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WO2025175208A1 - Dispositif d'administration intravasculaire de médicament et méthode d'administration focale de médicament par perfusion vasculaire - Google Patents

Dispositif d'administration intravasculaire de médicament et méthode d'administration focale de médicament par perfusion vasculaire

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Publication number
WO2025175208A1
WO2025175208A1 PCT/US2025/016091 US2025016091W WO2025175208A1 WO 2025175208 A1 WO2025175208 A1 WO 2025175208A1 US 2025016091 W US2025016091 W US 2025016091W WO 2025175208 A1 WO2025175208 A1 WO 2025175208A1
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WIPO (PCT)
Prior art keywords
drug
drug delivery
delivery device
iadd
devices
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Pending
Application number
PCT/US2025/016091
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English (en)
Inventor
Edward ZAGHA
Huinan Liu
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.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
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Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2025175208A1 publication Critical patent/WO2025175208A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • 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
    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances

Definitions

  • the present application discloses embodiments of a medical device and a method for focal targeting of drug-to-end-organs by deploying drug-eluting devices in the blood vessels supplying targeted tissues. Also disclosed herein is focal drug targeting, for example in inflammation, autoimmune disease, transplant, epilepsy, stroke, Parkinson’s disease, traumatic brain injury, psychiatric disorders, tumors, cancer, pain, infection, and pulmonary embolism.
  • focal drug targeting for example in inflammation, autoimmune disease, transplant, epilepsy, stroke, Parkinson’s disease, traumatic brain injury, psychiatric disorders, tumors, cancer, pain, infection, and pulmonary embolism.
  • PO, IV, IM intramuscular
  • Current attempts at achieving spatial specificity include 1) radioactive seeds placed directly within the prostate for treating prostate cancer, 2) engineering drugs to have widespread perfusion but only activate at the target tissue, and 3) using arterial catheterization for focal drug application, such as applying tissue plasminogen activator in cerebral vessels for ischemic stroke. Note, application (3) is only applied short-term, during the catheterization procedure.
  • Some embodiments relate to a drug delivery device including a metal substrate and a polymer composite containing a drug, wherein the drug delivery device has mucoadhesive or bioadhesive properties that bind to epithelial cells inside an artery.
  • the device comprises a metal substrate; and/or a polymer composite; wherein: the drug delivery device is capable of binding to epithelial cells.
  • the metal substrate comprises a biodegradable metal or alloy comprising one or more of magnesium (Mg), iron (Fe), zinc (Zn), manganese (Mn), lithium (Li), calcium (Ca), copper (Cu), tungsten (W), molybdenum (Mo), nickel (Ni), aluminum (Al), cadmium (Cd), tin (Sn) or neodymium (Nd), Yttrium (Y).
  • the alloy comprises biodegradable Mg, Zn, Fe, Mn, Ca and/or Li. In some embodiments, the alloy comprises Zn- Cu, Mg-Zn, Mg-Mn, or Zn-Mn, with or without addition of Ca and/or Li. In some embodiments, the drug delivery device does not comprise a stent structure.
  • the polymer composite comprises a biodegradable polymer, optionally wherein the polymer is poly(glycerol sebacate) (PGS). In some embodiments, the biodegradable polymer is silk, PLGA, or PCL. In some embodiments, the metal substrate and/or the polymer composite are biodegradable and/or bioresorbable.
  • the device further comprises a compound, optionally wherein the compound is a drug of known therapeutic effect.
  • the device is capable of binding to epithelial cells due to the presence of at least one hydrophilic functional group or at least one polymer.
  • the polymer contains a lectin and/or is a thiolated polymer.
  • the device comprises a ring structure that provides enhanced radial strength to hold the device in place without shifting.
  • the ring structure comprises at least one ring.
  • the ring structure is a helical metal coil structure.
  • the device has a C shape, a linear I shape, an L shape, or a flat or curved sheet shape such that the device is capable of conforming to an endovascular surface and assist the drug delivery device in staying locally in a vasculature.
  • the polymer composite is coated with a release-rate modulating polymer fdm.
  • the release-rate modulating polymer film comprises a polylactone.
  • the polylactone is selected from the group consisting of polycaprolactone (PCL); polyglycolic acid (PGA); polylactic acid (PLA); poly(lactic-co-glycolic acid) (PLGA); polyhydroxyalkanoates (PHA) such as polyhydroxybutyrate (PHB), polyhydroxy valerate (PHV), and poly(3- hydroxybutyrate-co-3 -hydroxy valerate) (PHBV); polyethylene adipate (PEA); polybutylene succinate (PBS); and polyesters with aromatic groups in their main chains, such as polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT), and polyethylene naphthalate (PEN).
  • PCL polycaprolactone
  • PGA polyglycolic acid
  • PLA polylactic acid
  • PLA poly(lactic-co-glycolic acid)
  • PHA polyhydroxyalkanoates
  • PB polyhydroxybutyrate
  • PV polyhydroxy va
  • Also disclosed herein is a method of delivering a molecule, compound, drug, or composition to a target or organ, the method comprising administering to a subject in need thereof the drug delivery device according to any one of the embodiments of the present disclosure.
  • the subject is treated for a condition selected from the group consisting of inflammation, epilepsy, a stroke, Parkinson’s disease, a psychiatric disorder, a traumatic brain injury, a tumor, cancer, pain, a pulmonary embolism and a focal hypertension.
  • the drug is administered in a small dosage with sustained delivery and released over a period of weeks to months to the target tissue or organ.
  • Also disclosed herein is a use of the drug delivery device of any one of the embodiments of the present disclosure for selectively targeting a tissue or an organ in a subject.
  • Also disclosed herein is a method of delivering a molecule, compound, drug, or composition to an epithelial cell, the method comprising contacting the epithelial cell with the drug delivery device of any one of the embodiments of the present disclosure.
  • the epithelial cell is part of an artery.
  • Also disclosed herein is a method of delivering a molecule, compound, drug, or composition to a cell, tissue, organ, or system, the method comprising contacting an epithelial cell with the drug delivery device of any one of the embodiments of the present disclosure, wherein the epithelial cell is near the cell, tissue, organ, or system, and wherein the molecule, compound, drug, or composition is transferred from the drug delivery device to the cell, tissue, organ, or system.
  • Figures 1A-1C show nonlimiting example representations of portions of an embodiment of a drug delivery device.
  • Figure 1A depicts example magnesium wires twisted into coils to form the scaffold of the devices (substrates).
  • Figure IB depicts the scaffolds coated with drug-loaded polymer. Scale bar, 200 um.
  • Figure 1C depicts an embodiment of a linear scaffold coated with drug- loaded polymer. Scale bar, 200 um.
  • Figure 2 shows a nonlimiting example quantification of DEX release from a polymer-based drug delivery device. Drug elution was measured periodically over 30 days via LC-MS/MS. Plots show cumulative drug release (left axis, solid lines) and instantaneous release rates (right axis, dashed lines).
  • Figure 3 shows a nonlimiting example quantification of DEX concentrations in venous blood (serum) versus kidneys, from oral (left plots) versus device (right plots) treatments in vivo.
  • Oral drug delivery resulted in similar drug concentrations in all samples.
  • Device delivery resulted in an average 40-fold increase in DEX concentration in the left kidney (distal to the implanted device, blue column) compared to the serum of the same subjects (teal column).
  • Figure 4A shows a nonlimiting example cartoon representation of the process to generate an elastomer from a pre-polymer.
  • Figure 4B shows a nonlimiting example representation of the setup for a 96- well plate used in the drug release profiling study as discussed in Example 6 below.
  • Figure 4C shows a nonlimiting example cartoon representation of the experimental procedure for the in vitro SRB assay, as discussed in Example 6 below.
  • Figure 5 shows a nonlimiting example representation of a device structure comprising a metal wire surrounded by a polymer coating.
  • Figure 6 shows a nonlimiting example representation of a 12-well plate set up used for in-lab synthesis of elastic polymers, as detailed in Example 6 below.
  • Figures 7A-7B show nonlimiting example quantifications of mass degradation overtime for six individual devices (Figure 7A) and for the average device ( Figure 7B).
  • Figures 8A-8B show nonlimiting example quantifications of the concentration of drug released over time by three devices (Figure 8A), and by the average device ( Figure 8B).
  • Figure 9 shows a nonlimiting example image of F98 cell aggregates on hydrogels treated with polylysines.
  • Figure 10 shows a nonlimiting example quantification of the cell growth inhibition rate over time resulting from the Sulforhodamine B (SRB) assay using F98 cells treated with cisplatin.
  • SRB Sulforhodamine B
  • Figure 11 shows a nonlimiting example diagram of Stimulus-evoked recording in mice.
  • Figures 12A-12D show nonlimiting example Stimulus-evoked recording of Mg@Ll (Figure 12A), Mg@L2 ( Figure 12B), Pt@L3 (Figure 12C), and glass@L0 ( Figure 12D) in response to a 50-ms broadband noise (BBN) tone.
  • BBN broadband noise
  • Figure 13 shows a nonlimiting example series (panels A-D) of optical and scanning electron microscopic (SEM) images for biodegradable neural electrodes.
  • Figure 14 shows a nonlimiting example representation of fluorescence images of hNSCs stained with SOX1 (red), PAX 6 (green) and DAPI (blue) after 72h culture with bi-polymer coated (panel A) bioresorbable metal and (panel B) Pt electrodes, single polymer coated (panel C) bioresorbable metal and (panel D) Pt electrodes, non-coated (panel E) bioresorbable metal and (panel F) Pt electrodes, (panel G) NiCr, and (panel H) Cell only control.
  • Figure 15 shows a nonlimiting example quantification for cumulative drug release in vitro from Cisplatin-loaded device for treating Glioblastoma (GBM).
  • Figures 19A-19M show nonlimiting example characterization of IADD devices.
  • Figure 19A depicts the viscosity of a PGS pre-polymer.
  • Figures 19B-19C depict two different designs of IADD devices (helical and cylindrical).
  • Figures 19D-19E depict the chemical structures of DEX and CIS.
  • Figure 19F depicts an SEM image, and
  • Figure 19G depicts the elemental composition of drug-loaded IADD devices.
  • the dashed white circle depicts the central Mg wire
  • the dashed yellow box depicts the surrounding PGS
  • the solid green box depicts the region of the device used for elemental composition analysis via EDS.
  • Figure 19H depicts the thermal decomposition DEX- and CIS-loaded IADD devices, nondrug-loaded IADD device, and standard model drugs of DEX and CIS.
  • Figure 191 depicts the FTIR-ATR spectra of DEX- and CIS-loaded IADD devices, non-drug-loaded IADD device, and standard model drugs of DEX and CIS.
  • Figures 19J-19M depict Figures 19F-19I in color, respectively.
  • Figures 20A-20H show nonlimiting example quantifications for the in vitro drug and magnesium ion release profiles.
  • Figure 20A depicts the absolute amount of DEX and CIS released from DEX-loaded and CIS-loaded IADD devices per day for 30 days.
  • Figure 20B depicts the cumulative amount of DEX and CIS released from DEX-loaded and CIS-loaded IADD devices per day for 30 days.
  • Figures 20C-20D compares the concentration of magnesium ion released from DEX-loaded ( Figure 20C) or CIS- loaded ( Figure 20D), versus non-drug-loaded IADD devices. Dashed lines reflect ion concentrations from culture media controls, 1.5mM (Figure 20C) and 1.3mM in ( Figure 20D).
  • Figures 20E-20H depict Figures 20A-20D in color, respectively.
  • Figures 21A-21E show nonlimiting example quantifications of the in vitro cytocompatibility of drugs, solvents, and drug-loaded IADD devices with HUVEC cells.
  • Figures 21A-21B depict the IC50 curves of standard DEX and CIS ( Figure 21A); and ethanol and DMF ( Figure 21B).
  • Figure 21C depicts the effect of DEX-loaded, CIS-loaded, ethanol soaked, and DMF soaked IADD devices on % cell viability of HUVECs compared to cells only controls.
  • Figures 21D-21E depict Figures 21A-21B in color, respectively.
  • Figures 22A-22B show nonlimiting example quantifications of the in vitro drug activity against F98 glioma cells.
  • Figure 22A depicts the IC50 curve of CIS.
  • Figures 22B- 22C shows the effects of CIS-loaded IADD (Figure 22C) and non-drug-loaded IADD devices (Figure 22D) on % cell growth inhibition. ‘Day’ refers to the release media collected on that day of device incubation (see Methods).
  • Figure 22D shows the magnesium ion and calcium ion concentrations in the culture media of the F98 cells cultured with CIS-loaded IADD release media (solid lines). Dashed lines reflect ion concentrations from culture media controls (0.8 mM of Mg2+ and 1.8 mM of Ca2+).
  • Figures 23A-23B show nonlimiting example representations of the in vivo testing of focal drug delivery to the kidney from DEX-loaded IADD devices.
  • Figure 23A depicts a schematic representation of the in vivo drug administration via IADD (left) and orally (right).
  • Figure 23B (left panel) quantifies the DEX concentrations in the kidneys and the serum 7-days post IADD implantation in the left renal artery;
  • Figure 23B (right panel) quantifies the DEX concentrations in the same compartments after 7 days of oral DEX administration.
  • An asterisk (“*”) represents statistical significance at p ⁇ 0.05 of the IADD device in the left kidney group compared to all other groups.
  • Figures 24A-24B show nonlimiting example representations of the in vivo testing of focal drug delivery to the brain from DEX-loaded IADD devices.
  • Figure 24A depicts a schematic representation of the in vivo drug administration via IADD (left) and orally (right).
  • Figure 24B quantifies the DEX concentrations in the brain, serum, and the liver 7- days post IADD implantation in the right carotid artery;
  • Figure 24B quantifies the DEX concentrations in the same compartments after 7 days of oral DEX administration.
  • An asterisk (“*”) represents statistical significance at p ⁇ 0.05 of the IADD device in the Brain- IADD group compared to all other groups.
  • the vascular system is a natural perfusion system, targeting every organ with well-established and fine-scaled spatial specificity.
  • the present disclosure relates generally to the problem of spatial specific drug delivery.
  • some embodiments of the devices disclosed herein are configured to provide spatial specific drug delivery.
  • Some embodiments of the present disclosure relate to a biodegradable intraarterial drug delivery (IADD) device.
  • this device can be implanted into large- or medium-sized arteries to deliver drugs directly to the downstream organ.
  • the IADD device has bioadhesive properties, enabling it to adhere to the arterial endothelium.
  • the nonlimiting example IADD device shapes (helical, cylinder, ring, etc.) are designed to minimally disrupt blood flow through the implanted vessel.
  • Polymer-metal composite or polymer-only constructs have been used in direct organ implants.
  • the major advantages of intra-arterial implantation over direct organ implantation include that: 1) the surgical access of the organ is not required, thereby limiting the risks of organ damage and infection, and 2) the devices allow the ability to achieve broad organ perfusion, rather than being diffusion-limited from the site of organ implantation.
  • the device of the present disclosure differs from these polymer-based stents at least in that the device 1) has a biodegradable metal based composite design with biodegradable polymer layers, 2) is tunable for any high potency drugs, 3) is not limited to arterial disease, and can target downstream organs, and 4) the design is tunable for different arteries of different size, without blocking blood flow.
  • the shape of the device is tunable for the desired level of drug loading capacity; for example, the drug loading capacity for a device with a helical shape is in some embodiments greater than tubular shape, which is greater than a C shape, which is greater than a cylindrical shape.
  • the concentration range of drug is tunable by varying the device design, drug chemistry, and dimension.
  • the device of the present disclosure has use in delivery small, medium, and large molecule drugs.
  • the device is capable of delivering drugs to any downstream organs/tissues from an upstream artery.
  • the device comprises biodegradable metal and biodegradable polymer(s).
  • the device’s dimension/ratio is designed based on the upstream artery dimension and drug release requirements of duration/amount.
  • the IADD device of the present disclosure was shown to achieve focal drug delivery in vivo in a rat model, targeting the kidney and brain. Surprisingly, IADD device implanted into the renal artery to target the kidney achieved a 28-fold improvement in focal delivery compared to oral drug administration; IADD device implantation into the carotid artery to target the brain achieved a 68-fold improvement in focal delivery compared to oral drug administration
  • drug-eluting polymer-metal-based devices are placed within the artery/vessel of a subject that perfuses the target tissue or organ. These devices can have a high drug-storage capacity, slow rates of release, and can be biocompatible and biodegradable. Some embodiments of the devices disclosed herein may be deployed using standard minimally invasive endovascular delivery techniques as used for cardiac catheterization and stent placement. In some embodiments, these devices are active (i.e. continuously elute drug) for at least hours, days, weeks, months, or years, depending on the indication and device fabrication. In some embodiments these devices are bioresorbable, meaning that they are eliminated from the vascular system after drug elution. This approach to drug delivery can be applied to any focal target, that is, any case in which drug is intended to target a specific organ or part of an organ.
  • Some embodiments of the drug delivery devices disclosed herein relate to focal drug delivery (also referred to herein as spatially specific drug delivery), and include placing drug-eluting polymer-based implants within an artery of a subject that perfuses the target tissue.
  • focal drug delivery also referred to herein as spatially specific drug delivery
  • the systemic application of a drug by not applying the drug directly to the target tissue would expose all organs in a subject to 1,000- 100,000 times more drug than would be necessary.
  • drug exposure without using the spatially specific delivery system disclosed herein may cause severe, lethal side effects, which limits the use and efficacy of medications in treating disease.
  • the implants of the drug delivery devices disclosed herein are biocompatible and bioresorbable, such that they are eliminated from the vascular system after drug elution.
  • the drug-loading polymer used in the devices disclosed herein is compatible with a wide range of drugs, and the implants can be placed in any large or medium-sized arteries, making this technology applicable to a wide diversity of disease processes.
  • the polymer used in the device disclosed herein has high drug loading capacity and/or long yet tunable drug release rates, and therefore can be designed for different treatment concentrations and durations. Some embodiments of these implants may be deployed using standard minimally invasive catheterization.
  • These implants can be active (continuously elute drug) for at least days, weeks, or months, depending on the clinical indication and implant fabrication. Since these implants are completely resorbable, they do not require a second procedure for removal, thereby limiting damage to the implanted vessel.
  • the drug devices disclosed herein are similar to a drug-eluting cardiac stent. Yet, there are two important differences. First, the intra-vascular drug delivery devices (I-VDDDs) have different structural design, composition, fabrication, property, and optimization. Cardiac stents are elongated tubular mesh or coil, to provide structural stability to the damaged vessel. In contrast, some embodiments of the devices disclosed herein have a range of shapes, designed to the specifications of the artery, and are not necessarily tubular as their function is drug release rather than structural stability. In some embodiments, the devices are optimized for drug loading capacity and rate of resorption, according to the treatment requirements of the distal organ.
  • I-VDDDs intra-vascular drug delivery devices
  • the drug on drug-eluting stents is operating on processes within the artery, to prevent thrombosis or restenosis.
  • drug-elution is meant to target the tissue that is perfused by the artery in which the device is placed.
  • I-VDDD may be used to deliver any drug to treat a focal process within organ tissues. Non-limiting examples include delivering steroids directly to the distal colon to treat ulcerative colitis and delivering chemotherapeutics directly to the brain to treat glioblastoma.
  • the drug delivery device is not a drug eluting cardiac stent.
  • a nonlimiting example polymer for drug delivery comprises poly(glycerol sebacate) (PGS), which has been developed previously for focal drug delivery due to its beneficial drug loading and release properties (e.g., Papkov et al., 2007 “Polymer carriers for drug delivery in tissue engineering” Adv Drug Deliver Rev 59(4-5): 187-206; Sun et al., 2009 “The application of poly(glycerol-sebacate) as biodegradable drug carrier” Biomaterials 30(28): 5209-5214; Mourino and Boccaccini 2010 “Bone tissue engineering therapeutics: controlled drug delivery in three-dimensional scaffolds” J.R.
  • PPS poly(glycerol sebacate)
  • a “carrier polymer” is given its standard scientific meaning and refers to a polymer suitable for blending with an agent, such as a drug, for use in some embodiments of the drug delivery devices disclosed herein.
  • a “time-dependent polymer” is given its standard scientific meaning and refers to a polymer that degrades in a time-dependent manner when a drug delivery device is deployed in an artery of a subject.
  • Non-limiting example carrier polymers suitable for use in some embodiments of the drug delivery devices disclosed herein include, but are not limited to, hydrophilic cellulose derivatives (such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose), cellulose acetate phthalate, poly(glycerol sebacate) (PGS), poly(vinyl pyrrolidone), ethylene/vinyl alcohol copolymer, poly(vinyl alcohol), carboxyvinyl polymer (Carbomer), Carbopol® acidic carboxy polymer, polycarbophil, poly(ethyleneoxide) (Polyox WSR), polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycols, chitosan, alginates, pectins, acacia, tragacanth, guar gum, locust bean gum, vinylpyrrolidoneviny
  • starch in particular pregelatinized starch, and starch-based polymers, carbomer, maltodextrins, amylomaltodextrins, dextrans, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane, poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid) (PLGA), polyhydroxyalkanoates, polyhydroxybutyrate, and copolymers, mixtures, blends and combinations thereof.
  • Poly(Glycerol Sebacate) (PGS) and Polycaprolactone (PCL) are preferred carrier polymers.
  • polydioxanone is used as the carrier polymer.
  • the carrier polymer used in the drug delivery device can comprise polycaprolactone, such as linear polycaprolactone with a number-average molecular weight (Mn) range between about 60 kiloDalton (kDa) to about 100 kDa; 75 kDa to 85 kDa; or about 80 kDa; or between about 45 kDa to about 55 kDa; or between about 50 kDa to about 110,000 kDa, or between about 80 kDa to about 110,000 kDa.
  • Mn number-average molecular weight
  • release of the drug by some embodiments of the device can be modulated by a wide variety of excipients included in the carrier polymer-agent component.
  • Soluble excipients include P407, Eudragit E, PEG, Polyvinylpyrrolidone (PVP), and Polyvinyl alcohol (PVA).
  • Insoluble, wicking excipients include Eudragit RS and Eudragit RL.
  • Degradable excipients include PLA, PLGA, PLA-PCL, polydioxanone, and linear copolymers of caprolactone and glycolide; polyaxial block copolymers of glycolide, caprolactone, and trimethylene carbonate; polyaxial block copolymers of glycolide, trimethylene carbonate, and lactide; polyaxial block copolymers of glycolide, trimethylene carbonate and polypropylene succinate; polyaxial block copolymers of caprolactone, lactide, glycolide, and trimethylene carbonate; polyaxial block copolymers of glycolide, trimethylene carbonate, and caprolactone; and linear block copolymers of lactide, caprolactone, and trimethylene carbonate; such as linear copolymers of caprolactone (95%) and glycolide (5%); polyaxial block copolymers of glycolide (68%), caprolactone (29%), and trimethylene carbonate (3%); polyaxial block copolymers of glycolide (86%), trimethylene carbonate
  • Insoluble, swellable excipients include Polyvinyl acetate (PVAc), Crospovidone, Croscarmellose, HPMCAS, and linear block copolymers of dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethyl carbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol; such as linear block copolymers of dioxanone (80%) and ethylene glycol (20%); linear block copolymers of lactide (60%) and ethylene glycol (40%); linear block copolymers of lactide (68%), ethylene glycol (20%), trimethyl carbonate (10%), and caprolactone (2%); linear block copolymers of lactide (88%), glycolide (8%), and ethylene glycol (4%); linear block
  • excipients can be added to the carrier polymers to modulate the release of the agent. Such excipients can be added in amounts from 1% or about 1% to 15% or about 15%, or from 5% or about 5% to 10% or about 10%, or from 5% or about 5% to 10% or about 10%, or of any of the values, approximate values, or ranges of values within any of the foregoing ranges. Examples of such excipients include Poloxamer 407 (available as Kolliphor P407, Sigma Cat #62035), poly(ethylene glycol)-block-poly(propylene glycol)-block- poly(ethylene glycol), CAS No.
  • Preferred soluble excipients include Eudragit E, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl alcohol (PVA).
  • Preferred insoluble excipients include Eudragit RS and Eudragit RL.
  • Preferred insoluble, swellable excipients include crospovidone, croscarmellose, hypromellose acetate succinate (HPMCAS), and carbopol.
  • EUDRAGIT RS and EUDRAGIT RL are registered trademarks of Evonik (Darmstadt, Germany) for copolymers of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups (trimethylammonioethyl methacrylate chloride), having a molar ratio of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate of about 1 :2:0.2 in Eudragit® RL and about 1 :2:0.1 in Eudragit® RS.
  • Preferred insoluble, swellable excipients include crospovidone, croscarmellose, hypromellose acetate succinate (HPMCAS), carbopol, and linear block copolymers of dioxanone and ethylene glycol; linear block copolymers of lactide and ethylene glycol; linear block copolymers of lactide, ethylene glycol, trimethyl carbonate, and caprolactone; linear block copolymers of lactide, glycolide, and ethylene glycol; linear block copolymers of glycolide, polyethylene glycol, and ethylene glycol; such as linear block copolymers of dioxanone (80%) and ethylene glycol (20%); linear block copolymers of lactide (60%) and ethylene glycol (40%); linear block copolymers of lactide (68%), ethylene glycol (20%), trimethyl carbonate (10%), and caprolactone (2%); linear block copolymers of lactide (88%), glycolide (8%), and ethylene
  • one or more elements of a drug delivery device may be coated with a release-rate modulating polymer fdm.
  • one or more arms of a drug delivery device may be coated with a release-rate modulating polymer film.
  • a release-rate modulating polymer film may help reduce an initial burst release of a therapeutic agent or API from the drug delivery device when administered to a patient.
  • a release-rate modulating polymer film may help improve the overall linearity of the therapeutic agent/ API release.
  • a release-rate modulating polymer film may be applied to one or more elements of a drug delivery device using a spin or spray or dip coating process. In particular, the coating components were dissolved in ethyl acetate and spin coating was performed using a Freund- Vector LDCS Hi-Coater Lab Coater.
  • a greater coating weight can provide a thicker diffusion barrier for slower release.
  • the release rate of the therapeutic agent/ API may additionally be tuned by varying the coating porosity, which can be achieved by changing the content of a water-soluble excipient (e.g., copovidone) in the coating.
  • a water-soluble excipient e.g., copovidone
  • the release-rate modulating polymer film may comprise a polymer.
  • suitable polymers may include polyesters that can be used in the drug delivery devices include polyesters with aliphatic groups as their main chains, including polylactones such as polycaprolactone (PCL); polyglycolic acid (PGA); polylactic acid (PLA); poly(lactic-co-glycolic acid) (PLGA); polyhydroxyalkanoates (PHA) such as polyhydroxybutyrate (PHB), polyhydroxy valerate (PHV), and poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV); polyethylene adipate (PEA); polybutylene succinate (PBS); and polyesters with aromatic groups in their main chains, such as polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT), and polyethylene naphthalate (PEN).
  • PCL polycaprolactone
  • PGA polyglycolic acid
  • PLA poly(
  • Heteropolymers including block or random copolymers, such as block or random copolymers incorporating the monomer constituents of the above polyesters, can also be used, including copolymers of lactide and caprolactone (poly-lactide-co-caprolactone; PLC). Mixtures of two or more polyesters can also be used.
  • cellulose acetate (CA), ethyl cellulose (EC), and copolymers of acrylate and methacrylate esters e.g., Eudragit RS
  • release rate-modulating polymer fdms can also be used as release rate-modulating polymer fdms.
  • R1 is selected from the group consisting of C1-C12 alkylene groups, such as C1-C8 alkylene groups or C1-C4 alkylene groups, ethers containing between two and twelve carbon atoms, two and eight carbon atoms or two and four carbon atoms, and polyethers containing between three and twelve carbon atoms or between three and eight carbon atoms.
  • the polyesters can terminate with hydroxy groups, hydrogens, — Cl -Cl 2 alkyl groups, — Cl- C8 alkyl groups, or — C1-C4 alkyl groups, or — C1-C12-0H, — C1-C8-0H, or — C1-C4-0H (alcohol) groups as appropriate.
  • the R1 groups can be the same moiety throughout the polymer to form a homopolymer.
  • the R1 groups can be chosen from two or more different moieties, to form a heteropolymer.
  • the heteropolymer can be a random copolymer, or a block copolymer.
  • the release-rate modulating polymer film may comprise from 1 wt. % or about 1 wt. % to 100 wt. % or about 100 wt. % polymer, or from 30 wt. % or about 30 wt. % to 90 wt. % or about 90 wt. % polymer or of any of the values, approximate values, or ranges of values within any of the foregoing ranges.
  • Both the degradable metal substrate and polymer coating can modulate release rate of drugs, depending on the material and processing design.
  • polymer coating may be 100% polymer or polymer-based composites containing up to 1-99% drugs, nanoparticles, secondary phases, dopants.
  • the release-rate modulating polymer film may comprise less than 90 wt. %, less than 80 wt. %, less than 70 wt. %, less than 60 wt. %, less than 50 wt. %, or less than 40 wt. % polymer. In some examples, the release-rate modulating polymer film may comprise more than 30 wt. %, more than 40 wt. %, more than 50 wt. %, more than 60 wt. %, more than 70 wt. %, or more than 80 wt. % polymer.
  • the release-rate modulating polymer film may comprise one or more excipients.
  • suitable excipients may include porogens, plasticizers, or both porogens and plasticizers to further tune the release rate of the agent in the carrier polymer-agent segment.
  • BMs Biodegradable metals
  • Ms represented by magnesium-, zinc-, and ironbased alloys
  • BMs possess higher mechanical strength and show better performance in some applications.
  • magnesium (Mg) and its alloys have tunable mechanical strength, and proper biodegradability, which can be further regulated by surface coating techniques, they are considered a promising alternative to permanent biomedical materials.
  • Iron (Fe) is an important cofactor in metabolism and is featured as the most abundant transition metal element in the brain.
  • the in vivo safety of Iron stents was initially verified in 2001 by implantation into rabbit's aortas (Peuster M., et al. “A novel approach to temporary stenting: degradable cardiovascular stents produced from corrodible metal — results 6-18 months after implantation into New Zealand white rabbits. Heart. 2001; 86(5): 563-569).
  • Biodegradable iron-based alloys such as iron-manganese alloys may be used.
  • zinc-based alloys such as Zn-Cu alloys
  • their acceptable biodegradability and reasonable biocompatibility have made them a promising BM for both vascular and orthopedic applications.
  • the Zn-Cu stent exhibited an antibacterial effect against S. aureus.
  • tungsten and molybdenum (Mo), nickel (Ni), aluminum (Al), cadmium (Cd), tin (Sn) and neodymium (Nd) and Yttrium (Y).
  • Mo molybdenum
  • Ni nickel
  • Al aluminum
  • Cd cadmium
  • Sn tin
  • Nd neodymium
  • Mg alloys Due to the complexity of cerebrovascular vessels, it is sometimes advantageous to select materials with a higher elastic modulus and better elasticity.
  • the biodegradable behaviors and mechanical properties of Mg alloys are tunable by suitable alloying elements.
  • Metals with low hydrogen overvoltage, including Ni, Fe, and Cu, can cause severe galvanic corrosion of magnesium alloys, while others like Al, Zn, Cd and Sn can induce a much lower corrosion rate.
  • the incorporation of Nd and Zn can improve the mechanical properties of Mg alloys through solid solution strengthening and precipitation strengthening techniques.
  • the drug delivery devices disclosed herein are completely biodegradable, biocompatible, and has mucoadhesive and bioadhesive properties for safety and easy placement in vasculatures.
  • Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface.
  • Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome.
  • Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism.
  • the mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation.
  • bioadhesion implies attachment of a drug carrier system to a specified biological location.
  • the biological surface can be epithelial tissue or the mucus coat on the surface of a tissue. If adhesive attachment is to a mucus coat, the phenomenon is referred to as mucoadhesion.
  • Mucoadhesion may invlove an interaction between a mucin surface and a synthetic or natural polymer. Mucoadhesion should not be confused with bioadhesion.
  • bioadhesion the polymer is attached to the biological membrane and if the substrate is mucus membrane the term mucoadhesion is used.
  • Mucoadhesive polymers have numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfate. These groups attach to mucus or the cell membrane by various interactions such as hydrogen bonding and hydrophobic or electrostatic interactions. These hydrophilic groups also cause polymers to swell in water and, thus, expose the maximum number of adhesive sites.
  • the polymer for a bioadhesive drug delivery system has at least one of the following characteristics:
  • the polymer and its degradation products should be nontoxic and biocompatible.
  • it forms a strong noncovalent bond with a mucus or an epithelial or endothelial cell surface inside a blood vessel.
  • the polymer should not decompose on storage or during the shelf life of a dosage form.
  • the cost of the polymer should not be high so that the prepared dosage form remains competitive.
  • Polymers possessing hydrophilic functional groups that hydrogen bond with similar groups on biological substrates possessing hydrophilic functional groups that hydrogen bond with similar groups on biological substrates.
  • Polymers that bind to specific receptor sites on the cell or mucus surface are Polymers that bind to specific receptor sites on the cell or mucus surface.
  • the latter polymer category includes lectins and thiolated polymers.
  • Lectins are generally defined as proteins or glycoprotein complexes of nonimmune origin that are able to bind sugars selectively in a noncovalent manner. Lectins are capable of attaching themselves to carbohydrates on the mucus or epithelial cell surface and have been extensively studied, notably for drug-targeting applications. These second-generation bioadhesives not only provide for cellular binding, but also for subsequent endo- and transcytosis.
  • Thiolated polymers also designated thiomers, are hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone. Due to these functional groups, various features of polyacrylates and cellulose derivatives were strongly improved.
  • thiol groups in the polymer allows the formation of stable covalent bonds with cysteine-rich subdomains of mucus glycoproteins leading to increased residence time and improved bioavailability.
  • Other advantageous mucoadhesive properties of thiolated polymers include improved tensile strength, rapid swelling, and water uptake behavior.
  • Some embodiments of the drug delivery devices disclosed herein can be optimized according to four criteria: (1) maximize drug storage and elution, (2) minimize disruptions to blood flow, (3) biocompatible for clinical use, and (4) biodegradable with tunable absorption rate when no longer needed.
  • the device has sufficient surface area to store and elute drug at therapeutic concentrations for extended periods of time. To minimize disruptions to blood flow, the device does not need to be shaped like a cardiac stent, which is prone to stenosis and thrombosis due to its elongated mesh network.
  • Some embodiments of the drug delivery devices disclosed herein may have different shapes, including rods or beads that embed within the vascular epithelium, or structures with ring components that embed within the artery lumen.
  • the ring structure may be single or multirings or could be a helical metal coil structure (see Figure 1) for enhanced drug loading and release and enhanced radial strength to hold the device in place without shifting.
  • the device has bioadhesive properties for safety and easy attachment to vascular endothelium; the device can also provide versatile shapes (e.g., C shape, L shape) to stay locally in any vasculatures.
  • Additional design features may be used to achieve temporal specificity. For example, release may be triggered by specific chemical or electrical conditions (as opposed to continuous release). For example, techniques such as compression, spray and dip coating, and encapsulation may be used to incorporate bioactive agents with polymers.
  • polymers may include cellulose derivatives, poly(ethylene glycol) PEG, and poly(N-vinyl pyrrolidone) (Rowe RC, et al. in Handbook of Pharmaceutical Excipients. 5th ed Pharmaceutical Press; American Pharmacists Association; Grayslake, IL: Washington, D.C.: 2005. p. 850).
  • polymer devices can be categorized as diffusion-controlled (monolithic devices), solvent-activated (swelling- or osmotically-controlled devices (Verma RK, et al. “Osmotically controlled oral drug delivery”, Drug Dev. Ind. Pharm. 2000;26(7):695- 708)), chemically controlled (biodegradable), or externally-triggered systems (e.g., pH, temperature) (Langer RS and Peppas NA. “Present and future applications of biomaterials in controlled drug delivery systems”, Biomaterials. 1981; 2(4):201-14).
  • Some polymers provide controlled release of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs (Liechty et al. 2012 “Polymers for Drug Delivery Systems” Annu Rev Chem Biomol Eng. 2010; 1 :149-173).
  • Environmentally-responsive polymers are a class of materials comprised of a large variety of linear and branched (co)polymers or crosslinked polymer networks.
  • a hallmark of responsive polymers is their ability to undergo a dramatic physical or chemical change in response to an external stimulus.
  • Temperature and pH changes are commonly used to trigger behavioral changes, but other stimuli, such as ultrasound, ionic strength, redox potential, electromagnetic radiation, and chemical or biochemical agents, can be used. These stimuli can be subsumed into discrete classifications of physical or chemical nature.
  • Physical stimuli i.e., temperature, ultrasound, light, and magnetic and electrical fields
  • Chemical stimuli i.e., pH, redox potential, ionic strength, and chemical agents
  • Chemical stimuli induce a response by altering molecular interactions between polymer and solvent (adjusting hydrophobic/hydrophilic balance) or between polymer chains (influencing crosslink or backbone integrity, proclivity for hydrophobic association, or electrostatic repulsion).
  • Types of behavioral change can include transitions in solubility, hydrophilic-hydrophobic balance, and conformation. These changes are manifested in many ways, such as the coil-globule transition of polymer chains, swelling/deswelling of covalently crosslinked hydrogels, sol-gel transition of physically crosslinked hydrogels, and selfassembly of amphiphilic polymers.
  • Many responsive polymers for drug delivery can be broadly categorized as hydrogels, micelles, polyplexes, or polymer-drug conjugates. Fabrication
  • the drug delivery device is fully absorbable, so that it is eliminated from the vasculature after extended drug delivery.
  • a ring or coil spring structure may be made of (1) biodegradable metals that provide strength to stay in place after deployment, and (2) drug-loaded biodegradable nanocomposites that control the drug release profiles and degradation/ab sorption timeline.
  • the drug release profiles can be controlled from short-term such as hours to days to long-term such as weeks/months/years by modifying material design, chemistry, synthesis, processing and fabrication factors (Liu H and Webster TJ. Ceramic/Polymer Nanocomposites with Tunable Drug Delivery Capability at Specific Disease Sites. Journal of Biomedical Materials Research. 93(3): 1180-1192, 2010).
  • Some devices consist of drug loaded polymer of glycerol and sebacic - poly(glycerol)sebacate) (PGS), coated onto biodegradable magnesium orZn or Mn, Mg-Zn or Mg-Mn, Zn-Mn alloy substrates, with or without addition of Ca and/or Li.
  • PGS is synthesized by polycondensation of glycerol and sebacic acid, both of which are degraded in the body without precipitating an aggravated immune response.
  • PGS is used due to its unique amalgamation of features that make it ideal for sustained intra-vascular drug elution: 1) high drug-loading capacity, 2) comparatively slow rates of degradation with complete resorption, 3) high biocompatibility, 4) compatible with storage and elution of a wide variety of drugs, and (5) degradation mode by surface erosion rather than bulk erosion.
  • drug-loading amounts and release/degradation rates are tunable during device fabrication, allowing for this technology platform to be used for diverse clinical applications that require different therapeutic drugs, drug levels, and treatment durations.
  • an I-VDDD as disclosed herein, with the appropriate drug identity, quantity, and elution rate, can be deployed to the feeding artery/vessel using standard catheterization techniques.
  • the intravascular drug delivery devices disclosed herein have numerous clinical applications, including the following non-limiting examples: Inflammation: anti-inflammatory drug in feeding vessel.
  • Example 2 muscimol in the anterior cerebral artery for frontal lobe epilepsy Stroke: drug to dissolve clots in cerebral vessel.
  • Psychiatric disorders neuromodulators in cerebral vessels.
  • Tumors/Cancer chemotherapeutics, angiogenesis inhibitors or radioactive agents in feeding vessel. a.
  • Example 1 cisplatin in the hepatic artery for hepatocellular carcinoma b.
  • Example 2 Avastin in the renal artery for renal cell carcinoma Pain: anesthetic drugs in feeding vessel.
  • a. Example: fentanyl in the posterior spinal artery for chronic back pain
  • Pulmonary embolism anti-clotting drugs in feeding vessel.
  • a. Example: coumadin in the pulmonary trunk for pulmonary embolism
  • Focal hypertension PDE5 inhibitor in feeding vessel.
  • sildenafd in the pudendal artery for erectile dysfunction b.
  • IADD Intra-arterial drug delivery
  • focal drug delivery systems represents a significant advancement in treating diseases localized to specific tissues or organs. Compared with conventional methods, such as intravenous (IV) and oral administration, these systems allow for precise medication delivery directly to the targeted area while reducing systemic exposure and off-target side effects.
  • IV intravenous
  • Several delivery techniques have been proven to achieve focal drug delivery, including intra-arterial injectables, pumps, and implants. However, despite these advancements, we still lack a platform technology for focal drug delivery across multiple clinical targets.
  • IADD devices which could be implanted into large- or middle-sized arteries to deliver drugs directly to the downstream organ.
  • IADD devices can be delivered endovascularly, offering a less invasive option while still achieving high local drug concentrations in the targeted downstream organ. This is critical for enhancing therapeutic efficacy locally, particularly when systemic toxicity limits the tolerable drug dose.
  • this method allows for enhanced pharmacokinetic control, enabling the regulation of infusion rates and drug concentrations within the target region - something more challenging to achieve with systemic administration.
  • Mg magnesium
  • PGS poly(glycerol sebacate)
  • Mg itself may improve intraarterial drug delivery, as previous studies of Mg in vascular stents have shown that the released Mg2+ enhances blood flow, inhibits platelet activation, and prevents vasoconstriction. Mg is fully bioresorbable, excreted through urine and feces as Mg2+ ions.
  • PGS has gained prominence in tissue engineering and drug delivery due to its customizable and straightforward synthesis process. PGS degrades via surface erosion in the body fluids, which affords stable drug release compared with polymers that degrade via bulk erosion such as poly-lactic acid (PLA) and poly-glycolic acid (PGA).
  • PPA poly-lactic acid
  • PGA poly-glycolic acid
  • the degradation products, glycerol and sebacic acid are biocompatible and are naturally found and metabolized in the human body.
  • the synthesis conditions of PGS can be fine-tuned to control the degree of esterification, allowing for precise tailoring of the chemical and mechanical properties of the synthesized polymer as well as its degradation behavior.
  • PGS is nonimmunogenic and has shown to be non-cytotoxic, causing minimal inflammatory response.
  • the mechanical properties of PGS which are similar to blood vessels, can minimize the mechanical mismatch between the IADD device and arteries. These characteristics make the IADD devices conducive for sustained intra-arterial drug delivery.
  • DEX dexamethasone
  • C22H29FO5 cisplatin
  • CIS cisplatin
  • CIS cisplatin
  • CIS cisplatin
  • NH32C12 cisplatin
  • Figures 19D and 19E Both are acknowledged not only for their effectiveness, but also for their high systemic toxicity.
  • DEX a synthetic corticosteroid, is used to treat inflammatory and autoimmune diseases, allergic reactions, respiratory issues, endocrine disorders, and certain cancers. However, its use is restricted due to side effects including metabolic disorders such as obesity and insulin resistance, hypertension, and susceptibility to infections.
  • CIS a chemotherapeutic agent
  • CIS a chemotherapeutic agent
  • its clinical application is limited by nephrotoxicity and other severe toxicities.
  • IADD devices could enhance target organ drug levels and reduce systemic exposure, thereby increasing drug efficacy and minimizing harmful off-target side effects.
  • IADD devices are also disclosed herein.
  • the in vivo efficacy of lADD-mediated focal drug delivery was monitored with two different organs having vastly different vascular permeabilities (the kidney and the brain). These studies demonstrate the efficacy of these novel IADD devices and provide a framework for the future development of the devices as a platform technology for intra-arterial drug delivery.
  • various other drug classes can be integrated into IADD devices to broaden their therapeutic applications.
  • IADD devices can be particularly effective for managing focal diseases such as localized cancers, neurological disorders such as epilepsy and Parkinson’s disease, and chronic inflammatory conditions such as inflammatory bowel disease.
  • focal diseases such as localized cancers, neurological disorders such as epilepsy and Parkinson’s disease
  • chronic inflammatory conditions such as inflammatory bowel disease.
  • IADD devices can pave the way for more effective therapeutic strategies.
  • Example 1 Non-Limiting Example Advantages of the Platform
  • a major advantage of this platform is that fewer side effects are predicted, due to reduced systemic drug exposure and/or the ability to deliver much higher drug concentrations to the targeted tissue than previously possible due to systemic toxicity.
  • in vivo data Figures 3, 23 and 24
  • LVDDD will allow for drug delivery to targeted tissues at approximately 20-50- fold greater concentrations than systemic exposure. For most existing drugs, this would effectively eliminate side effects of off-target drug exposure.
  • focal drug delivery through the disclosed devices may be sustained for long treatment durations.
  • the intra-vascular drug delivery devices (I- VDDDs) disclosed herein increase the effectiveness of drug treatments while reducing side effects. The devices provide continuous drug release over weeks to months, reducing medical non-compliance. Table 1
  • a prototype drug delivery system was developed with different structural designs, while parameterizing drug loading and drug release rates, resulting in a family of devices that can be used for different clinical applications. These devices may be loaded with a variety of drugs, demonstrating the generalization of the desired approach to multiple drug candidates.
  • Example clinical applications include delivering steroids to the renal artery for nephritis, chemotherapy to the middle cerebral artery for glioblastoma, coumadin in the pulmonary trunk for pulmonary embolism.
  • the device is designed to have 1) sustained and controlled drug release, 2) drug delivery directly to the target organ thereby limiting systemic drug levels, 3) be compatible with a wide variety of drugs, and 4) be biocompatible and biodegradable, such that the implants are eliminated from the vasculature after extended drug delivery.
  • Example 3 In vitro and in vivo validation
  • the prototype device was shown to release therapeutic drug levels (anti-inflammatory drug dexamethasone, DEX, and chemotherapeutic drug cisplatin, CIS, Figures 20A,B) for at least 30 days in vitro. Additionally, through implantation in the rat renal artery, usage of the device resulted in ⁇ 40-fold increased drug concentrations in the targeted kidney versus the systemic (venous) blood. Data from the in vivo implants demonstrate a >20-fold reduction of drug levels in the venous blood versus the target organ compared to oral drug delivery. For most drug treatments, a 20-fold reduction in blood levels would effectively eliminate off-target side effects. These data provide strong evidence that at least some embodiments of the drug delivery devices disclosed herein can achieve focal drug delivery over extended durations, potentially eliminating off-target side effects for many drug treatments.
  • therapeutic drug levels anti-inflammatory drug dexamethasone, DEX, and chemotherapeutic drug cisplatin, CIS, Figures 20A,B
  • Example 4 In vivo focal drug delivery
  • any artery that supplies specific tissues or organs may be utilized for placement of the drug delivery device.
  • some embodiments of the drug delivery devices disclosed herein can be used to deliver a drug to the kidney through the renal artery.
  • the device can be used to deliver a drug to the brain through the carotid artery.
  • Example 5 In vivo pre-clinical disease model testing
  • the results of the present disclosure provide a basis for drug delivery and function within a targeted organ.
  • the medical device may be placed within the left renal artery of an animal given an immunological challenge known to cause acute renal inflammation. Drug delivery by the device is expected to provide significant reduced inflammation in the targeted (left) kidney compared to the untargeted (right) kidney. Such studies would demonstrate efficacy of the drug delivery device within the targeted organ.
  • Example 6 In Vivo and /» Vitro Drug Release Profiling Studies of Metal/Polymer-composite Drug Delivery Devices
  • Elastic biopolymers hold many applications in regenerative medicine such as structural scaffolds or in this project, drug delivery, while maintaining biocompatibility.
  • the synthesis of the polymer disclosed herein involves a condensation that forms an esterified prepolymer. Once purified, the esterified prepolymers are then cured (i.e. the prepolymers cross link to form the full polymers). The time and temperatures for the curing of the prepolymers affect the mechanical properties of the final product.
  • a Magnesium (Mg)-polymer-based drug delivery device was fabricated using a metal wire as the base and polymer coating (Figure 5). The process for generating the polymer is as shown in Figure 4A, and was synthesized in a 12-well plate as shown in Figure 6.
  • the device was also tested for effectiveness using a drug release profiling study and an in vitro SRB assay following the experimental procedures as outlined in Figure 4B-4C.
  • Biodegradable metals and polymers have been widely used for medical implants due to their biocompatibility and biodegradability.
  • Polymer coatings are utilized to shield bioresorbable metals from rapid degradation, alter device properties, and attain specific functionalities.
  • Bioresorbable metal-based electrodes coated with biodegradable polymers can be used for neural recording ( Figures 11-13), and for targeted drug delivery ( Figures 14-18).
  • Bioabsorbable metal-based devices coated with polymer showed the ability to encapsulate Cisplatin and sustain its release continuously for a minimum of 30 days. The device demonstrated a clear advantage in achieving local drug delivery, as evidenced by the preliminary experimental results in vitro and in vivo. Polymer coated bioresorbable metals showed potential for neural applications.
  • IADD Intra-arterial drug delivery
  • PGS poly(glycerol sebacate)
  • Mg magnesium
  • the IADD devices are loaded with dexamethasone (DEX) or cisplatin (CIS) as two model drugs to provide sustained drug release for in vitro and in vivo evaluation.
  • DEX dexamethasone
  • CIS cisplatin
  • IADD devices were fabricated and characterized using various analytical techniques, such as scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). These analyses confirmed the successful incorporation and stability of the drugs within the device.
  • SEM scanning electron microscopy
  • EDS energy-dispersive X-ray spectroscopy
  • TGA thermogravimetric analysis
  • FTIR Fourier-transform infrared spectroscopy
  • CIS-loaded IADD devices provided substantial growth inhibition of glioma cells, thereby demonstrating sustained pharmacological activity throughout the release period.
  • Devices implanted into the renal artery to target the kidney achieved 28-fold improvement in normalized organ drug levels (NODE) compared to oral drug administration.
  • Devices implanted into the carotid artery to target the brain achieved 68-fold improvements in NODE compared to oral drug administration.
  • NODE normalized organ drug levels
  • the IADD devices with two distinct structural designs were fabricated as the first-generation prototypes for studying drug release and cell response in vitro and in vivo.
  • the IADD devices with cylindrical shape were used for physical and chemical characterizations, in vitro drug release, cell studies, and in vivo delivery to the brain.
  • the IADD devices with helical shapes were used for in vivo delivery to the kidney.
  • Magnesium wire (Sigma- Aldrich, 127 pm diameter) was cut into 4 mm segments. The segments were ultrasonically cleaned first in acetone and then in ethanol.
  • the synthesis procedure of PGS prepolymers was as follows: 60.67 g sebacic acid (ThermoScientific Chemicals, 98+% purity) was mixed with 27.62 g glycerol (Fisher Chemical, 99.5+% purity). The mixture with a stir bar was heated at 120 °C under nitrogen atmosphere using a Heidolph MR Hei-Tec Digital Hot Plate Stirrer for 2 h to melt the sebacic acid. Subsequently, the mixture was heated at 120 °C and 300rpm stirring under protective nitrogen gas for 24 h, then under vacuum at 120°C and 300rpm for 42 h to synthesize PGS prepolymers.
  • the prepolymer was slowly poured into 250 mL of Millipore water (4°C) to remove remaining glycerol. After mixing with a stir bar for 5 min, water was removed, and the process was repeated 3 times. Any remaining water was removed by freeze drying at -40°C in vacuum (Labconco Freezone) for 48 h and the prepolymer was stored at -20°C. The viscosity of the prepolymer was measured using a rheometer (Anton Paar, MCR92) from 0°C to 120°C. After heating up to 70°C, 2 g of the synthesized prepolymer was poured into an 82 mm x 36 mm Teflon mold to form a ⁇ 600 pm thick uniform layer.
  • the clean Mg segments were then submerged in the prepolymer layer.
  • the mold with samples was cured in a vacuum oven (Across International, AT32) at 120°C for 120 h.
  • Each device was then cut to 400 pm x 250 pm x 4200 pm using a blade under an optical microscope, ensuring one Mg wire remained at the center of each device.
  • the devices were 1000 pm diameter x 4000 pm length, fabricated using the clean Mg wire with a diameter of 127 pm and length of 25mm and a steel rod with a diameter of 650 pm and length of 20mm as the mandrel.
  • the design modification with the helical structure was designed to increase the drug-loading capacity and provided larger surface area for drug release.
  • the Mg wires were twined around a 650 pm diameter stainless steel rod to form a 3800 pm helix with uniform gaps. After removing the steel rod, the Mg helical coil was put into a Teflon mold with a diameter of 1000 pm and a depth of 5000 pm.
  • a stainless-steel rod with a diameter of 400 pm was placed in the center to retain the hollow tubular structure for blood flow once implanted in an artery.
  • the mold with samples was cured in a vacuum oven (Across International, AT32) at 120 °C for 120 h and the devices were cut to 4000 pm length after removing the steel rod.
  • the IADD devices were soaked in 100% ethanol for 24 h to remove residual sebacic acid from the PGS.
  • DEX Thermoscientific, 98%) was dissolved in ethanol at 10 mg/mL for drug loading and CIS (TCI, 98%) was dissolved in N,N- Dimethylformamide (DMF, Fisher Chemical) at 15 mg/mL concentration. The devices were incubated in the drug solution for 48 h.
  • Devices fabricated in the same batch were incubated in 100% ethanol (ethanol-IADD control) or DMF (DMF-IADD control) with no drug were used as IADD control devices.
  • the drug-loaded devices were dried at 50°C for 2 h in a vacuum oven (Across International, AT32) to remove solvent. The devices were then sterilized with UV for 30 min before use.
  • Example 10 Characterize Microstructures and Surface Elemental Compositions of Drug- loaded IADD Devices and Controls
  • the morphology of the devices was first examined using a 3D laser scanning microscope (Keyence VK-X150). Then scanning electron microscopy (SEM) was used to analyze the surface microstructure and the cross-sections of the drug-loaded IADD devices and non-drug-loaded controls. The devices were sputter-coated with a conductive layer of gold at 20 mA for 30 s (Sputter Model 108, Cressington Scientific Instruments Ltd., Watford, UK).
  • the cross-section morphology was examined using a SEM (Nova NanoSEM 450, FEI Co., Hillsboro, OR, USA) equipped with an X-Max50 detector and AZtecEnergy software (Oxford Instruments, Abingdon, Oxfordshire, UK). Energy-dispersive X-ray spectroscopy (EDS) was utilized to analyze the elemental compositions of the drug-loaded IADD devices and controls. An accelerating voltage of 15 kV was used for SEM scanning and EDS analysis.
  • Example 11 Thermogravimetric analysis of Drug-loaded IADD Devices and Controls
  • TGA Thermogravimetric analysis
  • TG 209 Fl Libra Netzsch
  • PGS was cured in the same process as for the devices.
  • 10 mm x 10 mm x 0.6 mm dimension and mass of 66 mg blocks were cut out and loaded with DEX and CIS in the same method as described in Example 9.
  • 10 mg of each sample was cut out from the block and loaded into alumina crucibles and heated from 200°C to 800°C at a heating rate of 10°C/min in an air flow rate of 20 mL/min.
  • DEX and CIS standard samples were analyzed in parallel.
  • FTIR-ATR Fourier-transform infrared spectroscopy-attenuated total reflectance
  • Example 13 Determine Drug and Mg Ions Release Profiles of Drug-loaded IADD Devices and Controls
  • rSBF revised-simulated body fluid
  • aCSF artificial cerebrospinal fluid
  • the compositions of the fluids were obtained from previous studies.
  • the plates were kept on a rotary shaker (Benchmark Incu-shaker Mini) at 37 °C and 120 rpm. Media samples were collected by complete media replacement (1 mL) every 24 h for 30 days.
  • the mobile phases were (A) water with 0.1% formic acid and (B) acetonitrile with 0.1% formic acid.
  • the flow rate was 400 pL/min, and the column was held at 40 °C.
  • the data acquisition utilized an injection volume of 5 pL.
  • the gradient was as follows: 0 min, 0% B; 1 .5 min, 0% B; 2.5 min, 95% B; 4.5 min, 95% B; 4.75 min, 0% B; 6.25 min, 0% B.
  • Target compound responses were normalized against the deuterated internal standard, and amounts were calculated using a standard curve.
  • the LC-MS data were acquired in positive electrospray ionization (ESI+) mode for a mass range from m/z 50 to 1000 with a scan time of 0.05 s.
  • the ESI mass spectra were acquired in positive mode using a capillary voltage of 1.5 kV and source temperature of 150°C. Desolvation was achieved by directing nitrogen at 600°C, 1000 L/h.
  • TOF MS/MS channels were developed in the method. These channels were utilized for identification and data analysis using unique fragment ions.
  • the CIS in the salt solutions was analyzed. Briefly, 5 pl of palladium acetate was added to 50 pl of collected physiological salt solution (PSS; rSBF or aCSF) followed by 15 pl of 1% v/v diethyldithiocarbamate (DTCC) in 0.1N NaOH solution. The mixture was vortexed followed by incubation at 40°C for 30 min in a water bath. Following incubation, 1.5 ml of acetonitrile containing 1 ng/ml of 8-Cyclopentyl-l,3-dipropylxanthine (DPCPX) (internal standard) was added to each tube.
  • PSS collected physiological salt solution
  • DTCC diethyldithiocarbamate
  • the samples were vortexed for 10 min and then centrifuged at 4000 rpm and the contents were dried under air.
  • the dried samples were reconstituted with 80:20:0.1% water: acetonitrile: formic acid and loaded onto a Waters FI- class UPLC coupled to G2-XS Q-TOF mass spectrometer (Waters Corporation, Milford, MA, USA) for the analysis.
  • the mobile phases were (A) water with 0.1% formic acid and (B) acetonitrile with 0.1% formic acid.
  • the flow rate was 350 pL/min, and the column was held at 25°C.
  • the data acquisition utilized an injection volume of 1 pL.
  • the gradient was as follows: 0 min, 1% B, 0.5 min, 1% B, 1 min, 75% B, 1.5 min, 90% B, 2.5 min, 99% B, 6 min, 99% B, 8 min, 1% B and 10 min, 1% B.
  • the samples were normalized against the internal standard and the amount of CIS was calculated using the standard curve.
  • the LC-MS data were acquired in positive electrospray ionization (ESI+) mode for a mass range from m/z 50 to 800 with a scan time of 0.3 s.
  • Mg 2+ ion concentration was measured using inductively coupled plasma optical emission spectrometry (ICP-OES; Optima 8000, PerkinElmer, Waltham, MA) to study Mg 2+ release from the devices. Specifically, 30 pL of solution from each sample was diluted with Millipore water to 3 mL and the diluted solution was analyzed using ICP-OES. The final results were calculated by multiplying with the dilution factor (lOOx).
  • ICP-OES inductively coupled plasma optical emission spectrometry
  • HUVEC Human umbilical vein endothelial cells
  • DEX-loaded IADD devices were prepared as described in Example 9.
  • the control cell wells were only exposed to the inserts without any devices.
  • Sulforhodamine B (SRB) assay was used to assess cell viability.
  • the cells in each well were fixed with 1 mL of ice-cold trichloroacetic acid (10% w/v) and incubated at 4 °C for 1 h. Then the plates were washed with water and air-dried. SRB solution (0.057% w/v, 2 mL) was added to each well and incubated for 30 min, followed by washing with 1% v/v acetic acid. The wells were dried, and 3 mL of 10 mM TRIS base (pH 10.5) was added to each well. Absorbance was measured at 510 nm using a microplate reader. Percentage cell viability and percentage growth inhibition were calculated as follows:
  • Equation (1) (mean ODsampie/ mean ODcontroi) x 100
  • F98 glioma cells (CRL-2397, ATCC) were used to assess the anti-cancer activity of CIS released from the CIS-loaded IADD devices using SRB assay.
  • F98 rat glioma cells were cultured in Dulbecco's Modified Eagle Medium (DMEM, Sigma-Aldrich) with 10% Fetal Bovine Serum (FBS, Gibco) and 1% Penicillin-Streptomycin (P/S, Corning) solution. The cells were seeded into a 96-well plate at a density of 5,000 cells/cm 2 .
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • P/S Penicillin-Streptomycin
  • the cells were cultured in of 150 pL culture media and after 24h, at approximately 50% confluency, 50 pL of CIS-containing solution collected from the drug release study in PSS (as described in Example 13) was added to each test well.
  • the PSS collected from non-drug-loaded IADD devices were used as controls.
  • the media from each well was collected, and 30 pL of media from each sample was diluted (1 :100) with Millipore water to 3 mL for ICP-OES analysis of Mg 2 and Ca 2+ concentrations.
  • the cells were stained using the same method mentioned in Example 14. The experiment was performed in triplicate, and results are reported as Mean ⁇ SD. Percentage growth inhibition was calculated as follows:
  • Equation (4)'. % growth inhibition 100-% of cell growth.
  • the Kidney-IADD group had DEX-loaded IADD devices surgically implanted in the left renal artery and Kidney-Control group received DEX (1 mg/mL) in drinking water.
  • Vessels were separated from connective tissue and fat using blunt dissecting curved forceps and wet cotton swabs.
  • the aorta was clamped above and below the renal artery bifurcation with microvascular clips.
  • both ends of the left renal artery were temporarily occluded using silk suture knot.
  • a 1 mm incision was made on the occluded renal artery, a sterile device was inserted, and the incision was closed with tissue adhesive.
  • the knot was opened first from the lateral, followed by the medial end. Clamps were released to allow kidney reperfusion, ensuring that the arterial occlusion did not exceed 15-20 min. The area was checked for active bleeding and observed for an additional 10-15 min.
  • the abdominal wall was closed in two layers with 4-0 absorbable sutures using a simple continuous pattern for the muscle and a simple interrupted pattern for the skin.
  • Topical ointment was applied to the suture site, and the animal was returned to its cage on a heating pad until fully recovered.
  • the total surgery time ranged from 30 to 45 min.
  • the internal diameter of the rat’s renal artery was approximately 1.1 mm with a cross-sectional area of 0.95 mm 2 .
  • the diameter of the helical device was approximately 1 mm with a cross-sectional area of approximately 0.79 mm 2 and a lumen diameter of 0.4 mm.
  • Post-surgery animals received meloxicam (2 mg/kg s.c.) every 24 h for 72 h.
  • Blood collection for serum drug level estimation was performed via retro-orbital puncture on day 7 under anesthesia with isoflurane.
  • the serum was separated by centrifugation (6000 rpm, 10 min, 4 °C).
  • the animals were sacrificed using pentobarbital and phenytoin cocktail (Euthasol) (200 mg/kg) and the left and right kidneys were isolated, homogenized in ice-cold phosphate buffer (10% w/v), centrifuged (10000 rpm, 10 min, 4 °C), and the supernatants were collected for DEX quantification using LC-MS/MS as described previously.
  • the Brain-Control group received DEX (5 mg/mL) in drinking water
  • the Brain-IADD group had DEX-loaded IADD devices surgically implanted in the right carotid artery.
  • the rats were transferred to a controlled heating pad, where inhalational isoflurane was maintained at 1% in 1 L/min O 2 , and veterinary ophthalmic lubricant (Paralube) was applied to their eyes.
  • veterinary ophthalmic lubricant (Paralube) was applied to their eyes.
  • a pre-operative subcutaneous injection of 10 mL/kg normal saline was given before placing the animal in a supine position with its limbs fixed to the surface using low-tack adhesive, ensuring the upper extremities remained in a normal position to prevent lung compression.
  • the hair over the incision site was shaved with a sterile razor blade, and the skin was cleaned with chlorhexidine followed by povidone-iodine solution. The site was then infused with bupivacaine.
  • an incision was made on the neck to expose the common carotid artery by dissecting the submandibular glands and sternohyoid muscles. The artery was occluded using vascular clamps. A 1mm incision was made on the artery, a sterile device was inserted, and the incision was closed using tissue adhesive.
  • the carotid artery was occluded for approximately 15 mins.
  • the device adhered to the wall of the artery owing to its property of tissue adhesion.
  • the skin incision was closed using simple interrupted sutures.
  • a topical ointment was applied to the suture site, and the animal was returned to its cage on a heating pad until fully recovered.
  • the total surgery time, from incision to suture, was approximately 30-45 min.
  • the internal diameter of the rat’s carotid artery was approximately 1.1 mm with a cross-sectional area of 0.95 mm 2 .
  • the dimensions of the oval devices were approximately 0.4 mm x 0.25 mm with a cross-sectional area of 0.08 mm 2 .
  • the ratio of carotid artery cross-sectional area: device was 11.88: 1.
  • Postsurgery the animals received meloxicam (2 mg/kg s.c.) every 12-24 h for 72 h.
  • Blood collection for serum drug level estimation was performed via retro-orbital puncture on day 7 under isoflurane anesthesia. The serum was separated by centrifugation (6000 rpm, 10 min, 4 °C).
  • NODL normalized organ drug levels
  • NODL ([Organ DEX] device/[Serum DEX]device) / ([Organ DEX] ora i/[ Serum DEX] oral)
  • Figures 19A-19M disclose non-limiting example results for drug-loaded IADD devices and non-drug-loaded controls.
  • Figure 19A shows the viscosity of pre-PGS from 0°C to 120°C. The viscosity of the pre-PGS is lower than that in literature, which is expected due to the reduced synthesis time used, to facilitate uniform PGS coating onto Mg substrates during device fabrication.
  • Figures 19B-19C show the micrograph images of IADD devices. A uniform PGS coating layer is observed covering the Mg wire core.
  • the gaps between the coils are filled with PGS, achieving a tubular morphology.
  • the Mg wire is in the middle of the device and there is a uniform layer of PGS around it.
  • Figure 19F is an SEM image of a drug-loaded IADD device along with elemental compositions (Figure 19G) of the drug loaded PGS section of the IADD device.
  • the SEM image confirms the cross-section morphology of the IADD devices, with the Mg wire embedded in the middle of PGS.
  • the PGS section of the devices are primarily composed of carbon (74 At%) and oxygen (25 At%).
  • the presence of Fluorine (F,0.6 At%) in DEX-loaded IADD device confirms the incorporation of DEX (structure as shown in Figure 19D).
  • the presence of platinum (Pt, 0.1 At%) and chlorine (Cl, 0.2 At%) in the CIS-loaded IADD devices confirms the incorporation of CIS.
  • the ratio of Pt and Cl was found to be 1 :2 which further confirms the presence of CIS which has one Pt and two Cl in each molecule ( Figure 19E).
  • FIG. 1(H) illustrates the heat decomposition curves of drug-loaded IADD devices, IADD device controls, DEX, and CIS.
  • PGS started to decompose at 394 °C and decomposed completely at 504 °C. No solid decomposition product was observed.
  • DEX-only sample started decomposition at 285 °C and decomposed almost completely at 495 °C with less than 2% solid decomposition remaining, which might be carbon black caused by incomplete combustion.
  • CIS-only sample started decomposition at 315 °C and continued to decompose to 364 °C with approximately 65% mass remaining due to Pt after heat decomposition.
  • FIG. 191 shows the FTIR-ATR results.
  • the FTIR-ATR spectra of drug-loaded IADD devices and IADD controls are similar and comparable with the FTIR-ATR results of PGS from literature. Additionally, the CIS-loaded IADD devices yielded a minor peak at -3300 Hz which is also present in the CIS spectrum. This peak corresponds to N-H stretching, and further confirms the presence of CIS in the CIS-loaded IADD devices.
  • the FTIR-ATR spectra of DEX-loaded IADD devices and IADD controls are similar, and no significant difference were observed, due to the low amount of drug relative to the PGS matrix and overlap of peaks between IADD controls and DEX.
  • Example 19 Sustained Release of Drugs from DEX-Loaded and CIS-Loaded IADD Devices and the Device Degradation In vitro
  • Figures 20A-20B and 20E-20F show the amount of absolute and cumulative DEX and CIS released from DEX-loaded and CIS-loaded IADD devices over 30 days (with complete media replacement each day), respectively.
  • DEX-loaded IADD devices exhibited a burst release on day 1 and daily variations up to day 15, releasing a cumulative 373.11 ⁇ 1.41 pg of DEX over the 30 days.
  • CIS-loaded IADD devices showed a stable release profde over 30 days, releasing 64.73 ⁇ 0.06 pg of CIS without an initial burst. After day 15, release of both DEX and CIS stabilized between 1-3 pg/day.
  • Mg 2+ ion concentrations were measured in the release media to assess for device degradation. As shown in Figures 20C-20D and 20G-20H, Mg 2+ ion concentrations were relatively stable over the 30 days, without burst release that would have been suggestive of abrupt degradation.
  • the rSBF with DEX-loaded IADD devices and controls showed a stable Mg 2+ concentration during the first 23 days, with Mg 2+ concentrations similar to rSBF controls, which was 36 mg/L (1.5 mM). The variation became larger after day 24 but the maximal concentration remained under 45 mg/L (1 .87 mM).
  • aCSF with CIS-loaded IADD devices and controls showed a stable concentration around 32 mg/L (1.33 mM), similar to the Mg 2+ concentrations in aCSF controls, which was 31.2 mg/L (1.3 mM).
  • the results demonstrate that the PGS layer effectively protects Mg in maintaining the device’s structural integrity during 30-day extended drug release when interfaced with media that simulates in vivo conditions.
  • FIG. 21 A-21B and 21 D-2 IE present the ICso curves of both the drugs and drugloading solvents. Drugs and solvents (ethanol and DMF) showed poor cytocompatibility (high growth inhibition) at high concentrations. However, these were higher than the drug or solvent concentrations expected to be released from the drug-loaded IADD devices.
  • Figure 21C presents cell viability data from HUVEC growth in the presence of the release media.
  • Example 21 CIS-loaded IADD Devices Inhibited Growth of Glioma Cells
  • Mg 2+ and Ca 2+ levels were measured in the culture media, as an index of cell metabolism (Figure 22D). Mg 2+ and Ca 2+ concentrations were stable across the 30-day media samples, at levels similar to 19.2 mg/L (0.8 mM) and 72 mg/L (1.8 mM) in the media control group, respectively. This data suggests that the release media from CIS-loaded IADD devices did not significantly affect the metabolism of Mg 2+ and Ca 2+ ions in F98 cells.
  • Example 22 In vivo Drug Targeting from DEX-loaded IADD Devices and Controls in Rats
  • the efficacy of IADD was tested for in vivo focal drug delivery in a rat model. It was sought to determine 1) whether focal delivery could be acheived (higher drug concentration in the target organ than in the systemic circulation) and 2) whether therapeutic drug levels in the target organ could be acheived.
  • DEX-loaded IADD devices were implanted in the left renal artery, upstream of the left kidney. In a separate set of animals, the devices were implanted in the right carotid artery, upstream of the brain.
  • the comparison group was DEX administered through drinking water (1 mg/mL and 5 mg/mL) ( Figure 23 A, Figure 24A), which in the literature is well-tolerated in the short term yet sufficient to induce adrenal suppression.
  • DEX levels in the brain from the IADD group were 20- fold higher than DEX levels in the brain from the oral administration group. These results replicate the key findings from the renal artery implant studies, demonstrating both focal and therapeutic drug delivery from the IADD devices.
  • NODL Normalized Organ Drug Levels
  • Example 23 Physicochemical Properties of Drugs Suitable for IADD devices
  • the IADD devices are versatile for incorporation of a wide range of therapeutic agents and can be tailored to address diverse disease processes.
  • one consideration is compatibility with the poly (glycerol sebacate) (PGS) matrix and magnesium (Mg) backbone.
  • PGS poly (glycerol sebacate)
  • Mg magnesium
  • drugs with at least moderate solubility in the solvents used during fabrication such as ethanol or N, N-Dimethylformamide (DMF)
  • DMF N, N-Dimethylformamide
  • Other considerations include the chemical stability of the drug during the fabrication and sterilization processes, as well as potential interactions with PGS and Mg that could affect drug efficacy or release kinetics.
  • drugs chosen for IADD should exhibit absorption and distribution profiles that favor localized action.
  • drug candidates that have low therapeutic dosage range and high systemic side-effects would benefit from the delivery approach via the IADD device.
  • the physicochemical properties of the drug such as molecular weight, lipophilicity, and charge — play crucial roles in determining the mechanism and rate of release from the PGS matrix.
  • Hydrophobic drugs may benefit from the hydrophobic nature of PGS, enabling sustained release, whereas hydrophilic agents might require modifications to the polymer matrix or the incorporation of encapsulating carriers to achieve desired release profiles.
  • the biodegradation rate of PGS should align with the therapeutic window of the drug to ensure consistent and controlled delivery over the intended treatment period.
  • the atomic percentage of fluorine in DEX-loaded IADD devices can be used to calculate DEX content in the IADD devices since all fluorine can be attributed to DEX.
  • the platinum and chlorine content in CIS-loaded IADD devices can be all attributed to CIS and used to calculate CIS amount.
  • To calculate the drug loading using the EDS data it is assumed (1) the mass of hydrogen is negligible; (2) the EDS data collected from the device cross-section are representative of the whole device; and (3) the drug is uniformly distributed within the poly(glycerol sebacate) (PGS) matrix.
  • the mass percentage of DEX and CIS can be calculated using the following equations (6 and 7). Based on the EDS data, the mass percentage of CIS in CIS-loaded IADD devices is calculated to be 2.5%, the mass percentage of DEX in DEX-loaded devices is calculated to be 17.9%.
  • TGA is a characterization method based on the entire sample, it is representative of the actual drug content within the sample.
  • EDS analyzes the elemental composition of the cross-section of the sample, operating under the assumption of uniform distribution throughout the sample. Therefore, while EDS provides a localized estimation, TGA offers a more accurate and reliable measurement of the overall drug distribution. Therefore, CIS loading capacity of 3.9% from TGA is more accurate than 2.5% from EDS calculation.
  • the total amount of drug loaded in IADD devices can be calculated using the Equation (9) below.
  • the amount of DEX loaded in helical device is calculated to be 581.5 pg.
  • the DEX and CIS amounts loaded into each cylindrical device are 73.03 pg and 15.91 pg respectively.
  • these calculated values are lower than the cumulative drug release amounts measured in Figure 20(B) in Example 19, indicating that these calculations likely underestimated the total drug loaded. Drug release was still evident at the 30-day endpoints.
  • One possible explanation for this discrepancy is the nonuniform distribution of the drugs within the devices. Specifically, the cross sections analyzed by EDS were taken near the center of the device, where drug loading may be lower compared to the outer layers.
  • the PGS blocks used for TGA analysis have a larger volume and thus a smaller surface-to-volume ratio than the actual devices, which could underestimate the drug loading in the IADD device.
  • the accuracy of DEX quantification based on the fluorine element is limited due to overlapping peaks from carbon and oxygen in the analysis. This overlap can underestimate the amount of DEX present in the devices.
  • the F98 glioma model was selected. Since the duration for cell growth in tissue culture is limited, the PSS collected from the drug release study was chosen to treat F98 cells. This approach allowed us to indirectly assess the cytotoxicity of CIS released from CIS-loaded IADD devices. The CIS present in the PSS inhibited the growth of glioma cells substantially after 24 h of incubation. The magnitude of this effect is as expected from the estimated daily release rate from CIS-loaded IADD devices and the observed IC50 ( ⁇ 2.5 pg/ml), thus validating the efficacy of the CIS-loaded IADD devices to maintain pharmacological activity over an extended period.
  • Example 25 Localized Drug Delivery and in Vivo Performance in a Rat Model
  • the in vivo results demonstrated successful focal DEX delivery to the kidney and brain, confirming the efficacy of the intra-arterial delivery system for two organs with vastly different patterns of blood supply and permeabilities.
  • the improvements in IADD- mediated focal drug delivery were extremely large as assessed by the NODE calculation, 28- fold for the kidney and 68-fold for the brain.
  • the smaller factor for the kidney may be due to saturation of drug uptake, as reflected in the supra-therapeutic DEX levels in the target kidney.
  • the difference may be intrinsic to organ perfusion and permeability. Nonetheless, such large improvements in focal drug delivery may be exploited in two different ways.
  • IADD can deliver standard drug levels to the target organ with substantially reduced systemic exposure.
  • IADD can deliver substantially more drug to the target organ with the same level of systemic exposure (as demonstrated in the in vivo experiments).
  • Rapid drug extraction and sustained retention are generally important for maximizing regional deposition. This principle is evident in herein, where a marked difference between target and non-target kidney drug concentrations was observed. However, elevated DEX levels in the serum, the contralateral kidney, and the liver indicate that optimization may be necessary to further reduce systemic leakage and enhance local retention. Modifying drug formulation and delivery parameters could improve these outcomes, similar to the strategies suggested by Cooke et al. for enhancing regional deposition.
  • the IADD has demonstrated ability to achieve focal drug delivery, which is particularly advantageous in treating localized diseases, such as tumors or inflammation. Previous studies have shown that intra-arterial delivery can confine the drug distribution to the target region only and thus reduce systemic toxicity. By enhancing the pharmacokinetic control of the IADD devices, the advantages of IADD can be leveraged for sustained and precise therapeutic effects.
  • the present disclosure reports the design and fabrication of novel drug- loaded IADD devices for focal delivery to targeted organs, kidney and brain respectively.
  • the comprehensive characterization of IADD devices verified successful drug loading into the prototype devices with two distinct geometries (cylindrical and helical).
  • the drug release profiles demonstrated that the IADD device sustained drug release for at least 30 days.
  • Cytocompatibility of drug-loaded IADD devices was confirmed with endothelial cells, and pharmacological efficacy of the released CIS in an in vitro glioma (F98) growth inhibition assay.
  • F98 in vitro glioma
  • the IADD device increased focal drug delivery to the target kidney and brain by 28-fold and 68-fold NODL respectively. Overall, the IADD devices exhibited promising drug loading and release capacities, cytocompatibility, pharmacological efficacy, and suitable focal drug delivery to targeted organs. The study suggests that the IADD devices hold a potential solution as a platform technology for a wide range of clinical applications and should be further explored, particularly where precision in focal drug administration is crucial for improving treatment outcomes.
  • a range includes each individual member.
  • a group having 1-3 markers refers to groups having 1, 2, or 3 markers .
  • a group having 1-5 markers refers to groups having 1, 2, 3, 4, or 5 markers, and so forth.
  • an effective amount or “effective dose” as used herein have their plain and ordinary meaning as understood in light of the specification, and refer to that amount of a recited composition or compound that results in an observable effect.
  • Actual dosage levels of active ingredients in an active composition of the presently disclosed subject matter can be varied so as to administer an amount of the active composition or compound that is effective to achieve the desired response for a particular subject and/or application.
  • the selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the composition, formulation, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated.
  • a minimal dose is administered, and dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of an effective dose, as well as evaluation of when and how to make such adjustments, are contemplated herein.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (e.g., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the recurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • Treating” and “treatment” as used herein also include prophylactic treatment.
  • Treatment methods include administering to a subject a therapeutically effective amount of an active agent.
  • the administering step may include a single administration or may include a series of administrations.
  • the compositions are administered to the subject in an amount and for a duration sufficient to treat the subject.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age and genetic profile of the subject, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof.
  • the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • the terms “individual”, “subject”, or “patient” as used herein have their plain and ordinary meaning as understood in light of the specification, and mean a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a nonhuman primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • the term “mammal” is used in its usual biological sense.
  • primates including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or the like.
  • administering includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intra-tumoral, intrathecal, intranasal, or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intra-tumoral, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • coadminister it is meant that a first compound described herein is administered at the same time, just prior to, or just after the administration of a second compound described herein.
  • “pharmaceutically acceptable” has its plain and ordinary meaning as understood in light of the specification and refers to carriers, excipients, and/or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed or that have an acceptable level of toxicity.
  • a “pharmaceutically acceptable” “diluent,” “excipient,” and/or “carrier” as used herein have their plain and ordinary meaning as understood in light of the specification and are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with administration to humans, cats, dogs, or other vertebrate hosts.
  • a pharmaceutically acceptable diluent, excipient, and/or carrier is a diluent, excipient, and/or carrier approved by a regulatory agency of a Federal, a state government, or other regulatory agency, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans as well as non-human mammals, such as cats and dogs.
  • the term diluent, excipient, and/or carrier can refer to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical formulation is administered.
  • Such pharmaceutical diluent, excipient, and/or carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin.
  • Water, saline solutions and aqueous dextrose and glycerol solutions can be employed as liquid diluents, excipients, and/or carriers, particularly for injectable solutions.
  • suitable pharmaceutical diluents and/or excipients include sugars, starch, glucose, fructose, lactose, sucrose, maltose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, salts, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • a non-limiting example of a physiologically acceptable carrier is an aqueous pH buffered solution.
  • the physiologically acceptable carrier may also include one or more of the following: antioxidants, such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, such as serum albumin, gelatin, immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids, carbohydrates such as glucose, mannose, or dextrins, chelating agents such as EDTA, sugar alcohols such as glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, isomalt, maltitol, or lactitol, salt-forming counterions such as sodium, and nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.
  • antioxidants such as ascorbic acid,
  • the formulation can also contain minor amounts of wetting, bulking, emulsifying agents, or pH buffering agents. These formulations can take the form of solutions, suspensions, emulsion, sustained release formulations and the like. The formulation should suit the mode of administration.
  • a range includes each individual member.
  • a group having 1-3 values refers to groups having 1, 2, or 3 values.
  • a group having 1-5 values refers to groups having 1, 2, 3, 4, or 5 values, and so forth.

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Abstract

Des aspects de la présente divulgation concernent un dispositif destiné à être utilisé dans l'administration d'un médicament à une cellule, un tissu ou un organe spécifique à l'intérieur d'un sujet. Dans certains modes de réalisation, le dispositif comprend un substrat métallique et un composite polymère. Dans certains modes de réalisation, le dispositif possède des propriétés mucoadhésives ou bioadhésives qui lui permettent de se fixer aux cellules épithéliales à l'intérieur d'une artère. Certains aspects de la présente divulgation concernent en outre une méthode d'administration d'un médicament à une cible ou à un organe, par exemple grâce à l'utilisation du dispositif divulgué dans la description.
PCT/US2025/016091 2024-02-16 2025-02-14 Dispositif d'administration intravasculaire de médicament et méthode d'administration focale de médicament par perfusion vasculaire Pending WO2025175208A1 (fr)

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