous silica material layer as represented by Step 2018. Then, as indicated by Step 1020, after potentially introducing a proton source, the sides of the trenches will be coated with a silane grafting tool in order to coat the external sides of the pore walls with cysteine. Then, as represented by Step 2022, the whole substrate will be flipped. Then, as represented by Step 2024, nanoimprinting lithography is used to apply fern like shaped resists with the leaves of the fern being smooth/semi-rounded prism like and twice as thick as the main stem. There are 2 main stems in this type of resist. Then as represented by step 2026, reactive ion etching is used to achieve the desired n-type morphology and isolate the NPVD Super Complexes and to gain access to the pore entrances and achieve the n-type layer morphology. In step 2028, after potentially introducing a proton source, a part of the pore locker coating is grafted on the pore entrances using a silane grafting tool. Then in step 2030, the surfactant inside the pores will be extracted and the mesopores will be loaded with therapeutic payload(s) (e.g.
chemotherapeutic drugs, etc.) and/or imaging/diagnostic payloads after potentially altering the interior of the pore walls. In step 2032, the pore locker coating will be finished by using a substrate with removable tethers on another part of the pore locker coating which will be introduced to loaded NPVDs which will result in the capping of one side of the loaded NPVD and then this substrate with one side of the loaded NPVD capped will be mixed with another part of the pore locker coating attached to an aptamer. Then as represented by step 2034, the tethers and any unnecessary bonds will be removed. Finally, as indicated by Step 2036, The NPVD Super Complexes will be stored. Overall, nanoimprinting lithography techniques and reactive ion etching allow for the production of small sized nanoparticles.
[0068] This NPVD based drug delivery system or invention overcomes many of the disadvantages of the prior art by using an interdisciplinary approach combining the fields of biotechnology, semiconductor physics, medicine, biochemistry, and engineering to selectively deliver the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects.
[0069] The drug delivery vehicle capable of selectively delivering the therapeutic payload(s), and/or imaging/diagnostic payload(s) to the desired target site(s) with minimal or no side effects to treat cancer are NPVD Super Complexes. The NPVD Super Complexes can have a protein adsorption prevention coating, phagocytosis prevention coating (this coating is present depending on the variation of the NPVD Super Complex being synthesized), targeting ligand coating, pore locker coating, fusogenic peptide coating, therapeutic payload(s), and/or imaging/diagnostic payload(s), and photovoltaic mechanisms. The bonds that bind these coatings to the NPVD complexes and super coating structures are sufficiently strong (except that of the pore locker and the fusogenic peptide). The bonds are illustratively less significantly affected by the body and tumor cells except the bonds of the pore locker and the fusogenic peptide. This unique and never before used coatings system provides powerful advantages to this new drug delivery system. The protein adsorption prevention coating can be a cysteine coating. The cysteine coating can prevent the adsorption of proteins to the surface of the NPVD Super Complexes due to its zwitterionic charge. Thus, a protein corona will not develop on the surface of the NPVD Super Complexes. This prevention of the formation of the protein corona will increase the effectivity of NPVD complex internalization into tumor cells and decrease the chance of capture by white blood cells present in the body. Therefore, the cysteine coating will significantly boost the efficacy of the drug delivery system as a whole. The phagocytosis prevention coating (e.g. CD47 coating) on the NPVD Super Complexes prevents phagocytosis of the NPVD Super Complexes by white blood cells if any interactions between white blood cells and NPVD Super Complexes take place. However, not all NPVD Super Complex variations have the phagocytosis prevention coating. The pore locker coating is a coating that coats the openings of the pores of the NPVDs and can be removed in the tumor cell. The pore locker coating is a pH based nanovalve coating and will only be activated once the pH is at the desired level. Once activated, the
chemotherapeutic drugs can be exposed. This pore locker coating is also strong enough to withstand the force of the activated drug release mechanism. The activated drug release mechanism is the result of shining the activation radiation (near infrared wavelength of 650 - 900 nm) on the NPVD Super Complex. When an NPVD Super Complex is in the presence of the activation radiation, the photovoltaic qualities of the NPVD Super Complex causes a change in its charge resulting in the expulsion of the positively charged therapeutic payload(s), and/or imaging/diagnostic payload(s) from the mesopores containing the positively charged therapeutic payload(s), and/or imaging/diagnostic payload(s). Without the presence of activation radiation, the NPVD Super Complex will store the therapeutic payload(s), and/or imaging/diagnostic payload(s) in its mesopores. Therefore, the therapeutic payload(s), and/or imaging/diagnostic payload(s) are selectively and exclusively released in the tumor cells. The targeting ligand coating (e.g. aptamer coating) enables the NPVD complex to be selectively internalized by the tumor cells. This aptamer targeting ligand coating is attached to the pore locker coating. This attachment means that once the NPVD Super Complex's pore locker coating is activated, it is small enough for renal filtration and can be exited from the body through renal filtration after it may undergo exocytosis from the target cell. The fusogenic peptide coating allows for endosomal escape of the NPVD Super Complex after the NPVD Super Complex undergoes receptor mediated endocytosis and forms the resulting endosome inside the target cell. This endosomal escape will allow for the therapeutic payload(s) (chemotherapeutic drugs, etc .. ) and/or imaging/diagnostic payload(s) being transported by the NPVD Super Complex to be released into the cytoplasm of the target cell. The endosomal escape can also allow for the exocytosis of the NPVD Super Complex. This coating system is expected to significantly reduce side effects and dramatically increase the overall effectiveness of the drug delivery system.
[0070] In an illustrative embodiment, and by way of non-limiting example, the physical dimensions of the NPVD, the NPVD is boxlike with smooth/semi-rounded edges and a smooth/semi-rounded top and bottom in general nature. The NPVD has a height of approximately ~6 nm, width of 5 nm and length of 6 nm. The overall structure of the NPVD is mesopores(s) (p-type layer) sandwiched between a layer of titanium (contact layer) and a layer of single-crystalline silicon <111> (n-type layer). Different combinations of p-type, n- type, and contact layers may be used. The titanium layer will act as a contact. The manufacturing process of the NPVD is multistep and called the NPVD Synthesis Process. The first step is to grow the MCM-41 variation of mesoporous silica nanoparticles with approximately 2.5 nm pore size on single-crystalline silicon <111>. The second step is to use reactive ion etching to reduce the MCM-41 variation of mesoporous silica nanoparticles to approximately 2.5 nm. The next step is to use sputtering techniques to apply a layer of titanium 1 nm thick on top of the MCM-41 variation of mesoporous silica nanoparticles with approximately 2.5 nm pore size. After that step, nanoimprinting lithography will be used to apply smooth/semi-rounded prism shaped resists with the width of 5 nm and length of 6 nm and height of 10 nm. Then, reactive ion etching or deep reactive ion etching will be used to create trenches 16 nm deep. After that has finished, the resists will be removed. Then, the single-crystalline silicon <111> will be flipped and nanoimprinting lithography techniques will be used to create a smooth/semi-rounded bottom in a manner similar to the one described previously. Then, reactive ion etching or deep reactive ion etching will be used to isolate the ~6 nm tall NPVDs. Then, the coatings and the therapeutic payload(s), and/or imaging/diagnostic payload(s) will be applied to the NPVDs to turn the NPVDs into NPVD Super Complexes. This turning of the NPVDs into NPVD Super Complexes can be called as the NPVD Super Complex Synthesis process. NPVDs and associated complexes can also be made through the NPVD Super Complex Synthesis Variation 1 and NPVD Super Complex Synthesis Variation 2 described previously.
[0071] This drug delivery system can be administered through IV infusion, injection, or through the tactical insertion mechanism. The tactical insertion mechanism is the process of releasing the NPVD Super Complexes from a catheter near the target site and this catheter used to release/deploy the NPVD Super Complexes will be tipped with a remotely controllable activation radiation source. In all of these cases, the therapeutic payload will only be released though the activated drug release mechanism. The treatment scheme is that the NPVD Super Complexes are injected into the bloodstream either by infusion or by injection. These NPVD Super Complexes are represented by widget 1502 in Fig. 15. Then these NPVD Super Complexes move from the blood vessels to the tumor cells as shown in Fig. 16 by the red arrow. Once close enough to the tumor cells, the NPVD Super Complexes (represented by NPVD Super Complex 1602 in Fig. 16) undergo receptor mediated endocytosis as a result of the aptamer coating. The initial part of the receptor mediated endocytosis is depicted by tile 17a in Fig. 17. The intermediate part receptor mediated endocytosis is represented by tile 17b. The final part of receptor mediated endocytosis is described in tile 17c of Fig. 17.
[0072] The development/implementation of the NPVD Synthesis Process and NPVD mechanisms are in progress. The exact details will be fumished at a later stage. Additionally, the NPVD based drug delivery systems can be extended into the field of diagnosis and imaging. Diagnostic and imaging compounds can be added to the NPVD Super Complexes to achieve these functions. These diagnostic and imaging compounds can be released as part of the overall of the therapeutic payload(s) and thus also aid in diagnosis and imaging.
[0073] The foregoing has been a detailed description of illustrative embodiments of the invention. Various modifications and additions can be made without departing from the spirit and scope if this invention. Each of the various embodiments described above may be combined with other described embodiments in order to provide multiple features.
Furthermore, while the foregoing describes a number of separate embodiments of the apparatus and method of the present invention, what has been described herein is merely illustrative of the application of the principles of the present invention. For example, the structure of the SPION Super Complex or NPVD Super Complex as described above is one of a variety of possible constructions for providing a drug delivery vehicle within the teachings of this invention. Also, as used herein various directional and dispositional terms such as "vertical", "horizontal", "up", "down", "bottom", "top", "side", "front", "rear", "left", "right", and the like, are used only as relative conventions and not as absolute
directions/dispositions with respect to a fixed coordinate system, such as the acting direction of gravity. Additionally, where the term "substantially" or "approximately" is employed with respect to a given measurement, value or characteristic, it refers to a quantity that is within a normal operating range to achieve desired results, but that includes some variability due to inherent inaccuracy and error within the allowed tolerances of the system. Accordingly, this description is meant to be taken only by way of example, and not to otherwise limit the scope of this invention.
[0074] What is claimed is:

Claims

CLAIMS 1. A treatment method for a disease using nanoparticles with therapeutic payload(s) and/or imaging/diagnostic payload(s), and multiple coatings applied to the surface of the nanoparticles comprising the steps of:
providing super paramagnetic iron oxide nanoparticles (SPIONs) with one or more desired coatings based on a disease being targeted in a body and the coatings can include at least one of therapeutic payload(s) or imaging/diagnostic payload(s) so as to provide SPION Super Complexes;
administering the SPION Super Complexes into the blood of the body and allowing the SPION Super Complexes to travel to a target site; and
activating the SPION Super Complexes when the SPION Super Complexes are at/in the cell by applying an activation mechanism to thereby activate, via a release mechanism at least one of the therapeutic payload(s) and
diagnostic/imaging payload(s).
2. The treatment method as set forth in claim 1 wherein the coatings include but not limited to the targeting ligand coating and adsorption prevention coating. The fusogenic peptide coating and the phagocytosis prevention coating will be present depending on the kind of nanoparticle or alternative embodiment of the nanoparticle.
3. The treatment method as set forth in claim 1 further comprising using
nanoparticles based on a SPION Super Complex Synthesis Process.
4. The treatment method as set forth in claim 1 further comprising using
nanoparticles that carry or encapsulate therapeutic payload(s) and/or
imaging/diagnostic payload(s).
5. The treatment method as set forth in claim 1 further comprising using
nanoparticles that use heat as a form of a therapy. The heat may be a result of applying a magnetic field(s).
6. The treatment method as set forth in claim 4 wherein the therapeutic payload(s) can activate or include any amount of heat, magnetism, or at least one of drug compounds or chemotherapeutic drugs.
7. The treatment method as set forth in claim 1 further comprising using
nanoparticles less than or equal to 30 nm in diameter.
8. The treatment method as set forth in claim 1 further comprising using
nanoparticles less than or equal to 30 nm in diameter exhibiting at least one of magnetic mechanisms, magnetic properties, thermal mechanisms and thermal properties.
9. The treatment method as set forth in claim 1 further comprising using super
paramagnetic nanoparticles less than or equal to 30 nm in diameter exhibiting heat or hyperthermic mechanisms and properties.
10. The treatment method as set forth in claim 1 further comprising using
nanoparticles that can be activated by at least one of magnetism, heat generation mechanism, and heat properties.
11. The treatment method as set forth in claim 1 further comprising using
nanoparticles that exhibit renal clearance and other clearance characteristics.
12. The treatment method as set forth in claim 1 wherein the disease comprises a form of cancer or any other medical condition that is treatable at a target site in the body accessed by either blood or lymph.
13. A diagnostic method for a disease comprising the steps of:
providing SPIONs and SPION Super Complexes to a body; and
using SPIONs and SPION Super Complexes to diagnose or treat a condition in the body.
14. The method as set forth in claim 13 wherein the disease is cancer.
15. An imaging method for a disease comprising the steps of:
providing SPION Super Complexes to a body; and
using SPION Super Complexes in association with an imaging device that captures images of internal regions of the body including the SPION Super Complexes.
16. An imaging method for a disease comprising the steps of:
providing SPIONs; and
using SPIONs in a body bloodstream that provide a marker or trackable unit detectable to at least one of an imaging device and a diagnostic device.
17. The method as set forth in claim 16 wherein the disease is cancer.
18. A method for administering a SPION Super Complex comprising the steps of: providing the SPION Super Complex in a predetermined form for insertion; and administering the SPION Super Complex in the predetermined form to a body through a tactical insertion mechanism.
19. The SPION Super Complex and/or any compound containing of the SPION Super Complex.
20. A nanoparticle comprising:
SPION, potential/optional therapeutic payload(s) (not including the SPION if it is to be used as a therapeutic payload), and coatings such as the therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s) encapsulation layer containing therapeutic payload(s) (chemotherapeutic drugs, etc.) and/or imaging/diagnostic payload(s), fusogenic peptide coating (the presence of this coating is dependent on the kind of nanoparticle), phagocytosis prevention coating (the presence of this coating is dependent on the kind of nanoparticle), adsorption prevention coating, and targeting ligand coating.
21. A treatment method for a disease using nanoparticles with therapeutic payload(s), and/or imaging/diagnostic payload(s) and multiple coatings applied to the surface of the nanoparticles comprising the steps of:
Creating nanoscopic photovoltaic devices (NPVDs) with one or more desired coatings based on a disease being targeted in a body, the coatings including at least one of therapeutic payload(s), and imaging/diagnostic payload(s) so as to provide NPVD Super Complexes;
Injecting the NPVD Super Complexes into the blood of the body and allowing the NPVD Super Complexes to travel to a target site; and
Activating the NPVD Super Complexes when the NPVD Super Complexes undergo aptamer initiated receptor mediated endocytosis and escape the resulting endosome, by the removal of a pore locker coating and applying an activation mechanism to thereby release, via a release mechanism, the at least one of the therapeutic payload(s) and diagnostic/imaging payload(s).
22. The treatment method as set forth in claim 21 wherein the coatings include but not limited to the pore locker coating, targeting ligand coating, adsorption prevention coating, fusogenic peptide coating, and phagocytosis prevention coating, whereby presence of the coating is dependent on kind of nanoparticle.
23. The treatment method as set forth in claim 21 wherein the nanoparticles comprise titanium, mesoporous silica, and single-crystalline silica <111>.
24. The treatment method as set forth in claim 21 wherein the nanoparticles exhibit photovoltaic mechanisms as the release mechanism.
25. The treatment method as set forth in claim 24 wherein the activation mechanism comprises activation radiation.
26. The treatment method as set forth in claim 21 further comprising using
nanoparticles based on an NPVD Synthesis Process.
27. The treatment method as set forth in claim 21 further comprising using nanoparticles and pore locker coatings that encapsulate chemotherapeutic drugs.
28. The treatment method as set forth in claim 21 further comprising using
nanoparticles that encapsulate therapeutic payload(s) and/or imaging/diagnostic payload(s).
29. The treatment method as set forth in claim 28 wherein the therapeutic payload(s) include at least one of drug compounds or chemotherapeutic drugs.
30. The treatment method as set forth in claim 21 further comprising using
nanoparticles less than or equal to 10 nm in diameter.
31. The treatment method as set forth in claim 21 further comprising using
nanoparticles less than or equal to 10 nm in diameter exhibiting photovoltaic mechanisms and properties.
32. The treatment method as set forth in claim 21 further comprising using
nanoparticles employing the activated drug release mechanism.
33. The treatment method as set forth in claim 21 further comprising using
nanoparticles that exhibit renal and other clearance characteristics.
34. The treatment method as set forth in claim 21 wherein the disease comprises a form of cancer or any other medical condition that is treatable at a target site in the body accessed through blood flow.
35. A diagnostic method or process for any disease, including cancer, using NPVD Super Complexes.
36. A diagnostic method or process for any disease, including cancer, using NPVDs.
37. An imaging method or process for any disease, including cancer, using NPVD Super Complexes.
38. An imaging method or process for any disease, including cancer, using NPVDs in a body bloodstream that provide a marker visible to an imaging device.
39. A nanoparticle comprising:
silica, a contact layer, therapeutic payload(s), and coatings such as the drug encapsulation layer containing therapeutic payload(s) (chemotherapeutic drugs, etc.), and/or imaging/diagnostic payload(s), fusogenic peptide coating, phagocytosis prevention (the presence of this coating is dependent on the kind of nanoparticle), protein adsorption prevention coating, pore locker coating, and targeting ligand coating.
PCT/US2016/043858 2015-07-23 2016-07-25 System and method for the treatment of disease using nanoparticles Ceased WO2017015659A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562196285P 2015-07-23 2015-07-23
US62/196,285 2015-07-23
US201662320426P 2016-04-08 2016-04-08
US62/320,426 2016-04-08

Publications (1)

Publication Number Publication Date
WO2017015659A1 true WO2017015659A1 (en) 2017-01-26

Family

ID=57834712

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/043858 Ceased WO2017015659A1 (en) 2015-07-23 2016-07-25 System and method for the treatment of disease using nanoparticles

Country Status (1)

Country Link
WO (1) WO2017015659A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021263221A1 (en) * 2020-06-26 2021-12-30 Novather, Inc. Binding modulator

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050215687A1 (en) * 2004-02-11 2005-09-29 Hatton T A Multi-polymer-coated magnetic nanoclusters
WO2013123523A1 (en) * 2012-02-19 2013-08-22 Nvigen, Inc. Uses of porous nanostructure in delivery
WO2014047318A1 (en) * 2012-09-21 2014-03-27 Memorial Sloan-Kettering Cancer Center Delivery of therapeutic compounds with iron oxide nanoparticles
WO2014081322A1 (en) * 2012-11-21 2014-05-30 Uniwersytet Jagiellonski Superparamagnetic iron oxide nanoparticles with ultra-thin polymer layers, the method of their preparation and application
US20140234226A1 (en) * 2014-05-06 2014-08-21 Morteza Mahmoudi Plasmonic stable fluorescence superparamagnetic iron oxide nanoparticles and a method of synthesizing the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050215687A1 (en) * 2004-02-11 2005-09-29 Hatton T A Multi-polymer-coated magnetic nanoclusters
WO2013123523A1 (en) * 2012-02-19 2013-08-22 Nvigen, Inc. Uses of porous nanostructure in delivery
WO2014047318A1 (en) * 2012-09-21 2014-03-27 Memorial Sloan-Kettering Cancer Center Delivery of therapeutic compounds with iron oxide nanoparticles
WO2014081322A1 (en) * 2012-11-21 2014-05-30 Uniwersytet Jagiellonski Superparamagnetic iron oxide nanoparticles with ultra-thin polymer layers, the method of their preparation and application
US20140234226A1 (en) * 2014-05-06 2014-08-21 Morteza Mahmoudi Plasmonic stable fluorescence superparamagnetic iron oxide nanoparticles and a method of synthesizing the same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021263221A1 (en) * 2020-06-26 2021-12-30 Novather, Inc. Binding modulator

Similar Documents

Publication Publication Date Title
Cheng et al. Advances in magnetic nanoparticle‐mediated cancer immune‐theranostics
Pouponneau et al. Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation
Dozono et al. HPMA copolymer-conjugated pirarubicin in multimodal treatment of a patient with stage IV prostate cancer and extensive lung and bone metastases
Cattaneo et al. Nanotechnology and human health: risks and benefits
US12151021B2 (en) Implantable nanochannel delivery devices
MX2014007131A (en) Nanoparticles comprising metallic and hafnium oxide materials, preparation and uses thereof.
Hao et al. Enhancing radiotherapy for lung cancer using immunoadjuvants delivered in situ from new design radiotherapy biomaterials: a preclinical study
Ramazani et al. Locoregional cancer therapy using polymer-based drug depots
Wang et al. Recent advances in nanoenzymes based therapies for glioblastoma: overcoming barriers and enhancing targeted treatment
Hood et al. Nanochannel implants for minimally-invasive insertion and intratumoral delivery
US20150050349A1 (en) Systems and methods for particle radiation enhanced delivery of therapy
Kiseleva et al. Gold‐Enhanced Brachytherapy by a Nanoparticle‐Releasing Hydrogel and 3D‐Printed Subcutaneous Radioactive Implant Approach
Behl et al. Nano-based drug delivery of anticancer chemotherapeutic drugs targeting breast cancer
Delcassian et al. Nanotechnology and drug delivery
Jadhav et al. Bee venom loaded nanomaterials for cancer therapy: a novel approach
WO2017015659A1 (en) System and method for the treatment of disease using nanoparticles
EP3180085B1 (en) Means and methods for targeted x-ray therapy
Peng et al. The emerging nanomedicine-based technology for non-small cell lung cancer immunotherapy: how far are we from an effective treatment
CA2695985C (en) Systems and methods for particle radiation enhanced delivery of therapy
Rongpi et al. Unraveling the Frontiers of Nanomedicine: Exploring Advancements and Envisioning the Future
Fymat Nanooncology: Perspective on promising anti-tumor therapies
Joshi et al. Application of biomaterials in cancer research
TSOURKAS Developing targeted theranostic nanoparticles: challenges and potential solutions
Brusentsov Nanotechnologies in diagnostics and therapy of oncological diseases
Hashmi et al. Gold Nano Particles (GNPs): An Emerging Solution of Cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16828683

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16828683

Country of ref document: EP

Kind code of ref document: A1