Search

US-12616656-B2 - Adventitial painting modality of local drug delivery to abate intimal hyperplasia

US12616656B2US 12616656 B2US12616656 B2US 12616656B2US-12616656-B2

Abstract

In one aspect, the disclosure relates to unimolecular micelles having N-hydroxysuccinimide ester (NHS), sulfo-NHS terminal groups, or other adhesive terminal groups, compositions including the same, methods of making the same, and methods of treating intimal hyperplasia in a subject using the same. In some aspects, the unimolecular micelles can further include fluorescent labels or drugs for treating intimal hyperplasia. In one aspect, the unimolecular micelles and compositions comprising the same are biocompatible, non-toxic, and non-inflammatory. In another aspect, the unimolecular micelles and compositions are substantially free from hydrogel, or are completely free from hydrogel. In still another aspect, the disclosed compositions and methods can be easily and quickly deployed in the operating room. Also disclosed is a method of applying the unimolecular micelles and compositions via direct penbrush painting.

Inventors

  • Kenneth Craig Kent
  • Lian-Wang Guo
  • Takuro SHIRASU
  • Bowen Wang
  • Shaoqin GONG
  • Nisakorn YODSANIT

Assignees

  • UNIVERSITY OF VIRGINIA PATENT FOUNDATION
  • WISCONSIN ALUMNI RESEARCH FOUNDATION

Dates

Publication Date
20260505
Application Date
20220520

Claims (20)

  1. 1 . A method for treating or preventing intimal hyperplasia in a subject, the method comprising applying a composition comprising unimolecular micelles to adventitia of a vessel in the subject, wherein the composition is free from hydrogel.
  2. 2 . The method of claim 1 , wherein the unimolecular micelles comprise N-hydroxysuccinimide ester (NHS) terminal groups, aldehyde terminal groups, dopamine terminal groups, or any combination thereof.
  3. 3 . The method of claim 2 , wherein the NHS terminal groups comprise sulfo-NHS terminal groups.
  4. 4 . The method of claim 2 , wherein the NHS terminal groups form amide bonds with the adventitia.
  5. 5 . The method of claim 2 , wherein the unimolecular micelles comprise a structure wherein PAMAM comprises polyamidoamine dendrimers; wherein n is from about 10 to about 230; and wherein each R′ in the unimolecular micelles is individually selected from the NHS ester, a methoxy group, or a fluorescent label.
  6. 6 . The method of claim 5 , wherein the fluorescent label comprises Cy5, ICG, AF647, Cy7-azide, IR-820, CY7.5-NH2, DY-547, DY-647, Cy5.5, DY-700-COOH, DY-676-NH 2 , NileBlue, NileRed, Hostasol, Norbonenyl coumarin, amino-coumarin, nitrobenzoxadiazole (NBD), rhodamine, fluorescein, BODIPY, or any combination thereof.
  7. 7 . The method of claim 1 , wherein the unimolecular micelles have an average molecular weight of from about 15 kDa to about 520 kDa.
  8. 8 . The method of claim 1 , wherein the composition further comprises a drug for treating intimal hyperplasia.
  9. 9 . The method of claim 8 , wherein the drug comprises rapamycin, sirolimus, paclitaxel, apabetalone, JQ1, EPZ5676, centrinone-B, GSK2606414, EED226, UNC1999, tubastatin-A, disulfiram, halofugenone, resveratrol, a DOT1L inhibitor, or any combination thereof.
  10. 10 . The method of claim 9 , wherein the DOT1L inhibitor comprises pinometostat (EPZ5676).
  11. 11 . The method of claim 8 , wherein the composition comprises from about 0.1 to about 20 wt % of the drug.
  12. 12 . The method of claim 1 , wherein the applying the composition to the adventitia comprises pen-brush painting the composition to the vessel.
  13. 13 . The method of claim 1 , wherein the subject is a mammal.
  14. 14 . The method of claim 1 , wherein IH is prevented or reduced for a period of at least 2 weeks.
  15. 15 . The method of claim 2 , wherein the NHS ester terminal group reacts with an amine in an extracellular matrix (ECM) protein to form an amide bond, releasing NHS or a derivative thereof.
  16. 16 . The method of claim 15 , wherein the derivative of NHS is sulfo-NHS and the method further comprises removing the sulfo-NHS from an adventitial site of application.
  17. 17 . The method of claim 8 , wherein performing the method delivers a dose of from about 5 μg per kg of body weight to about 10 mg per kg of body weight of the drug to the vessel adventitia.
  18. 18 . A unimolecular micelle comprising a structure wherein PAMAM comprises polyamidoamine dendrimers; wherein n is from about 10 to about 230; and wherein each R′ in the unimolecular micelles is individually selected from the NHS ester, a methoxy group, or a fluorescent label.
  19. 19 . The unimolecular micelle of claim 18 , wherein the unimolecular micelle has an average molecular weight of at least about 15 kDa.
  20. 20 . The unimolecular micelle of claim 18 , wherein the fluorescent label comprises Cy5, ICG, AF647, Cy7-azide, IR-820, CY7.5-NH 2 , DY-547, DY-647, Cy5.5, DY-700-COOH, DY-676-NH 2 , NileBlue, NileRed, Hostasol, Norbonenyl coumarin, Amino-coumarin, nitrobenzoxadiazole (NBD), rhodamine, fluorescein, BODIPY, or any combination thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a U.S. national phase application under 35 U.S.C. 371 of International Patent Application No. PCT/US2022/072462, filed on May 21, 2022, which claims the benefit of and priority to U.S. Provisional Application No. 63/191,443 filed on May 21, 2021 both of which are incorporated herein by reference in their entireties. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers R01HL143469, R01HL129785, and R01 HL133665 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Coronary artery disease, carotid artery disease, and peripheral artery disease share a common etiology of atherosclerosis, which affects around one third of adults and is a leading cause of death. The prevalence of atherosclerosis increases with age and is predicted to grow globally. While endovascular approaches (e.g., stenting) are gaining momentum in current clinical managements of atherosclerosis, open surgical reconstructions such as bypass grafting, endarterectomy, and arteriovenous fistula, collectively over a million per year in the US alone, remain the gold standard surgical procedures for cardiovascular diseases and hemodialysis access. Unfortunately, treatments often fail, due to neointimal hyperplasia (IH) in the vessel wall that narrows the lumen. Despite numerous investigations, currently no suitable clinical method exists to prevent post-operative failure of open vascular reconstructions. A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative IH, which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation. With a long-term goal to meet this medical need, a perivascular drug administration system using unimolecular micelle (UM) was previously developed. This nanoparticle formulation consisted of a hydrophobic “core” to provide high drug-loading capacity and sustained drug release, and a hydrophilic “shell” that enabled solubility. To retain the soluble UM from flowing away at the desired area, a thermosensitive phase-transition hydrogel was synthesized to hold UM in the perivascular space. This UM/hydrogel hybrid system proved to be effective in hampering IH when applied periadventitially in a rat model. However, potential issues remained, especially in the perspective of translation toward a clinical utility, including the following: 1) The semi-solid hydrogel can momentarily be dislocated from the treatment site. 2) Once the UM-containing hydrogel decomposes, the UM can diffuse away. 3) Due to gel bulkiness, this UM/hydrogel system is not applicable at some locations with limited perivascular space. 4) During the decomposition process of bulk hydrogel, local pH can decrease due to large amounts of acidic by-products, which can accelerate gel degradation while inciting inflammation. Bulk gels may also produce degradation products that are generally pro-inflammatory. Among other solutions, perivascular drug-releasing polymer cuffs, wraps, or meshes reduced IH in earlier preclinical studies, but these devices can impinge on the vessel, imposing physical harm. It would be advantageous to have a nanoparticle platform that can be periadventitially applied and is effective at preventing or reducing IH but that does not require a bulky hydrogel and does not physically harm vessels. It would further be advantageous if the nanoparticle platform could be easily and quickly applied in clinical settings and was biocompatible, non-toxic, and/or non-inflammatory. These needs and other needs are satisfied by the present disclosure. SUMMARY In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to unimolecular micelles having N-hydroxysuccinimide ester (NHS), sulfo-NHS terminal groups, or other adhesive terminal groups, compositions including the same, methods of making the same, and methods of treating intimal hyperplasia in a subject using the same. In some aspects, the unimolecular micelles can further include fluorescent labels or drugs for treating intimal hyperplasia. In one aspect, the unimolecular micelles and compositions comprising the same are biocompatible, non-toxic, and non-inflammatory. In another aspect, the unimolecular micelles and compositions are substantially free from hydrogel, or are completely free from hydrogel. In still another aspect, the disclosed compositions and methods can be easily and quickly deployed in the operating room. Also disclosed is a method of applying the unimolecular micelles and compositions via direct pen-brush painting. Othe