Therapeutic inhibitor of vascular smooth muscle cells

• US 6,599,928 B2
• Filed: 07/20/2001
• Issued: 07/29/2003
• Est. Priority Date: 09/25/1992
• Status: Expired due to Fees

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: NeoRx Corporation
• Inventors: Klein, Richard A., Kunz, Lawrence L.
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US09/910,387
• Publication Number:
  US 20020040064A1
• Time in Patent Office: 739 Days
• Field of Search: 514/411,449,441,319 604/96,101,99,51,52,53 623/1,112 606/194,195 424/422,490,484
• US Class Current: 514/411
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/131 acyclic
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/51 the non-active ingredient being a modifying agent
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6809 : Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6817 : Toxins
• CPC Class Codes: A61K 47/6831 : Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
• CPC Class Codes: A61K 47/6843 : the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6923 : the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6927 : the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 47/6957 : the form being a device or a kit, e.g. stents or microdevices
• CPC Class Codes: A61K 9/0024 : Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/416 : Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/604 : Biodegradation
• CPC Class Codes: A61L 2300/606 : Coatings
• CPC Class Codes: A61L 31/148 : Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: G01N 2800/323 : Arteriosclerosis, Stenosis
• CPC Class Codes: Y10S 977/775 : Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/808 : Exterior attachment for targeting, e.g. drug targeting
• CPC Class Codes: Y10S 977/905 : Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/916 : Gene therapy

Abstract

Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent.

Claims

1. A method for maintaining vessel luminal area, comprising inserting into a mammalian vessel an intravascular stent comprising a cytostatic agent that does not exhibit substantial cytotoxicity in an amount which allows for vascular repair and extracellular matrix production and reduces stenosis or restenosis upon placement of the stent.

3. The method of claim 1 or 2 wherein the intravascular stent comprises metal or plastic.

4. The method of claim 3 wherein the intravascular stent comprises a biodegradable material.

5. The method of claim 4 wherein the intravascular stent consists essentially of a biodegradable material.

6. The method of claim 1 or 2 wherein the agent is a cytoskeletal inhibitor.

7. The method of claim 1 or 2 wherein the agent is in sustained release form.

11. The method of claim 1 or 8 wherein the stent further comprises a therapeutic agent which is an inhibitor of smooth muscle cell proliferation.

24. The method of claim 1 wherein the intravascular stent comprises a biodegradable coating or a porous non-biodegradable coating comprising the agent.

40. The method of claim 1, 2, 8 or 15 wherein the agent releases nitric oxide.

41. The method of claim 1, 2, 8 or 15 wherein the agent is a cytochalasin or an analog thereof.

42. The method of claim 1, 2, 8 or 15 wherein the agent inhibits the proliferation of smooth muscle cells.

43. The method of claim 1, 2, 8 or 15 wherein the amount of the agent has a minimal effect on protein synthesis.

2. A method for Maintaining vessel luminal area, comprising inserting into a mammalian vessel an intravascular stent and a cytostatic agent that does not exhibit substantial cytotoxicity in an amount which allows for vascular repair and extracellular matrix production and reduces stenosis or restenosis upon placement of the stent.

8. A method for providing an intravascular stent effective to maintain vessel luminal area in a mammal, comprising coating the intravascular stent with a coating comprising a sustained release dosage form which comprises a cytostatic agent that does not exhibit substantial cytotoxicity in an amount which allows for vascular repair and extracellular matrix production and reduces stenosis or restenosis of said vessel upon placement of the stent.

9. The method of claim 8 wherein the stent comprises a biodegradable material.

10. The method of claim 8 wherein the stent comprises plastic or metal.

12. The method of claim 8 wherein the coating is biodegradable.

13. The method of claim 8 wherein the coating is porous.

14. The method of claim 8 wherein the agent is a cytoskeletal inhibitor.

15. A method for providing an intravascular stent effective to maintain vessel luminal area in a mammal, comprising introducing into the matrix of the intravascular stent a cytostatic agent that does not exhibit substantial cytotoxicity in an amount which allows for vascular repair and extracellular matrix production and reduces stenosis or restenosis of said vessel upon placement of the stent.

16. The method of claim 15 wherein the stent comprises a biodegradable material.

17. The method of claim 15 wherein the stent comprises plastic or metal.

18. The method of claim 15 wherein the stent further comprises a coating comprising a sustained release dosage form which comprises the agent.

19. The method of claim 18 wherein the coating is biodegradable.

20. The method of claim 18 wherein the coating is porous.

21. The method of claim 15 wherein the agent is a cytoskeletal inhibitor.

22. The method of claim 8 or 15 wherein the agent is in sustained release form.

23. The method of claim 22 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or extracellular matrix surrounding smooth muscle cells.

25. An intravascular stent comprising a matrix and a cytostatic agent that does not exhibit substantial cytotoxicity in an amount which has a minimal effect on protein synthesis, allows for vascular repair and extracellular matrix production in the vessel and reduces stenosis or restenosis following placement of the stent.

26. The intravascular stent of claim 25 wherein the agent is a cytoskeletal inhibitor.

27. The intravascular stent of claim 25 which comprises metal or plastic.

28. The intravascular stent of claim 25 which comprises a biodegradable material.

29. The intravascular stent of claim 28 which consists essentially of a biodegradable material.

30. The intravascular stent of claim 25 which comprises the agent in a sustained release form.

31. The intravascular stent of claim 26 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

32. The intravascular stent of claim 30 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or extracellular matrix surrounding smooth muscle cells.

33. The intravascular stent of claim 25 wherein the stent comprises a biodegradable coating or a porous non-biodegradable coating comprising the agent.

34. The intravascular stent of claim 25 which further comprises an inhibitor of smooth muscle cell proliferation.

35. The intravascular stent of claim 33 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

36. The intravascular stent of claim 25 wherein the agent releases nitric oxide.

37. The intravascular stent of claim 25 wherein the stent comprises a coating comprising the agent.

38. The intravascular stent of claim 25 wherein the agent is in the stent matrix.

39. The intravascular stent of claim 25 wherein the agent inhibits the proliferation of smooth muscle cells.