Local regional chemotherapy and radiotherapy using in situ hydrogel

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.

Description

[0001] This application claims priority to U.S. Provisional Patent Application 60 / 256,514 filed Dec. 18, 2000.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention is directed to the fields of disease therapy, cancer biology, and cancer therapy. More specifically, the present invention is directed to providing local regional treatment in an individual in situ by administering a polymer and a cross-linking agent. More preferably, the local regional treatment in situ is of a tumor in the individual. [0004] 2. Description of Related Art [0005] Systemic administration of anticancer agents often results in severe dose-limiting toxic effects. Therefore, site-specific delivery of anticancer drugs, such as in local regional therapy, is extremely beneficial for solid tumors. During local regional therapy for treatments of tumors, current methods include transcatheter arterial chemoembolization (TACE), brachytherapy, and peritumor / intralesional injection. P...

AI Technical Summary

Benefits of technology

[0032] In an additional embodiment of the present invention, there is a kit for treating a tumor in situ in an individual comprising, in a suitable containing means a first container having a polymer composition; and a second container having a cross-linking composition. In a specific embodiment, the polymer composition further comprises a therapeutic agent. In another specific embodiment, the polymer is a polysaccharide, a polyamino acid polymer, or a combination thereof. In an additional specific embodiment, the polymer is a polysaccharide, and the polysaccharide polymer is alginate, hydroxycellulose, chondroitin, chitosan, or hyaluronate. In an additional specific embodiment, the polymer is a polyamino acid polymer, and the polyamino acid polymer is polyglutamate or polyaspartate. In an additional specific embodiment, the cross-linking agent is a salt of a divalent cation. In a specific embodiment, the divalent cation is Ca2+, Mg2+, Mn2+, Cu2+, Cr2+, Sr2+, Zn2+, Ra2+, or Be2+. In another specific embodiment the salt of a divalent cation is 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. In an additional specific embodiment, the therapeutic agent is an anticancer drug, a hormone, a gene therapy composition, a radionuclide, a nutriceutical, or a combination thereof. In an additional specific embodiment, the therapeutic agent is an anticancer drug, and the anticancer drug is cisplatin, doxorubicin, Taxol, daunorubicin, mitomycin, actinomycin D, bleomycin, VP16, tumor necrosis factor, vincristine, vinblastine, carmustine, melphalan, cyclophosphamide, chlorambucil, bisulfan, lomustine, or a combination thereof. In an additional specific embodiment, the therapeutic agent is a radionuclide, and the radionuclide is 188Re, 166Ho, 213Bi, 211At, or a combination thereof. In another specific embodiment, 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, and a combination thereof. In an additional specific embodiment, the vector is a plasmid, an adenoviral vector, an adeno-associated viral vector, a retroviral vector, a liposome, or a combination thereof. In another specific embodiment, 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, acetylcholine, 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 aminobutyric 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. In another specific embodiment, the therapeutic agent is a radionuclide, and the radionuclide is 188Re, 213Bi, 166Ho, 211At, or a combination thereof. In an additional specific embodiment, 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, chlorella, chondroitin sulfate, chromium yeast, citrus aurantium, 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, 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, or yohimbe bark extract. In another specific embodiment, the therapeutic agent further comprises a detectable identifier, and the detectable identifier is an X-ray contrasting agent, a CT contrasting agent, an MRI contrasting agent, a fluorophore, or a luminophore.

[0033]

Problems solved by technology

Systemic administration of anticancer agents often results in severe dose-limiting toxic effects.

Patients with malignancies which are inoperable or unsuitable for surgery often have a poor prognosis, and current palliative treatments have an associated morbidity and mortality.

However, conventional TACE has some disadvantages.

Intraorgan collateral vessels rapidly develop around the occlusions, and effective dearterialization of the organ may be difficult to achieve even after repeated embolization.

Although lipiodal chemoembolization has been considered the most effective of these methods, on the basis of reports of a decrease in tumor size in a nonrandomized trial, the embolization effect is questionable.

Repeated peripheral embolization of the hepatic artery with very small particles can cause occlusion of the collateral vessels as well as the primary hepatic artery, but this might well result in necrosis of normal tissue as well as tumor in patients whose metastases are being embolized.

In addition, complications are frequent and side effects have been reported.

However, current brachytherapy seed-dispensing methods dictate less than desirable loading yields, are more expensive, are cumbersome to administer, and render a less than ideal treatment response.

However, this method requires surgical removal of the tumor, which is not always feasible.

However, these sustained release delivery systems administered by direct injection are subject to leakage into surrounding tissues in the absence of an agent, such as a cross-linking agent, or other means to retain the chemotherapeutic within the tumor itself.

However, the preparation is generated outside the body and not in situ in the tumor.

Furthermore, none of the methods or polymer compositions in these patents utilize radionuclides as therapeutic agents.

This process is cumbersome and generates significant loss of therapeutic material, which can be costly.

However, the gel formation is temperature-activated and generates only after sufficient time to reach the required temperature, thereby permitting leakage into surrounding tissues in the meantime.

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