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WO2025085507A2 - Compositions de zéolite à effets thérapeutiques ostéoinductifs et anti-inflammatoires et leurs procédés d'utilisation - Google Patents

Compositions de zéolite à effets thérapeutiques ostéoinductifs et anti-inflammatoires et leurs procédés d'utilisation Download PDF

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Publication number
WO2025085507A2
WO2025085507A2 PCT/US2024/051553 US2024051553W WO2025085507A2 WO 2025085507 A2 WO2025085507 A2 WO 2025085507A2 US 2024051553 W US2024051553 W US 2024051553W WO 2025085507 A2 WO2025085507 A2 WO 2025085507A2
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WIPO (PCT)
Prior art keywords
growth factor
composition
porous nanoparticle
coating
nanoparticle
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PCT/US2024/051553
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English (en)
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WO2025085507A3 (fr
Inventor
Alireza MOSHAVERINIA
Weihao YUAN
Peter Moy
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Publication of WO2025085507A2 publication Critical patent/WO2025085507A2/fr
Publication of WO2025085507A3 publication Critical patent/WO2025085507A3/fr
Pending legal-status Critical Current
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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • 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
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/06—Titanium or titanium alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • Titanium-based dental implants are widely used due to their excellent biocompatibility and mechanical properties, but exhibit poor osteointegration and low bioactivities.
  • various materials have been applied in the surface coating of titanium-based implants, such as hydroxyapatite (HAP), biomacromolecules, and bioactive peptides or growth factors.
  • HAP hydroxyapatite
  • biomacromolecules biomacromolecules
  • bioactive peptides or growth factors i.e., complicated procedures, high costs, short storage times
  • the present invention relates to a composition comprising a porous nanoparticle and at least one growth factor at least partially encapsulated within the porous nanoparticle, wherein the porous nanoparticle comprises a metal ion and an organic linker.
  • the metal comprises a four-coordinate metal ion.
  • the organic linker comprises a bridging ligand.
  • the porous nanoparticle comprises a zeolite.
  • the porous nanoparticle comprises a zeolitic imidazolate framework (ZIF).
  • the porous nanoparticle comprises zeolitic imidazolate framework-8 (ZIF-8). In one embodiment, the porous nanoparticle is monodispersed. In one embodiment, the ratio of organic linker to metal ion is about 1:1 to about 100:1. In one embodiment, the ratio of organic linker to metal ion is about 70:1. In one embodiment, the ratio of the porous nanoparticle is about 10 nm to about 100 nm. In one embodiment, the ratio of the porous nanoparticle is about 80 nm.
  • the at least one growth factor is selected from the group consisting of a) an amino acid sequence selected from SEQ ID NOs: 1-22, or a variant or fragment thereof, b) a nucleic acid molecule encoding the amino acid sequence selected from SEQ ID NOs: 1-22, or a variant or fragment thereof, and c) any combination thereof.
  • the at least one growth factor is the amino acid sequence set forth in SEQ ID NO: 1 or a variant or fragment thereof, or a nucleic acid molecule encoding the amino acid sequence set forth in SEQ ID NO: 1.
  • the at least one growth factor is the amino acid sequence set forth in SEQ ID NO: 10 or a variant or fragment thereof, or a nucleic acid molecule encoding the amino acid sequence set forth in SEQ ID NO: 10. In one embodiment, the growth factor is a combination of the amino acid sequence set forth in SEQ ID NO: 1. In one embodiment, the growth factor is the amino acid sequence set forth in SEQ ID NO: 10. In one embodiment, the growth factor is a combination of the amino acid sequence set forth in SEQ ID NO: 1 and the amino acid sequence set forth in SEQ ID NO: 10. In one embodiment, the concentration of the at least one growth factor is between about 0.1 mg/mL to about 2.0 mg/mL.
  • the concentration of the at least one growth factor is about 1 mg/mL. In one embodiment, the at least one growth factor is fully encapsulated in the porous nanoparticle. In one embodiment, the composition is a coating. Attorney Docket No.206030-0278-00WO In another aspect, the present invention relates to a coating for medical devices comprising the composition. In one aspect, the medical device is a titanium implant. In another aspect, the present invention relates to a method of promoting osteogenesis in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the coating.
  • the present invention relates to a method of promoting an anti- inflammatory effect in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the coating.
  • the present invention relates to a method of simultaneously promoting osteogenesis and an anti-inflammatory effect in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the coating.
  • the method comprises the steps of applying the composition or the coating to a titanium implant and applying the titanium implant to the subject.
  • the porous nanoparticle fully encapsulates at least one growth factor.
  • the nanoparticle releases the encapsulated growth factor over time.
  • the nanoparticle releases the encapsulated growth factor over about 1 minute to about 1 months.
  • Fig.1 comprises Fig.1A and Fig.1B.
  • Fig.1A depicts representative AFM images of a zeolite-imidazole framework (ZIF) and ZIF with peptide encapsulation (Peptides@ZIF) nanoparticles.
  • Fig.1B depicts representative scanning electron microscopy (SEM) images and quantification of diameters and densities of ZIF and ZIF with peptide encapsulation (Peptides@ZIF).
  • Fig.2 comprises Fig.2A and Fig.2B.
  • Fig.2A depicts representative expression level of mitogen-activated protein kinases (MAPKs) of mesenchymal stem cells (MSCs) cultured Attorney Docket No.206030-0278-00WO on ZIF-coated titanium (ZIF@Ti) and ZIF with peptide encapsulation-coated titanium (Peptides@ZIF@Ti) substrates.
  • MAPKs mitogen-activated protein kinases
  • Fig.2B depicts representative expression level of alkaline phosphatase (ALP), type I collagen (Col 1), osteocalcin (OCN), and runt-related transcription factor 2 (Runx2) of MSCs cultured on ZIF@Ti and Peptides@ZIF@Ti substrates.
  • Fig.3 comprises Fig.3A and Fig.3B.
  • Fig.3A depicts representative expression level of nuclear factor kappa-light chain-enhancer of activated B cells (NF ⁇ B) of macrophages cultured on ZIF@Ti and Peptides@ZIF@Ti substrates.
  • NF ⁇ B activated B cells
  • Fig.3B depicts representative expression level of VEGF of acrophages cultured on ZIF@Ti and Peptides@ZIF@Ti substrates.
  • Fig.4 comprises Fig.4A and Fig.4B.
  • Fig.4A depicts a representative schematic of the preparation of ZIF nanoparticles (ZNano) via biomineralization.
  • Fig.4B depicts a schematic illustration of interactions between ZNano and stem cells.
  • the cell-adhesive peptides can bind with integrin on cell surface to activate the mechanotransduction-mediated differentiation.
  • the anti-inflammatory and antimicrobial peptides can create a tissue-regeneration favorable microenvironment.
  • Fig.5 comprises Fig.5A through Fig.5D.
  • Fig.5A depicts representative atomic force microscopy (AFM) images and the curves derived from height sensor of AFM showed the similar size of ZIF and ZNano coatings. Scale bar: 600 nm (left), 60 nm (right).
  • Fig.5B depicts dynamic light scattering (DLS) data which shows the similar hydrated diameter of ZIF and ZNano NPs.
  • Fig.5C depicts representative SEM images and quantification of size distribution and coating density of ZIF and ZNano NPs. Scale bar: 100 nm.
  • Fig.5D depicts representative SEM images which demonstrate the successful coating of ZIF and ZNano NPs on the surface of titanium and zirconia via spray.
  • Fig.6 comprises Fig.6A through Fig.6K.
  • Fig.6A depicts a live/dead staining and quantification of viability of stem cells cultured on Ti substrates coated with ZIF and ZNano NPs.
  • Fig.6B depicts a quantification of cell area of stem cells cultured on ZIF and ZNano substrates.
  • Fig.6C depicts immunofluorescent staining of MAPK of stem cells cultured on ZIF and ZNano substrates.
  • Fig.6D depicts a quantification of MAPK expression level of stem cells cultured on ZIF and ZNano substrates.
  • Fig.6E depicts staining of osteogenic differentiation marker, ALP, of stem cells cultured on ZIF and ZNano substrates.
  • Fig.6F depicts representative qPCR results the expression levels of key osteogenic markers, including ALP, Col 1, OCN and Runx 2, of stem cells cultured on ZIF and ZNano substrates.
  • Fig.6G depicts stem cells cultured Attorney Docket No.206030-0278-00WO on the dental implants coated with ZIF and ZNano NPs via spray technology showed similar viability.
  • Fig.6J depicts alizarin red staining of biominerals produced by stem cells cultured on ZIF and ZNano substrates.
  • Fig.6K depicts quantification of the amounts of biomineralization produced by stem cells cultured on ZIF and ZNano substrates.
  • Fig.7 comprises Fig.7A through Fig.7G.
  • Fig.7A depicts immunofluorescent staining of CD3 and NF ⁇ B of T cells cultured on ZIF and ZNano substrates and the quantification of CD3, in Fig.7B, and NF ⁇ B expression level, in Fig.7C, of T cells cultured on ZIF and ZNano substrates.
  • Fig.7D depicts immunofluorescent staining of iNOS (M1 polarization marker) and Arginase (M2 polarization marker) of macrophages cultured on ZIF and ZNano substrates and the quantification of iNOS and Arginase expression level of macrophages cultured on ZIF and ZNano substrates.
  • Fig.7E depicts qPCR results and the expression levels of key M1 polarization markers, including iNOS and CD80, M2 polarization markers, including Arginase and CD206 and mechanotransduction marker, including YAP.
  • Fig.7F depicts the antimicrobial properties of ZIF and ZNano coatings as demonstrated by the inhibition of the growth of P.g.
  • Fig.7G depicts the quantification of bacterial inhibition of ZIF and ZNano coatings.
  • Fig.8 comprises Fig.8A through Fig.8E.
  • Fig.8A depicts immunofluorescent staining of MAPK of macrophages cultured on ZIF and ZNano substrates.
  • Fig.8B depicts the quantification of MAPK expression level of macrophages cultured on ZIF and ZNano substrates.
  • Fig.8C depicts the immunofluorescent staining of PGC1 ⁇ of macrophages cultured on ZIF and ZNano substrates.
  • Fig.8D depicts the quantification of PGC1 ⁇ expression level of macrophages cultured on ZIF and ZNano substrates.
  • Fig.8E depicts staining of JC-1 to indicate the mitochondria membrane potential of stem cells cultured on ZIF and ZNano substrates.
  • the present invention is based, in part, on the unexpected results that a coating comprising zeolitic imidazolate framework-8 (ZIF-8) and a growth factor peptide demonstrated multi-functions of osteoinduction, osteointegration, and/or anti-inflammatory properties.
  • the present invention provides a composition comprising a porous nanoparticle and at least one growth factor.
  • the porous nanoparticle comprises a zeolite Attorney Docket No.206030-0278-00WO imidazolate framework (ZIF).
  • the porous nanoparticle comprises ZIF-8. In one embodiment, the porous nanoparticle encapsulates the at least one growth factor. In one embodiment, the at least one growth factor is released over time from the porous nanoparticle.
  • the composition is a coating. In one embodiment, the coating is used in medical applications (e.g., dentistry, orthopedics, medical devices, basic research, wound healing, dental composites, dental implants, titanium implant, coatings, such as surface coating of a titanium implant, etc.). In one embodiment, the invention provides a method for promoting osteoinduction, promoting osteointegration, preventing inflammation, or any combination thereof. In one embodiment, the method comprises applying the composition of the present invention to a subject in need thereof.
  • the composition is applied to a dental implant. In one embodiment, the composition is applied to a titanium-based implant.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. As used herein, each of the following terms has the meaning associated with it in this section.
  • the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • nanoparticle refers to particles having a particle size on the nanometer scale, less than 1 micrometer.
  • the nanoparticle may have a particle size up to about 50 nm.
  • the nanoparticle may have a particle size up to about Attorney Docket No.206030-0278-00WO 10 nm.
  • the nanoparticle may have a particle size up to about 6 nm.
  • nanoparticle refers to a number of nanoparticles, including, but not limited to, nanoclusters, nanocapsules, core-shell nanocapsules, nanovesicles, micelles, block copolymer micelles, lamaellae shaped particles, polymersomes, dendrimers, and other nano-size particles of various other small fabrications that are known to those of skill in the art.
  • the shapes and compositions of nanoparticles may be guided during condensation of atoms by selectively favoring growth of particular crystal facets to produce spheres, rods, wires, discs, cages, core- shell structures and many other shapes.
  • nanocapsule refers to a vesicular system or hollow particle with a shell surrounding a core-forming space, which, in certain instances, can be used for transporting a payload on a nanoscale level.
  • a nanocapsule may also be a nano-sized version of a container.
  • the payload of the nanocapsule can be, but is not limited to drugs, medicaments, pharmaceutical compositions, chemical compositions, therapeutic compositions, biological macromolecules, dyes, biological material, immunological compositions, nutritional compositions, vitamins, proteins, nucleic acids, antibodies and vaccines.
  • Various materials may be used for producing such nanocapsules.
  • Nanocapsule refers to a particle having a hollow core that is surrounded by a shell, such that the particle has a size of less than about 1000 nanometers. When a nanocapsule includes a bioactive component, the bioactive component is located in the core that is surrounded by the shell of the nanocapsule.
  • the term “nanocage” refers to a nanocapsule, whereby the shell is not solid, as described for the nanocapsule, but has multiple holes or pores in its shell, thereby making it possible for the payload within the core of the nanocage to come into contact with the surrounding environment. These holes or pores may be regular or irregular in shape and/or spacing on the surface of the particle.
  • the terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In some non-limiting embodiments, the patient, subject or individual Attorney Docket No.206030-0278-00WO is a human.
  • the subject is a human subject, and may be of any race, sex, and age.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • a disease or disorder is “alleviated” if the severity of at least one sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.
  • modulating is meant mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated subject.
  • the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, such as, a human.
  • inhibitor means to suppress or block an activity or function by at least about ten percent relative to a control value.
  • the activity is suppressed or blocked by at least 50% compared to a comparator value, or by at least 55%, or by at least 60%, or by at least 65%, or by at least 70%, or by at least 75%, or by at least 80%, or by at least 85%, or by at least 90%, or by at least 95%.
  • diagnosis refers to the determination of the presence of a disease or disorder. In various embodiments of the present invention, methods for making a diagnosis are provided which permit determination of the presence of a particular disease or disorder.
  • a disease as the term is used herein, means to reduce the frequency and/or severity of at least one sign or symptom of a disease or disorder experienced by a subject.
  • the terms “effective amount” and “pharmaceutically effective amount” refer to a sufficient amount of an agent to provide the desired biological result. That result can be Attorney Docket No.206030-0278-00WO reduction and/or alleviation of a sign, symptom, or cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • therapeutic as used herein means a treatment and/or prophylaxis.
  • a therapeutic effect is obtained by suppression, diminution, remission, prevention, or eradication of at least one sign or symptom of a disease or disorder.
  • the term “therapeutically effective amount” refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the term “therapeutically effective amount” includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the signs or symptoms of the disorder or disease being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • “Pharmaceutically acceptable” refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • “Pharmaceutically acceptable carrier” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.
  • pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt, which upon administration to the subject is capable of providing (directly or indirectly) a compound as described herein. Such salts preferably are acid addition salts with physiologically acceptable organic or inorganic acids.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methane sulphonate, and p-toluenesulphonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methane sulphonate, and p-toluenesulphonate.
  • alkali addition salts examples include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- Attorney Docket No.206030-0278-00WO dialkylenethanolamine, triethanolamine, and basic amino acids salts.
  • organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- Attorney Docket No.206030-0278-00WO dialkylenethanolamine, triethanolamine, and basic amino acids salts.
  • non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. Procedures for salt formation are conventional in the art.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington’s Attorney Docket No.206030-0278-00WO Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • solvate in accordance with this invention should be understood as meaning any form of the active compound in accordance with the invention in which said compound is bonded by a non-covalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates.
  • pharmaceutical composition refers to a mixture of at least one compound of the invention with other chemical components and entities, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • a compound that is administered for such purpose.
  • therapeutic compound therapeutic agent
  • drug drug
  • active pharmaceutical active pharmaceutical ingredient
  • Non-limiting examples of therapeutic agents include, but are not limited to, hydrophilic therapeutic agents, hydrophobic therapeutic agents, antibiotics, antibodies, small molecules, anti-cancer agents, chemotherapeutic agents, immunomodulatory agents, RNA molecules, siRNA molecules, DNA molecules, gene editing agents, gene-silencing agents, CRISPR-associated agents (e.g., guide RNA molecules, endonucleases, and variants thereof), analgesics, vaccines, anticonvulsants; anti-diabetic agents, antifungal agents, antineoplastic agents, anti-parkinsonian agents, anti-rheumatic agents, appetite suppressants, biological response modifiers, cardiovascular agents, central nervous system stimulants, contraceptive agents, dietary supplements, vitamins, minerals, lipids, saccharides, metals, amino acids (and precursors), nucleic acids and precursors, contrast agents, diagnostic agents, dopamine receptor agonists, erectile dysfunction agents, fertility agents, gastrointestinal agents, hormones, immunomodulators, antihypercalcemia agents,
  • the one or more therapeutic agents are water-soluble, poorly water-soluble drug or a drug with a low, medium or high melting point.
  • the therapeutic agents may be provided with or without a stabilizing salt or salts.
  • Some examples of active ingredients suitable for use in the pharmaceutical formulations and methods of the present invention include: hydrophilic, lipophilic, amphiphilic or hydrophobic, and that can be solubilized, dispersed, or partially solubilized and dispersed, on or about the nanocluster.
  • the active agent-nanocluster combination may be coated further to encapsulate the agent-nanocluster combination and may be directed to a target by functionalizing the nanocluster with, e.g., aptamers and/or antibodies.
  • an active ingredient may also be provided separately from the solid pharmaceutical composition, such as for co- administration.
  • Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, nutraceuticals, diagnostic agents, nutritional agents, and the like.
  • the active agents described herein may be found in their native state, however, they will generally be provided in the form of a salt.
  • the active agents described herein include their isomers, analogs and derivatives. “Fragment” may mean a polypeptide fragment of an antigen that is capable of eliciting an immune response in a mammal.
  • a fragment of an antigen may be 100% identical to the full length except missing at least one amino acid from the N and/or C terminal, in each case with or without signal peptides and/or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full length antigen, excluding any heterologous signal peptide added.
  • the fragment may comprise a fragment of a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the antigen and additionally comprise an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise an N terminal methionine and/or a signal peptide such as an Attorney Docket No.206030-0278-00WO immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The N terminal methionine and/or signal peptide may be linked to a fragment of an antigen.
  • a fragment of a nucleic acid sequence that encodes an antigen may be 100% identical to the full length except missing at least one nucleotide from the 5' and/or 3' end, in each case with or without sequences encoding signal peptides and/or a methionine at position 1.
  • Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full length coding sequence, excluding any heterologous signal peptide added.
  • the fragment may comprise a fragment that encode a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the antigen and additionally optionally comprise sequence encoding an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise coding sequences for an N terminal methionine and/or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The coding sequence encoding the N terminal methionine and/or signal peptide may be linked to a fragment of coding sequence.
  • “Variant” used herein with respect to a nucleic acid may mean (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequences substantially identical thereto. “Variant” with respect to a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity.
  • Variant may also mean a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at least one biological activity.
  • a conservative substitution of an amino acid i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change.
  • Attorney Docket No.206030-0278-00WO These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art. Kyte et al., J. Mol. Biol.157:105-132 (1982). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge.
  • amino acids of similar hydropathic indexes can be substituted and still retain protein function.
  • amino acids having hydropathic indexes of ⁇ 2 are substituted.
  • the hydrophilicity of amino acids can also be used to reveal substitutions that would result in proteins retaining biological function.
  • a consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity.
  • U.S. Patent No.4,554,101 incorporated fully herein by reference.
  • Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity, as is understood in the art.
  • Substitutions may be performed with amino acids having hydrophilicity values within ⁇ 2 of each other. Both the hyrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties.
  • a variant may be a nucleic acid sequence that is substantially identical over the full length of the full gene sequence or a fragment thereof.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have Attorney Docket No.206030-0278-00WO specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6.
  • the present invention provides a composition comprising a porous nanoparticle and at least one growth factor.
  • the porous nanoparticle comprises a zeolite imidazolate framework (ZIF).
  • the porous nanoparticle comprises ZIF-8.
  • the porous nanoparticle encapsulates the at least one growth factor.
  • the ZIF nanoparticles encapsulate the at least one growth factor.
  • the composition is used in a coating.
  • the coating is used in medical applications (e.g., dentistry, orthopedics, medical devices, basic research, wound healing, dental composites, dental implants, titanium implant, coatings, such as surface coating of a titanium implant, etc.).
  • the invention provides a method for promoting osteoinduction, promoting osteointegration, preventing inflammation, or any combination thereof.
  • the method comprises applying the coating to a subject in need thereof.
  • the coating is applied to a dental implant.
  • the coating is applied to a titanium-based implant.
  • the coating is applied to a titanium implant.
  • the present invention can be provided in a variety of configurations (embedded in resin composites, as surface treatment of existing biomaterials) for use in several medical applications including dentistry, orthopedics, medical devices, basic research, wound healing.
  • Composition and Coatings Attorney Docket No.206030-0278-00WO
  • the present invention provides a composition comprising a porous nanoparticle.
  • the composition is a multi-functional coating.
  • the composition possesses osteoinductive properties, osteointegrative properties, anti-inflammatory properties, or any combination thereof.
  • the composition comprises porous nanoparticles comprising a metal and an organic linker.
  • the composition comprises porous nanoparticles comprising a metal-organic framework which comprises a metal and an organic linker.
  • the porous nanoparticle comprises a zeolitic imidazolate framework (ZIF).
  • the porous nanoparticle comprises zeolitic imidazolate framework-8 (ZIF-8).
  • the porous nanoparticle is synthesized in aqueous solution.
  • the porous nanoparticle is synthesized in organic solution.
  • the metal is a metal ion.
  • the metal is a four-coordinate metal ion.
  • the metal is a transition metal ion.
  • the metal ions include, but are not limited to, an ion of magnesium, an ion of aluminum, an ion of calcium, an ion of zirconium, an ion of silver, an ion of palladium, an ion of zinc, ion of iron, ion of cobalt, and/or ion of copper.
  • the metal is an ion of zinc.
  • the organic linker comprises a bridging ligand. Examples of organic linkers include, but are not limited to, hydroxides, oxides, hydrosulfidos, amidos, nitrides, carbonyls, halides, cyanides, phosphides, and conjugate bases of weak acids.
  • the organic linker comprises an imidazolate. In one embodiment, the nanoparticles comprising a metal-organic framework are monodispersed. In one embodiment, the ratio of organic linker to metal is about 1:1 to about 100:1. In one embodiment, the ratio of organic linker to metal is about 1:1 to about 90:1. In one embodiment, the ratio of organic linker to metal is about 1:1 to about 80:1. In one embodiment, the ratio of organic linker to metal is about 1:1 to about 70:1. In one embodiment, the ratio of organic linker to metal is about 1:1 to about 60:1. In one embodiment, the ratio of organic linker to metal is about 1:1 to about 50:1. In one embodiment, the ratio of organic linker to metal is about 10:1 to about 50:1.
  • the ratio of organic linker to metal is about 10:1 to about 60:1. In one embodiment, the ratio of organic linker to metal is about 10:1 to about 70:1. Attorney Docket No.206030-0278-00WO In one embodiment, the ratio of organic linker to metal is about 10:1 to about 80:1. In one embodiment, the ratio of organic linker to metal is about 10:1 to about 90:1. In one embodiment, the ratio of organic linker to metal is about 10:1 to about 100:1. In one embodiment, the ratio of organic linker to metal is about 20:1 to about 50:1. In one embodiment, the ratio of organic linker to metal is about 20:1 to about 60:1. In one embodiment, the ratio of organic linker to metal is about 20:1 to about 70:1.
  • the ratio of organic linker to metal is about 20:1 to about 80:1. In one embodiment, the ratio of organic linker to metal is about 20:1 to about 90:1. In one embodiment, the ratio of organic linker to metal is about 20:1 to about 100:1. In one embodiment, the ratio of organic linker to metal is about 30:1 to about 50:1. In one embodiment, the ratio of organic linker to metal is about 30:1 to about 60:1. In one embodiment, the ratio of organic linker to metal is about 30:1 to about 70:1. In one embodiment, the ratio of organic linker to metal is about 30:1 to about 80:1. In one embodiment, the ratio of organic linker to metal is about 30:1 to about 90:1.
  • the ratio of organic linker to metal is about 30:1 to about 100:1. In one embodiment, the ratio of organic linker to metal is about 40:1 to about 50:1. In one embodiment, the ratio of organic linker to metal is about 40:1 to about 60:1. In one embodiment, the ratio of organic linker to metal is about 40:1 to about 70:1. In one embodiment, the ratio of organic linker to metal is about 40:1 to about 80:1. In one embodiment, the ratio of organic linker to metal is about 40:1 to about 90:1. In one embodiment, the ratio of organic linker to metal is about 40:1 to about 100:1. In one embodiment, the ratio of organic linker to metal is about 50:1 to about 60:1.
  • the ratio of organic linker to metal is about 50:1 to about 70:1. In one embodiment, the ratio of organic linker to metal is about 50:1 to about 80:1. In one embodiment, the ratio of organic linker to metal is about 50:1 to about 90:1. In one embodiment, the ratio of organic linker to metal is about 50:1 to about 100:1. In one embodiment, the ratio of organic linker to metal is about 100:1. In one embodiment, the ratio of organic linker to metal is about 90:1. In one embodiment, the ratio of organic linker to metal is about 85:1. In one embodiment, the ratio of organic linker to metal is about 80:1. In one embodiment, the ratio of organic linker to metal is about 75:1. In one embodiment, the ratio of organic linker to metal is about 70:1.
  • the ratio of organic linker to metal is about 65:1. In one embodiment, the ratio of organic linker to metal is about 60:1. In one embodiment, the ratio of organic linker to metal is about 50:1. In one embodiment, the ratio of organic linker to metal is about 40:1. In one embodiment, the ratio of Attorney Docket No.206030-0278-00WO organic linker to metal is about 30:1. In one embodiment, the ratio of organic linker to metal is about 20:1. In one embodiment, the ratio of organic linker to metal is about 10:1. In one embodiment, the ratio of organic linker to metal is about 4:1. In one embodiment, the ratio of organic linker to metal is about 2:1. In one embodiment, the ratio of organic linker to metal is about 1:1.
  • the diameter of the porous nanoparticle is about 10 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 20 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 30 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 40 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 50 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 60 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 10 nm to about 20 nm.
  • the diameter of the porous nanoparticle is about 20 nm to about 30 nm. In one embodiment, the diameter of the porous nanoparticle is about 30 nm to about 40 nm. In one embodiment, the diameter of the porous nanoparticle is about 40 nm to about 50 nm. In one embodiment, the diameter of the porous nanoparticle is about 50 nm to about 60 nm. In one embodiment, the diameter of the porous nanoparticle is about 60 nm to about 70 nm. In one embodiment, the diameter of the porous nanoparticle is about 70 nm to about 80 nm. In one embodiment, the diameter of the porous nanoparticle is about 80 nm to about 90 nm.
  • the diameter of the porous nanoparticle is about 90 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 65 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle is about 60 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle is about 65 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle is about 70 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle is about 75 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle is about 70 nm to about 80 nm.
  • the diameter of the porous nanoparticle is about 60 nm to about 65 nm. In one embodiment, the diameter of the porous nanoparticle is about 65 nm to about 70 nm. In one embodiment, the diameter of the porous nanoparticle is about 70 nm to about 75 nm. In one embodiment, the diameter of the porous nanoparticle is about 75 nm to about 80 nm. In one embodiment, the diameter of the porous nanoparticle is about 10 nm. In one Attorney Docket No.206030-0278-00WO embodiment, the diameter of the porous nanoparticle is about 20 nm. In one embodiment, the diameter of the porous nanoparticle is about 30 nm.
  • the diameter of the porous nanoparticle is about 40 nm. In one embodiment, the diameter of the porous nanoparticle is about 50 nm. In one embodiment, the diameter of the porous nanoparticle is about 60 nm. In one embodiment, the diameter of the porous nanoparticle is about 70 nm. In one embodiment, the diameter of the porous nanoparticle is about 75 nm. In one embodiment, the diameter of the porous nanoparticle is about 80 nm. In one embodiment, the diameter of the porous nanoparticle is about 85 nm. In one embodiment, the diameter of the porous nanoparticle is about 90 nm. In one embodiment, the diameter of the porous nanoparticle is about 100 nm.
  • the composition further comprises one or more growth factors.
  • the growth factor is a peptide or a variant or fragment thereof promoting cell expression, a protein or a variant or fragment thereof promoting cell expression, a nucleic acid molecule encoding a peptide or a variant or fragment thereof promoting cell expression, a nucleic acid molecule encoding a protein or a variant or fragment thereof promoting cell expression, or any combination thereof.
  • Exemplary growth factors include, but are not limited to, an amino acid sequence selected from SEQ ID NOs: 1-22, or a variant or fragment thereof, a nucleic acid molecule encoding the amino acid sequence selected from SEQ ID NOs: 1-22, or a variant or fragment thereof, and any combination thereof.
  • the growth factors are antibacterial growth factors. In some embodiments, the growth factors are antimicrobial growth factors. In some embodiments, the growth factors promote cell adhesion. In some embodiments, the growth factors promote cell growth. In some embodiments, the growth factors promote cell expression. In one embodiment, the growth factor is a combination of the amino acid sequence set forth in SEQ ID NO: 1 or a variant or fragment thereof. In one embodiment, the growth factor is the amino acid sequence set forth in SEQ ID NO: 1 or a variant or fragment thereof. In one embodiment, the growth factor is a combination of the amino acid sequence set forth in SEQ ID NO: 10 or a variant or fragment thereof. In one embodiment, the growth factor is the amino acid sequence set forth in SEQ ID NO: 10 or a variant or fragment thereof.
  • the concentration of the growth factor solution is about 0.1 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is Attorney Docket No.206030-0278-00WO about 0.2 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.3 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.4 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.5 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.6 mg/mL to 2.0 mg/mL.
  • the concentration of the growth factor solution is about 0.7 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.8 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.9 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.0 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.1 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.2 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.3 mg/mL to 1.0 mg/mL.
  • the concentration of the growth factor solution is about 0.4 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.5 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.6 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.7 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.8 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.9 mg/mL to 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.1 mg/mL to 1.5 mg/mL.
  • the concentration of the growth factor solution is about 0.2 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.3 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.4 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.5 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.6 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.7 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 0.8 mg/mL to 1.5 mg/mL.
  • the concentration of the growth factor solution is about 0.9 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.0 mg/mL to 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.1 mg/mL Attorney Docket No.206030-0278-00WO to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.2 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.3 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.4 mg/mL to 2.0 mg/mL.
  • the concentration of the growth factor solution is about 1.5 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.6 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.7 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.8 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is about 1.9 mg/mL to 2.0 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.1 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.2 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.3 mg/mL.
  • the concentration of the growth factor solution is 0.4 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.5 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.6 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.7 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.8 mg/mL. In one embodiment, the concentration of the growth factor solution is 0.9 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.0 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.1 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.2 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.3 mg/mL.
  • the concentration of the growth factor solution is 1.4 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.5 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.6 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.7 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.8 mg/mL. In one embodiment, the concentration of the growth factor solution is 1.9 mg/mL. In one embodiment, the concentration of the growth factor solution is 2.0 mg/mL. In one aspect of the invention, the growth factors are encapsulated in the porous nanoparticle. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 10 nm to about 100 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 20 nm to about 100 nm. In one Attorney Docket No.206030-0278-00WO embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 30 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 40 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 45 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 50 nm to about 100 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 55 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 60 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 65 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 70 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 80 nm to about 100 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 90 nm to about 100 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 10 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 20 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 30 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 40 nm to about 90 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 45 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 50 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 55 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 60 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 65 nm to about 90 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 70 nm to about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 45 nm to about 50 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 50 nm to about 55 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 55 nm to about 60 nm. In one embodiment, the diameter of Attorney Docket No.206030-0278-00WO the porous nanoparticle with encapsulated growth factors is about 60 nm to about 65 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 65 nm to about 70 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 70 nm to about 75 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 75 nm to about 80 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 10 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 20 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 30 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 40 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 45 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 50 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 55 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 60 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 70 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 80 nm.
  • the diameter of the porous nanoparticle with encapsulated growth factors is about 90 nm. In one embodiment, the diameter of the porous nanoparticle with encapsulated growth factors is about 100 nm. In one aspect of the invention, the composition further comprises one or more therapeutic agents. In one embodiment, the nanoparticle comprises the therapeutic agent. In one embodiment, the therapeutic agent is a hydrophobic therapeutic agent. In one embodiment, the therapeutic agent is a hydrophilic therapeutic agent.
  • therapeutic agents include, but are not limited to, one or more drugs, proteins, amino acids, peptides, antibodies, antibiotics, anti-inflammatory agents, anti-infection agents, anti-bacterial agents, anti-viral agents, anti- fungal agents, small molecules, anti-cancer agents, chemotherapeutic agents, immunomodulatory agents, RNA molecules, siRNA molecules, DNA molecules, gene editing agents, gene-silencing agents, CRISPR-associated agents (e.g., guide RNA molecules, endonucleases, and variants thereof), medical imaging agents, therapeutic moieties, one or more non-therapeutic moieties or a combination to target cancer or atherosclerosis, selected from folic acid, peptides, proteins, aptamers, antibodies, siRNA, poorly water soluble drugs, anti-cancer drugs, antibiotics, Attorney Docket No.206030-0278-00WO analgesics, vaccines, anticonvulsants; anti-diabetic agents, antifungal agents, antineoplastic agents, anti-par
  • the therapeutic agent may be an anti-inflammatory agent.
  • Any suitable anti-inflammatory agent may be used in the compositions and methods of the present disclosure. The selection of a suitable anti-inflammatory agent may depend upon, among other things, the type of inflammation to be treated and the composite of the present disclosure.
  • anti-inflammatory agents include, but are not limited to, non-steroidal anti- inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs, beta-agonists, anticholingeric agents, antihistamines (e.g., ethanolamines, ethylenediamines, piperazines, and phenothiazine), and methyl xanthines.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • beta-agonists steroidal anti-inflammatory drugs
  • anticholingeric agents e.g., antihistamines (e.g., ethanolamines, ethylenediamines, piperazines, and phenothiazine)
  • antihistamines e.g., ethanolamines, ethylene
  • NSAIDs include, but are not limited to, aspirin, ibuprofen, salicylates, acetominophen, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoralac, oxaprozin, nabumentone, sulindac, tolmentin, rofecoxib, naproxen, ketoprofen and nabumetone.
  • NSAIDs function by inhibiting a cyclooxgenase enzyme (e.g., COX-1 and/or COX-2).
  • steroidal anti-inflammatory drugs include, but are not limited to, glucocorticoids, dexamethasone, cortisone, hydrocortisone, prednisone, prednisolone, triamcinolone, azulfidine, and eicosanoids such as prostaglandins, thromboxanes, and leukotrienes.
  • the therapeutic agent may be an anti-infection agent. Any suitable anti-infection agent may be used in the compositions and methods of the present disclosure. The selection of a suitable anti-infection agent may depend upon, among other things, the type of infection to be treated and the composite of the present disclosure.
  • the anti-infection agent may be an anti-bacterial agent, anti-fungal agent, anti-viral Attorney Docket No.206030-0278-00WO agent, or any combination thereof.
  • the anti-infection agent may be effective for treating one or more of bacterial infection, viral infection, fungal infection, or any combination thereof.
  • the composition is a coating.
  • the composition is a biomaterial.
  • the biomaterial comprises a porous nanoparticle.
  • the biomaterial further comprises one or more peptides.
  • the biomaterial is a medical device.
  • the medical device is an implant.
  • the medical device is a dental composite.
  • the biomaterial is a coating. In one embodiment, the biomaterial is a surface coating. In one embodiment, the biomaterial is a surface coating of medical devices. For example, in one embodiment, the biomaterial is a surface coating of titanium implant. In one embodiment, the biomaterial promotes bone growth, prevents or reduces an infection, prevents or reduces inflammation, prevents or treats diseases or disorders, or any combination thereof. In some embodiments, the infection is a bacterial infection, fungal infection, viral infection, or any combination thereof. For example, in one embodiment, the biomaterial promotes bone growth and prevents or reduces an infection. In another embodiment, the biomaterial improves oral health. In various aspects, the present invention also provides compositions comprising at least one biomaterial of the present invention.
  • antibacterial agents or antibiotics include, but are not limited to, aminoglycoside antibiotics (e.g., apramycin, arbekacin, bambermycins, butirosin, dibekacin, neomycin, neomycin, undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, and spectinomycin), amphenicol antibiotics (e.g., azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol), ansamycin antibiotics (e.g., rifamide and rifampin), carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem and imipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cef
  • antibacterial agents include Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Berythromycin; Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride; Bispyrithi
  • anti-fungal agent examples include, but are not limited to, polyenes (e.g., amphotericin b, candicidin, mepartricin, natamycin, and nystatin), allylamines (e.g., butenafine, and naftifine), imidazoles (e.g., bifonazole, butoconazole, chlordantoin, flutrimazole, isoconazole, ketoconazole, and lanoconazole), thiocarbamates (e.g., tolciclate, tolindate, and tolnaftate), triazoles (e.g., fluconazole, itraconazole, saperconazole, and terconazole), bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, ciclopirox, azaserine, Attorney Docket No.206030-0278-00WO griseofulvin, oligomycins
  • antifungal compounds include but are not limited to Acrisorcin; Ambruticin; Amphotericin B; Azaconazole; Azaserine; Basifungin; Bifonazole; Biphenamine Hydrochloride; Bispyrithione Magsulfex; Butoconazole Nitrate; Calcium Undecylenate; Candicidin; Carbol-Fuchsin; Chlordantoin; Ciclopirox; Ciclopirox Olamine; Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin; Denofungin; Dipyrithione; Doconazole; Econazole; Econazole Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin; Fluconazole; Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole; Itraconazole; Kalafungin; Ketoconazole; Lomofing
  • anti-viral agents include, but are not limited to, proteins, polypeptides, peptides, fusion protein antibodies, nucleic acid molecules, organic molecules, inorganic molecules, and small molecules that inhibit or reduce the attachment of a virus to its receptor, the internalization of a virus into a cell, the replication of a virus, or release of virus from a cell.
  • antiviral compounds that can be used in combination with the compounds of the invention are known in the art and include but are not limited to: rifampicin, nucleoside reverse transcriptase inhibitors (e.g., AZT, ddl, ddC, 3TC, d4T), non-nucleoside reverse transcriptase inhibitors (e.g., Efavirenz, Nevirapine), protease inhibitors (e.g., aprenavir, indinavir, ritonavir, and saquinavir), idoxuridine, cidofovir, acyclovir, ganciclovir, zanamivir, amantadine, and Palivizumab.
  • nucleoside reverse transcriptase inhibitors e.g., AZT, ddl, ddC, 3TC, d4T
  • non-nucleoside reverse transcriptase inhibitors e.g., Efavirenz,
  • anti-viral agents include but are not limited to Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride; Attorney Docket No.206030-0278-00WO Fiacitabine; Fialuridine; Fosarilate; Foscamet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine Hydrochloride; Methisazone;
  • the present invention also provides a method of promoting osteogenesis, promoting bone growth, promoting cell adhesion, promoting cell expression, promoting anti- infection effect (e.g., promoting anti-bacterial effect, promoting anti-fungal effect, promoting anti-viral effect, etc.), promoting anti-inflammatory effect, preventing or treating diseases or disorders, or any combination thereof in a subject in need thereof.
  • the present invention provides a method of promoting bone growth, cell expression, and cell adhesion around a dental implant.
  • the present invention provides a method of preventing, reducing, or treating infection, preventing, reducing, or treating inflammation, or any combination thereof in a subject in need thereof.
  • the present invention provides a method of preventing, reducing, or treating fungal infection, bacterial infection, viral infection, or any combination thereof in a subject in need thereof.
  • the disease or disorder is an infection, inflammation, cancer, or any combination thereof.
  • the present invention comprises a method of simultaneously promoting bone growth, promoting cell adhesion, promoting cell expression, promoting anti- infection effect (e.g., promoting anti-bacterial effect, promoting anti-fungal effect, promoting anti-viral effect, etc.), promoting anti-inflammatory effect, preventing or treating diseases or disorders, preventing, reducing, or treating infection, preventing, reducing, or treating inflammation, and improving health of a subject in need thereof.
  • the present invention provides a method of promoting osteogenesis in a subject in need thereof, wherein the method comprises administering to the Attorney Docket No.206030-0278-00WO subject a therapeutically effective amount of the composition comprising a porous nanoparticle.
  • the porous nanoparticle encapsulates a growth factor.
  • the dosage concentration is about 0.01 wt % to about 100 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 90 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 80 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 70 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 60 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 50 wt %.
  • the dosage concentration is about 0.01 wt % to about 40 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 30 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 20 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 10 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 9 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 8 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 7 wt %.
  • the dosage concentration is about 0.01 wt % to about 6 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 5 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 4 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 3 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 2 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 1 wt %. In one embodiment, the dosage concentration is about 0.01 wt % to about 0.10 wt %.
  • the dosage concentration is about 0.10 wt % to about 1 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 9 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 8 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 7 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 6 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 5 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 4 wt %.
  • the dosage concentration is about 1 wt % to about 3 wt %. In one embodiment, the dosage concentration is about 1 wt % to about 2 wt %. In one embodiment, the composition increases the expression of protein transcription factors. In one embodiment, the composition decreases the expression of protein transcription factors. In one embodiment, the composition increases the expression of signaling Attorney Docket No.206030-0278-00WO proteins. In one embodiment, the composition decreases the expression of signaling proteins. In one embodiment, the composition lowers the M1 polarization marker. In one embodiment, the composition increases the M2 polarization marker.
  • the method comprises the steps of: applying the composition comprising a porous nanoparticle or coating comprising a porous nanoparticle to a titanium implant and applying the titanium implant to the subject in need thereof.
  • the porous nanoparticle encapsulates at least one growth factor.
  • growth factors include, but are not limited to, the amino acid sequence selected from SEQ ID Nos: 1-22, or a variant or fragment thereof, or a nucleic acid molecule encoding the amino acid sequence selected from SEQ ID Nos: 1-22, or any combination thereof.
  • the coating is uniform. In one embodiment, the coating is non-uniform.
  • the present invention provides a method of promoting an anti- inflammatory effect in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the composition comprising a porous nanoparticle.
  • the method simultaneously promotes osteogenesis and an anti- inflammatory effect in a subject in need thereof.
  • the method comprises the steps of: applying the composition comprising a porous nanoparticle or coating comprising a porous nanoparticle to a titanium implant and applying the titanium implant to the subject in need thereof.
  • the porous nanoparticle encapsulates at least one growth factor.
  • the coating is uniform. In one embodiment, the coating is non-uniform.
  • the coating has a thickness of about 0.1 ⁇ m to about 100 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 90 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 80 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 70 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 60 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 50 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 40 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 30 ⁇ m.
  • the coating has a thickness of about 0.1 ⁇ m to about 20 ⁇ m. In one Attorney Docket No.206030-0278-00WO embodiment, the coating has a thickness of about 0.1 ⁇ m to about 10 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 9 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 8 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 7 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 6 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 5 ⁇ m.
  • the coating has a thickness of about 0.1 ⁇ m to about 4 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 3 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 2 ⁇ m. In one embodiment, the coating has a thickness of about 1 ⁇ m to about 2 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 1 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.9 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.8 ⁇ m.
  • the coating has a thickness of about 0.1 ⁇ m to about 0.7 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.6 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.5 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.4 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.3 ⁇ m. In one embodiment, the coating has a thickness of about 0.1 ⁇ m to about 0.2 ⁇ m. In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 1,000 particles/ ⁇ m 2 .
  • the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 900 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 800 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 700 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 600 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 500 particles/ ⁇ m 2 .
  • the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 400 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 300 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 200 particles/ ⁇ m 2 . In one embodiment, the density of the nanoparticle in the coating is about 1 particle/ ⁇ m 2 to about 100 particles/ ⁇ m 2 . Attorney Docket No.206030-0278-00WO In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 10 mg/mL.
  • the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 9 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 8 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 7 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 6 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 5 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 4 mg/mL.
  • the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 3 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 2 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 0.01 mg/mL to about 1 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 2 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 3 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 5 mg/mL.
  • the concentration of the nanoparticle in the coating is about 1 mg/mL to about 6 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 7 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 8 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 9 mg/mL. In one embodiment, the concentration of the nanoparticle in the coating is about 1 mg/mL to about 10 mg/mL. In one embodiment, the porous nanoparticle releases the growth factor over time. In one embodiment, the porous nanoparticle releases the growth factor over about 1 minute to about 1 year.
  • the porous nanoparticle releases the growth factor over about 1 minute to about 1 hour. In one embodiment, the porous nanoparticle releases the growth factor over about 1 minute to about 1 months. In one embodiment, the porous nanoparticle releases the growth factor over about 10 minutes to about 1 hour. In one embodiment, the porous nanoparticle releases the growth factor over about 30 minutes to about 1 hour. In one embodiment, the porous nanoparticle releases the growth factor over about 1 hour to about 6 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 1 hour Attorney Docket No.206030-0278-00WO to about 12 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 1 hour to about 18 hours.
  • the porous nanoparticle releases the growth factor over about 1 hour to about 24 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 24 hours to about 1 week. In one embodiment, the porous nanoparticle releases the growth factor over about 1 week to about 4 weeks. In one embodiment, the porous nanoparticle releases the growth factor over about 1 week to about 1 month. In one embodiment, the porous nanoparticle releases the growth factor over about 4 weeks to about 16 weeks. In one embodiment, the porous nanoparticle releases the growth factor over about 4 weeks to about 1 year. In one embodiment, the porous nanoparticle releases the growth factor over about 1 minute. In one embodiment, the porous nanoparticle releases the growth factor over about 30 minutes.
  • the porous nanoparticle releases the growth factor over about 1 hour. In one embodiment, the porous nanoparticle releases the growth factor over about 6 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 12 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 18 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 24 hours. In one embodiment, the porous nanoparticle releases the growth factor over about 1 week. In one embodiment, the porous nanoparticle releases the growth factor over about 4 weeks. In one embodiment, the porous nanoparticle releases the growth factor over about 16 weeks. In one embodiment, the porous nanoparticle releases the growth factor over about 1 year.
  • the release profile of the growth factor can be modified based on the application, bioactive molecule, drug, or any combination thereof.
  • the coating promotes bone growth, prevents or reduces an infection, prevents or reduces inflammation, prevents or treats diseases or disorders, or any combination thereof.
  • the infection is a bacterial infection, fungal infection, viral infection, or any combination thereof.
  • the coating promotes bone growth and prevents or reduces an infection.
  • the coating improves oral health.
  • the coating prevents inflammation.
  • the coating reduces inflammation.
  • Example 1 Synthesis of Zeolite Imidazole Framework (ZIF) Nanoparticles Zeolite Imidazole Framework nanoparticles (ZIF NPs/ZNanos) were synthesized by mixing 2-methylimidazole (2-MeIM) and zinc nitrate (Zn 2+ ) in aqueous solution. To achieve monodispersed nanoscale ZIF NPs, the ratio of 2-MeIM and Zn 2+ was optimized to 70:1 at concentrations of 3150 mM and 45 mM, respectively. RGD and thrombin-derived C-terminal peptides (TCP-25) were chosen to study the biomineralization-mediated loading of biomacromolecules.
  • ZIF Zeolite Imidazole Framework nanoparticles
  • the RGD and TCP-25 peptides were added into the 2-MeIM solution at a concentration of 1 mg/mL, followed by the addition of Zn 2+ .
  • the size and coating density of ZIF NPs and ZIF with RGD/TCP-25 encapsulation (RGD/TCP-25@ZIF) NPs were characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM) (Fig.1A and Fig. 1B). Both methods of characterization showed an average size of 80 nm and uniform coatings on the surface of titanium substrates.
  • RT-qPCR Quantitative reverse transcription PCR
  • the developed coatings were also examined for their ability to inhibit local inflammation.
  • the M1 polarization marker nuclear factor kappa B (NF ⁇ B) of macrophages cultured on Peptides@ZIF@Ti substrates was significantly lower than those on ZIF@Ti substrates (Fig.3A).
  • the M2 polarization marker (NF ⁇ B) of macrophages cultured on Peptides@ZIF@Ti was significantly higher than those on ZIF@Ti substrates (Fig.3B).
  • the cell-adhesive peptides can bind with integrin on cell surface to activate the mechanotransduction-mediated differentiation.
  • the anti-inflammatory and antimicrobial peptides can create a tissue-regeneration favorable microenvironment (Fig.4).
  • the present results demonstrate that ZNano coatings can be applied to uniformly on Ti or Zr surfaces of dental implants (Fig.5). It was found that ZNano coatings effectively promoted cell mechanotransduction and osteogenic differentiation (Fig.6) and created a tissue regeneration favorable microenvironment via manipulating the function of T cells and macrophages (Fig.7). Lastly, it was found that the coatings effectively promoted the function of M2 macrophages via metabolic regulation (Fig.8).
  • zeolitic imidazolate framework-8 (ZIF-8) NPs were formed through biomimetic mineralization process, in which the concentration and crystallization of framework building blocks were facilitated under mild condition.
  • the dynamic ligand–ion coordination bonds and highly porous structures in ZIF-8 NPs enabled the efficient loading and controlled release of loaded peptides.
  • the multiple physical interactions between ZIF- 8 shells and BMP-2 proteins restricted the conformational changes of encapsulated peptides, thereby preventing the denature of them under extreme conditions.
  • the ideal coating enabled efficient loading and controlled release of loaded peptides and prevented the denature of them under extreme conditions.
  • Example 3 Sequences Growth factor 1 (SEQ ID NO: 1) RGD Growth factor 2 (SEQ ID NO: 2) Attorney Docket No.206030-0278-00WO PHSRN Growth factor 3 (SEQ ID NO: 3) REDV Growth factor 4 (SEQ ID NO: 4) YIGSR Growth factor 5 (SEQ ID NO: 5) IKVAV Growth factor 6 (SEQ ID NO: 6) DGEA Growth factor 7 (SEQ ID NO: 7) GFOGER/GFPGER Growth factor 8 (Eptifibatide) (SEQ ID NO: 8) XXGDWPC Growth factor 9 (SEQ ID NO: 9) RRETAWA Growth factor 10 (Thrombin-derived C-terminal peptide (TCP-25)) (SEQ ID NO: 10) GKYGFYTHVFRLKKWIQKVIDQFGE Growth factor 11 (SEQ ID NO: 11) GFPGER Growth factor 12 (SEQ ID NO: 12) GTPGPQGIAGQRGVV Growth factor 13 (SEQ ID NO: 13) Attorney

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Abstract

La présente invention concerne des compositions multifonctionnelles (par exemple, repoussant les biofilms, favorisant la formation de minéraux, et ayant des propriétés anti-infectieuses) et leurs procédés d'utilisation. Dans divers modes de réalisation, la présente invention concerne également un procédé de favorisation de la croissance osseuse, de favorisation de l'adhérence cellulaire, de favorisation de l'expression cellulaire, de favorisation de l'effet anti-infectieux (par exemple, de favorisation de l'effet antibactérien, de favorisation de l'effet antifongique, de favorisation de l'effet antiviral, etc.), de favorisation de l'effet anti-inflammatoire, de prévention ou de traitement des maladies ou des troubles, ou toute combinaison de ceux-ci chez un sujet en ayant besoin.
PCT/US2024/051553 2023-10-16 2024-10-16 Compositions de zéolite à effets thérapeutiques ostéoinductifs et anti-inflammatoires et leurs procédés d'utilisation Pending WO2025085507A2 (fr)

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