Local regional chemotherapy and radiotherapy using in situ hydrogel

• US 7,008,633 B2
• Filed: 12/18/2001
• Issued: 03/07/2006
• Est. Priority Date: 12/18/2000
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Yu, Dong-Fang, Yang, David J., Kim, E. Edmund, Azhdarinia, Ali, Lee, Tommy L.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US10/024,678
• Publication Number:
  US 20050227910A1
• Time in Patent Office: 1,540 Days
• Field of Search: 424/422, 424/484, 424/488, 424/93.21, 604/82
• US Class Current: 424/422
• CPC Class Codes: A61K 31/717 Celluloses
• CPC Class Codes: A61K 31/718 Starch or degraded starch, e.g. amylose, amylopectin
• CPC Class Codes: A61K 31/721 Dextrans
• CPC Class Codes: A61K 31/722 Chitin, chitosan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/729 Agar; Agarose; Agaropectin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 51/06 Macromolecular compounds , carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules peptides, proteins, polyamino acids A61K51/08; antibodies A61K51/10
• CPC Class Codes: A61K 51/1213 Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature
• CPC Class Codes: A61K 51/1255 Granulates, agglomerates, microspheres
• 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: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Methods regarding local regional treatment in situ for an individual, such as of a tumor, are provided herein. A hydrogel composition is generated in situ in the tumor by administering a polymer, such as a polysaccharide or a polyamino acid, with a therapeutic agent, such as a radionuclide or a drug, and administering a cross-linking agent. The hydrogel/therapeutic agent composition is retained in the tumor for safe and efficient tumor therapy. Alternatively, a hydrogel composition is generated in situ in an artery which nourishes a tumor to occlude the artery.

Claims

1. A method of dispensing a therapeutic agent in situ to a localized region in an individual comprising administering to said region a polymer composition that comprises a biocompatible polymer, a cross-linking composition that comprises a cross-linker, and the therapeutic agent, wherein the biocompatible polymer and the cross-linking composition are administered to allow formation of a cross-linked polymer in situ at the localized region, which cross-linked polymer comprises the therapeutic agent, and wherein the biocompatible polymer and the cross-linking composition are administered to the localized region from separate containers, wherein a first container comprises the biocompatible polymer and a second container comprises the cross-linking composition.

2. The method of claim 1, wherein the biocompatible polymer comprises the therapeutic agent.

3. The method of claim 1, wherein the polymer composition and the cross-linking composition are separately administered to the localized region.

4. The method of claim 1, wherein the first and second containers are syringes.

5. The method of claim 3, wherein the separate administrations of said polymer composition and said cross-linking composition are by syringe.

6. The method of claim 1, wherein the polymer composition and cross-linking compositions are administered separately from a syringe having at least two compartments, said compartments further defined as said separate containers.

7. The method of claim 1, wherein the polymer is a polysaccharide, a polyamino acid polymer, or a combination thereof.

8. The method of claim 7, wherein the polymer is a polysaccharide, and the polysaccharide polymer is an alginate, hydroxycellulose, chondroitin, chitosan, hyaluronate, dextran, or starch.

9. The method of claim 7, wherein the polymer is a polyamino acid, and the polyamino acid is a polyglutamate or a polyaspartate.

10. The method of claim 1, wherein said cross-linking agent is a salt of a divalent cation.

11. The method of claim 10, wherein said divalent cation is Ca²⁺, Mg²⁺, Mn²⁺, Cu²⁺, Cr²⁺, Sr²⁺, Zn²⁺, Ra²⁺, Sn²⁺, or Be²⁺.

12. The method of claim 10, wherein said salt of a divalent cation is tin chloride, calcium chloride, calcium sulfate, calcium phosphate, calcium carbonate, calcium chlorate, calcium fluoride, calcium bromide, magnesium chloride, magnesium sulfate, magnesium phosphate, magnesium carbonate, magnesium chlorate, magnesium fluoride, magnesium bromide, manganese chloride, manganese sulfate, manganese phosphate, manganese carbonate, manganese chlorate, manganese fluoride, manganese bromide, copper chloride, copper sulfate, copper phosphate, copper carbonate, copper chlorate, copper fluoride, copper bromide, chromium chloride, chromium sulfate, chromium phosphate, chromium carbonate, chromium chlorate, chromium fluoride, chromium bromide, strontium chloride, strontium sulfate, strontium phosphate, strontium carbonate, strontium chlorate, strontium fluoride, strontium bromide, zinc chloride, zinc sulfate, zinc phosphate, zinc carbonate, zinc chlorate, zinc fluoride, zinc bromide, radium chloride, radium sulfate, radium phosphate, radium carbonate, radium chlorate, radium fluoride, radium bromide, beryllium chloride, beryllium sulfate, beryllium phosphate, beryllium carbonate, beryllium chlorate, beryllium fluoride, or beryllium bromide.

13. The method of claim 1, wherein the therapeutic agent is a drug, a hormone, a gene therapy composition, a radionuclide, a nutriceutical, or a combination thereof.

14. The method of claim 13, wherein the therapeutic agent is a drug, and the drug is cisplatin, doxorubicin, Taxol, daunorubicin, mitomycin, actinomycin D, bleomycin, VP16, tumor necrosis factor, vincristine, vinblastine, carmustine, melphalan, cyclophosphamide, chlorambucil, bisulfan, lomustine, penicillin, erythromycin, amoxicillin, cefazolin, imipenem, aztreonam, sulbactam, linezolid, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, fusidic acid, trimethoprim, metronidazole, clindamycin, mupirocin, amphotericin B, rifampin, fluconazoleor, or a combination thereof.

15. The method of claim 13, wherein the therapeutic agent is a hormone, and the hormone is luteinizing hormone, growth hormone, growth hormone releasing hormone, estrogen, progesterone, testosterone, androgen, corticotropin, prolactin, gonadotropin releasing hormone, corticotropin releasing hormone, prolactin releasing hormone, pro-opiomelanocortin, melanotropin, calcitonin, gastrin, secretin, aldosterone, epinephrine, norepinephrine, follicle stimulating hormone, insulin, acetylcholine, aldosterone, angiotensin II, arginine vasopressin, bombesin, bradykinin, caerulein, calcitonin, cholecystokinin, chymodenin, corticosterone, cortisol, cortisone, dihydrotestosterone, dopamine, β

-endorphin, epidermal growth factor, erthropoetin, estrdiol, fibroblast growth factor, gamma aminobutyric acid, gastric inhibitory peptide, gastrin, glucagon, histamine, human chorionic gonadotropin, human placental lactogen, inhibin, insulinlike growth factor I, insulinlike growth factor II, leucine enkaephalin, leukotrienes, lysine vasopressin, lysylbradykinin, melanin concentrating hormone, α

-melanocyte stimulating hormone, mesotocin, methionin enkephalin, motilin, MSH release inhibiting factor, Mullerian regression factor, nerve growth factor, neurotensin, oxytocin, pancreatic polypeptide, parathormone, platlet-derived growth factor, prolactin inhibiting factor, prostacyclin I2, prostaglandin E2, prostaglandin F2a, relaxin, serotonin, serum thymic factor, substance P, thromboxane A2, thymopoietin, thymosina, thyrotopin (thyroid stimulating hormone;

TSH), thyrotropin releasing hormone, thyroxine, triiodothyronine, urogastrone, vasoactive intestinal peptide, vasotocin, vitamin D3, or a combination thereof.

16. The method of claim 13, wherein the therapeutic agent is a gene therapy composition, and the gene therapy composition is a vector containing p53, thymidine kinase, cytosine deaminase, oxidoreductase, thymidine kinase thymidilate kinase, deoxycytidine kinase, ras ;

myc, raf, erb, src, fms, jun, trk, ret, gsp, hst, bcl abl;

Rb, CFTR, p16, p21, p27, p57, p73, C-CAM, APC, CTS-1, zac1, scFV ras, DCC, NF-1, NF- 2, WT-1, MEN-I, MEN-II, BRCA1, VHL, MMAC1, FCC, MCC, BRCA2, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, GM-CSF, G-CSF, or a combination thereof.

17. The method of claim 16, wherein the vector is a plasmid, an adenoviral vector, an adeno-associated viral vector, a retroviral vector, a liposome, or a combination thereof.

18. The method of claim of 13, wherein the therapeutic agent is a radionuclide, and the radionuclide is ¹⁸⁸Re, ²¹³Bi, ¹⁶⁶Ho, ²¹¹At, or a combination thereof.

19. The method of claim 13, wherein the therapeutic agent is a nutriceutical, and the nutriceutical is arabinogalactan, acerola cherry, agnus castus (vitex), amla, andrographis, artichoke (globe), ashwagandha, astragalus, bacopa, beta 1,3 glucans, beta sitosterol, bilberry, borage oil, boswellia, broccoli cruciferous, bromelam, butcher'"'"'s broom, calcium hydroxyl apatite, cascara sagrada, cat'"'"'s claw, cetyl myristoleate, chamomile, chitosan, chlorella, chondroitin sulfate, chromium yeast, citrus aurantiurn, citrus seed extract, co-enzyme Q10, colostrum, cordyceps, cranberry, creatine monohydrate, devil'"'"'s claw, DHEA, DMG, dong quai, echinacea, elderberry, ephedra, evening primrose oil, feverfew, fish marine lipids, fish oil concentrate powder, fish protein powder, flaxseed oil, garcinia HCA, garlic T.A.P., germanium Ge-132, ginger, ginkgo, ginseng-American, ginseng-Siberian, ginseng-Asian, glucosamine, goldenseal, gotu kola, grapeseed extract, green tea extract, guarana, gymnema, hawthorne, hops, horse chestnut, horsetail, kava kava, kola nut, lecithin, licorice, lipoic acid, lycopene, medium chain tri-glycerides, melatonin, milk thistle, MSM, muira puama, nag, nettles, noni, ocimum sanctum, octacosonol, olivir, passion flower, pau d'"'"'arcophosphatidylserine, picrorbiza, potassium glycero phosphate, pygeum, quercetin, reishi, saw palmetto, schisandra, sea cucumber, selenium yeast bound, shark cartilage, shark liver oil, shiitake, shilajit, sodium copper chiorophyllin, spirulina, squalene, St. John'"'"'s Wort, stevia, suma, tribulus (Bulgarian) triphala, tumeric, uva ursi, valerian, wild yam extract, willow bark, yohimbe bark extract, or a combination thereof.

61. The method of claim 1, wherein said administration is to a tumor.

20. A method of treating a tumor in situ in an individual comprising the steps of administering to said tumor a polymer composition that comprises a biocompatible polymer, a cross-linking composition that comprises a cross-linker, and a therapeutic agent, wherein the biocompatible polymer and the cross-linking composition are administered to allow formation of a cross-linked polymer in situ at the tumor, which cross linked polymer comprises the therapeutic agent, and wherein the biocompatible polymer and the cross-linking composition are administered to the tumor from separate containers, wherein a first container comprises the biocompatible polymer and a second container

21. The method of claim 20, wherein the biocompatible polymer comprises the therapeutic agent.

22. The method of claim 20, wherein the polymer composition and the cross-linking composition are separately administered to the localized region.

23. The method of claim 20, wherein the first and second containers are syringes.

24. The method of claim 22, wherein the separate administrations of said polymer composition and said cross-linking composition are by syringe.

25. The method of claim 20, wherein the polymer composition and cross-linking compositions are administered separately from a syringe having at least two compartments, said compartments further defined as said separate containers.

26. The method of claim 20, wherein the polymer is a polysaccharide, a polyamino acid polymer, or a combination thereof.

27. The method of claim 26, wherein the polymer is a polysaccharide, and the polysaccharide polymer is an alginate, hydroxycellulose, chondroitin, chitosan, hyaluronate, dextran or starch.

28. The method of claim 26, wherein the polymer is a polyainino acid, and the polyamino acid is a polyglutamate or a polyaspartate.

29. The method of claim 20, wherein said cross-linking agent is a salt of a divalent cation.

30. The method of claim 29, wherein said divalent cation is Ca²⁺, Mg²⁺, Mn²⁺, Cu²⁺, Cr²⁺, Sr²⁺, Zn²⁺, Ra²⁺, or Be2+.

31. The method of claim 29, wherein said salt of a divalent cation is tin chloride, calcium chloride, calcium sulfate, calcium phosphate, calcium carbonate, calcium chlorate, calcium fluoride, calcium bromide, magnesium chloride, magnesium sulfate, magnesium phosphate, magnesium carbonate, magnesium chlorate, magnesium fluoride, magnesium bromide, manganese chloride, manganese sulfate, manganese phosphate, manganese carbonate, manganese chlorate, manganese fluoride, manganese bromide, copper chloride, copper sulfate, copper phosphate, copper carbonate, copper chlorate, copper fluoride, copper bromide, chromium chloride, chromium sulfate, chromium phosphate, chromium carbonate, chromium chlorate, chromium fluoride, chromium bromide, strontium chloride, strontium sulfate, strontium phosphate, strontium carbonate, strontium chlorate, strontium fluoride, strontium bromide, zinc chloride, zinc sulfate, zinc phosphate, zinc carbonate, zinc chlorate, zinc fluoride, zinc bromide, radium chloride, radium sulfate, radium phosphate, radium carbonate, radium chlorate, radium fluoride, radium bromide, beryllium chloride, beryllium sulfate, beryllium phosphate, beryllium carbonate, beryllium chlorate, beryllium fluoride, or beryllium bromide.

32. The method of claim 20, wherein said therapeutic agent is a drug, a hormone, a gene therapy composition, a radionuclide, a nutriceutical, or a combination thereof.

33. The method of claim 32, wherein the therapeutic agent is a drug, and the drug is cisplatin, doxorubicin, Taxol, daunorubicin, mitomycin, actinomycin D, bleomycin, VP16, tumor necrosis factor, vincristine, vinbiastine, carmustine, meiphalan, cyclophosphamide, chiorambucil, bisulfan, lomustine, penicillin, erythromycin, amoxicillin, cefazolin, imipenem, azireonani, sulbactam, linezolid, gentamicin, sulfaniethoxazole, vancomycin, ciprofloxacin, fusidic acid, trimethoprim, metronidazole, clindaniycin, mupirocin, amphotericin B, rifampin, fluconazoleor, or a combination thereof.

34. The method of claim 32, wherein the therapeutic agent is a hormone, and the hormone is luteinizing hormone releasing hormone, growth hormone, growth hormone releasing hormone, estrogen, progesterone, testosterone, androgen, corticotropin, prolactin, gonadotropin, somatotropin, somatostatin, somatotropin releasing hormone, gonadotropin releasing hormone, corticotropin releasing hormone, prolactin releasing hormone, pro-opiomelanocortin, melanotropin, calcitonin, gastrin, secretin, aldosterone, epinephrine, norepinephrine, follicle stimulating hormone, insulin, acetyicholine, aldosterone, angiotensin II, arginine vasopressin, bombesin, bradykinin, caerulein, calcitonin, cholecystokinin, chymodemn, corticosterone, cortisol, cortisone, dihydrotestosterone, dopamine, β

-endorphin, epidermal growth factor, erythropoietin, estradiol, fibroblast growth factor, gamma aminobutyric acid, gastric inhibitory peptide, gastrin, glucagon, histamine, human choriomc gonadotropin, human placental lactogen, inhibin, insulinlike growth factor I, insulinlike growth factor II, leucine enkephalin, leukotrienes, lysine vasopressin, lysyibradykinin, melanin concentrating hormone, α

-melanocyte stimulating hormone, mesotocin, methionin enkephalin, motilin, MSH release inhibiting factor, Mullerian regression factor, nerve growth factor, neurotensin, oxytocin, pancreatic polypeptide, parathormone, platelet-derived growth factor, prolactin inhibiting factor, prostacyclin I2, prostaglandin E2, prostaglandin F2a, relaxin, serotonin, serum thymic factor, substance P. thromboxane A2, thymopoietin, thymosina, thyrotopin (thyroid stimulating hormone;

TSH), thyrotropin releasing hormone, thyroxine, triiodothyronine, urogastrone, vasoactive intestinal peptide, vasotocin, vitamin D3, or a combination thereof.

35. The method of claim 32, wherein the therapeutic agent is a gene therapy composition, and the gene therapy composition is a vector containing p53, thymidine kinase, cytosine deaminase, oxidoreductase, thymidine kinase thymidilate kinase, deoxycytidine kinase, ras ;

myc, raf, erb, src, fms, jun, trk, ret, gsp, hst, bcl abl, Rb, CFTR, p16, p21, p27, p57, p73, C-CAM, APC, CTS-1, zac1, scFV ras, DCC, NF-1, NF-2, WT-1, MEN-I, MEN-II, BRCA1, VHL, MMAC1, FCC, MCC, BRCA2, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, GM-CSF, G-CSF, or a combination thereof.

36. The method of claim 35, wherein the vector is a plasmid, an adenoviral vector, an adeno-associated viral vector, a retroviral vector, a liposome, or a combination thereof.

37. The method of claim 32, wherein the therapeutic agent is a radionuclide, and the radionuclide is ¹⁸⁸Re, ²¹³Bi, ¹⁶⁶Ho, ²¹¹At, or a combination thereof.

38. The method of claim 32, wherein the therapeutic agent is a nutriceutical, and the nutriceutical is arabinogalactan, acerola cherry, agnus castus (vitex), amla, andrographis, artichoke (globe), ashwagandha, astragalus, bacopa, beta 1,3 glucans, beta sitosterol, bilberry, borage oil, boswellia, broccoli cruciferous, bromelain, butcher'"'"'s broom, calcium hydroxyl apatite, cascara sagrada, cat'"'"'s claw, cetyl myristoleate, chamomile, chitosan, chiorella, chondroitin sulfate, chromium yeast, citrus aurantium, citrus seed extract, co-enzyme QIO, colostrum, cordyceps, cranberry, creatine monohydrate, devil'"'"'s claw, DHEA, DMG, dong quai, echinacea, elderberry, ephedra, evening primrose oil, feverfew, fish marine lipids, fish oil concentrate powder, fish protein powder, flaxseed oil, garcinia HCA, garlic T.A.P., germanium Ge-132, ginger, ginkgo, ginseng-American, ginseng-Siberian, ginseng-Asian, glucosamine, goldenseal, gotu kola, grapeseed extract, green tea extract, guarana, gymnema, hawthorne, hops, horse chestnut, horsetail, kava kava, kola nut, lecithin, licorice, lipoic acid, lycopene, medium chain tri-glycerides, melatonin, milk thistle, MSM, muira puama, nag, nettles, noni, ocinium sanctum, octacosonol, olivir, passion flower, pay d'"'"'arcophosphatidylserine, picrorhiza, potassium glycero phosphate, pygeum, quercetin, reishi, saw palmetto, schisandra, sea cucumber, selenium yeast bound, shark cartilage, shark liver oil, shiitake, shilajit, sodium copper chlorophyllin, spirulina, squalene, St. John'"'"'s Wort, stevia, suma, tribulus (Bulgarian) triphala, tumeric, uva ursi, valerian, wild yam extract, willow bark, vohimbe bark extract, or a combination thereof.

39. A method of occluding an artery associated with a tumor in an individual comprising the step of administering to said tumor a polymer composition that comprises a biocompatible polymer and a cross-linking composition that comprises a cross-linker, wherein the biocompatible polymer and the cross-linking composition are administered to allow formation of the cross-linked polymer in situ at the tumor, wherein the biocompatible polymer and the cross-linking composition are administered to the tumor from separate containers, wherein a first container comprises the biocompatible polymer and a second container comprises the cross-linking composition.

40. The method of claim 39, wherein the biocompatible polymer further comprises a therapeutic agent.

41. The method of claim 39, wherein the polymer composition and the cross-linking composition are separately administered to the tumor.

42. The method of claim 39, wherein the first and second containers are svrinaes.

43. The method of claim 41, wherein the separate administrations of said polymer composition and said cross-linking composition are by syringe.

44. The method of claim 39, wherein the polymer composition and cross-linking compositions are administered separately from a syringe having at least two compartments, said compartments further defined as said separate containers.

45. The method of claim 39, wherein the polymer is a polysaccharide, a polyamino acid polymer, or a combination thereof.

46. The method of claim 45, wherein the polymer is a polysaccharide, and the polysaccharide polymer is an alginate, hydroxycellulose, chondroitin, chitosan, hyaluronate, dextran or starch.

47. The method of claim 45, wherein the polymer is a polyamino acid, and the polyamino acid is a polyglutaxnate or a polyaspartate.

48. The method of claim 39, wherein said cross-linking agent is a salt of a divalent cation.

49. The method of claim 48, wherein said divalent cation is Ca²⁺, Mg²⁺, Mn²⁺, Cu²⁺, Cr²⁺, Sr²⁺, Zn²⁺, Ra²⁺, or Be²⁺.

50. The method of claim 48, wherein said salt of a divalent cation is tin chloride, calcium chloride, calcium sulfate, calcium phosphate, calcium carbonate, calcium chlorate, calcium fluoride, calcium bromide, magnesium chloride, magnesium sulfate, magnesium phosphate, magnesium carbonate, magnesium chlorate, magnesium fluoride, magnesium bromide, manganese chloride, manganese sulfate, manganese phosphate, manganese carbonate, manganese chlorate, manganese fluoride, manganese bromide, copper chloride, copper sulfate, copper phosphate, copper carbonate, copper chlorate, copper fluoride, copper bromide, chromium chloride, chromium sulfate, chromium phosphate, chromium carbonate, chromium chlorate, chromium fluoride, chromium bromide, strontium chloride, strontium sulfate, strontium phosphate, strontium carbonate, strontium chlorate, strontium fluoride, strontium bromide, zinc chloride, zinc sulfate, zinc phosphate, zinc carbonate, zinc chlorate, zinc fluoride, zinc bromide, radium chloride, radium sulfate, radium phosphate, radium carbonate, radium chlorate, radium fluoride, radium bromide, beryllium chloride, beryllium sulfate, beryllium phosphate, beryllium carbonate, beryllium chlorate, beryllium fluoride, or beryllium bromide.

51. The method of claim 47, wherein said therapeutic agent is a drug, a hormone, a gene therapy composition, a radionuclide, a nutriceutical, or a combination thereof.

52. The method of claim 51, wherein the therapeutic agent is a drug, and the drug is cisplatin, doxorubicin, Taxol, daunorubicin, mitomycin, actinomycin D, bleomycin, VP 16, tumor necrosis factor, vincristine, vinblastine, carmustine, meiphalan, cyclophosphamide, chlorambucil, bisulfan, lomustine, penicillin, erythromycin, amoxicillin, erythromycin, cefazolin, imipenem, aztreonam, sulbactam, linezolid, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, fusidic acid, trimethoprim,

53. The method of claim 51, wherein the therapeutic agent is a hormone, and the hormone is luteinizing hormone releasing hormone, growth hormone, growth hormone releasing hormone, estrogen, progesterone, testosterone, androgen, corticotropin, prolactin, gonadotropin, somatotropin, somatostatin, somatotropin releasing hormone, gonadotropin releasing hormone, corticotropin releasing hormone, prolactin releasing hormone, pro-opiomelanocortin, melanotropin, calcitonin, gastrin, secretin, aldosterone, epmephrine, norepinephrine, follicle stimulating hormone, insulin. acetyicholine, aldosterone, angiotensin II, arginine vasopressin. bombesin, bradykinin. caerulein, calcitonin, cholecystokinin, chymodenin, corticosterone, cortisol, cortisone, dihydrotestosterone, dopamine, β

-endorphin, epidermal growth factor, erythropoietin, estradiol, fibroblast growth factor, gamma amuiobutyric acid, gastric inhibitory peptide, gastrin, glucagon, histamine, human chorionic gonadotropin, human placental lactogen, inhibin, insulinlike growth factor I, insulinlike growth factor II, leucine enkephalin, leukotrienes, lysine vasopressin, lysylbradykinin, melanin concentrating hormone, α

-melanocyte stimulating hormone, mesotocin, methionin enkephalin, motilin, MSH release inhibiting factor, Mullerian regression factor, nerve growth factor, neurotensin, oxytocin, pancreatic polypeptide, parathormone, platelet-derived growth factor, prolactin inhibiting factor, prostacyclin I2, prostaglandin E2, prostaglandin F2a, relaxin, serotonin, serum thymic factor, substance P, thromboxane A2, thymopoietin. thymosina, thyrotopin (thyroid stimulating hormone;

TSH), thyrotropin releasing hormone, thyroxine, triiodothyronine, urogastrone, vasoactive intestinal peptide, vasotocin, vitamin D3, or a combination thereof.

54. The method of claim 51, wherein the therapeutic agent is a gene therapy composition, and the gene therapy composition is a vector containing p53, thymidine kinase, cytosine deaminase, oxidoreductase, thymidine kinase thymidilate kinase, deoxycytidine kinase, ras;

myc, raf, erb, src, fms, jun, trk, ret, gsp, hst, bcl abl, Rb, CFTR, p16, p21, p27, p57, p73, C-CAM, APC, CTS-1, zac1, scFV ras, DCC, NF-1, NF-2, WT-1, MEN-I, MEN-II, BRCA1, VHL, MMAC1, FCC, MCC, BRCA2, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, GM-CSF, G-CSF, or a combination thereof.

55. The method of claim 54, wherein the vector is a plasmid, an adenoviral vector, an adeno-associated viral vector, a retroviral vector, a liposome, and a combination thereof.

56. The method of claim 51, wherein the therapeutic agent is a radionuclide, and the radionuclide is ¹⁸⁸Re, ²¹³Bi, ¹⁶⁶Ho, ²¹¹At, or a combination thereof.

57. The method of claim 51, wherein the therapeutic agent is a nutriceutical, and the nutriceutical is arabinogalactan, acerola cherry, agnus castus (vitex), amla, andrographis, artichoke (globe), ashwagandha, astragalus, bacopa, beta 1,3 glucans, beta sitosterol, bilberry, borage oil, boswellia, broccoli cruciferous, bromelain, butcher'"'"'s broom, calcium hydroxyl apatite, cascara sagrada, cat'"'"'s claw, cetyl myristoleate, chamomile, chitosan, chiorella, chondroitin sulfate, chromium yeast, citrus aurantium, citrus seed extract, co-enzyme QIO, colostruni, cordyceps, cranberry, creatine monohydrate, devil'"'"'s claw, DHEA, DMG, doug quai, echinacea, elderberry, ephedra, evening primrose oil, feverfew, fish marine lipids, fish oil concentrate powder, fish protein powder, flaxseed oil, garcinia HCA, garlic T.A.P., germanium Ge-132, ginger, ginkgo, ginseng-American, ginseng-Siberian, ginseng-Asian, glucosamine, goldenseal, gotu kola, grapeseed extract, green tea extract, guarana, gymnenia, hawthorne, hops, horse chestnut, horsetail, kava kava, kola nut, lecithin, licorice, lipoic acid, lycopene, medium chain tri-glycerides, melatonin, milk thistle, MSM, muira puama, nag, nettles, noni, ocimum sanctum, octacosonol, olivir, passion flower, pau d'"'"'arcophosphatidylserine, picrorhiza, potassium glycero phosphate, pygeum, quercetin, reishi, saw palmetto, schisandra, sea cucumber, selenium yeast bound, shark cartilage, shark liver oil, shiitake, shilajit, sodium copper chlorophyllin, spirulina, squalene, St. John'"'"'s Wort, stevia, suma, tribulus (Bulgarian) triphala, tumeric, uva ursi, valerian, wild yam extract, willow bark, yohimbe bark extract, or a combination thereof.

58. The method of claim 39, wherein said administration step occurs through a catheter.

59. A method of dispensing a therapeutic agent in situ to a localized region in an individual comprising administering to said region a polymer composition that comprises a biocompatible polymer, a cross-linking composition that comprises a cross-linker, and the therapeutic agent, wherein the polymer composition and the cross-linking composition are administered to allow formation of a cross-linked polymer in situ at the localized region, which cross-linked polymer comprises the therapeutic agent, wherein the polymer composition and the cross-linking composition are separately administered to the localized region by means of a single container having at least two compartments, wherein one compartment comprises the polymer composition and another compartment comprises the cross-linking composition.

60. A method of dispensing a therapeutic agent in situ to a localized region in an individual comprising administering to said region a polymer composition that comprises a biocompatible polymer, a cross-linking composition that comprises a cross-linker, and the therapeutic agent, wherein the polymer composition and the cross-linking composition are administered to allow formation of a cross-linked polymer in situ at the localized region, which cross-linked polymer comprises the therapeutic agent, wherein the polymer composition and the cross-linking composition are separately administered to the localized region by means of a single container having a hollow cylindrical compartment, wherein the polymer composition and cross-linking composition are administered separately through said compartment.