Method for the Treatment of a Solid Tumour

Abstract

The present invention relates generally to a method of treating a neoplastic condition and to agents useful for same. More particularly, the present invention is directed to a method of facilitating the treatment of a solid tumor in a localised manner via the co-administration of particulate material and a cellular toxin. The method of the present invention is useful in a range of therapeutic treatments including the treatment of primary and metastatic tumors.

1 . A method of treating a solid tumour in a subject, said method comprising co-administering to said subject an effective amount of particulate material and a cellular toxin for a time and under conditions sufficient to facilitate distribution of said particulate material and toxin to said tumour wherein:
 (i) said particulate material is administered in the form of a dispersion in a liquid carrier, the particulate material being maintained in the dispersed state by a stabiliser; and   (ii) said stabiliser comprising an anchoring portion that (a) anchors the stabiliser to the particulate material, and (b) is different from the remainder of the stabiliser;   and wherein said particulate material and toxin penetrate said solid tumour.   
     
     
         2 . Use of particulate material and a cellular toxin in the manufacture of a medicament for the treatment of a solid tumour wherein:
 (i) said particulate material is in the form of a dispersion in a liquid carrier, the particulate material being maintained in the dispersed state by a stabiliser; and   (ii) said stabiliser comprising an anchoring portion that (a) anchors the stabiliser to the particulate material, and (b) is different from the remainder of the stabiliser;   and wherein said particulate material and toxin penetrate said solid tumour.   
     
     
         3 . The method according to  claim 1 , wherein the stabiliser is a steric stabiliser comprising a steric stabilising polymeric segment and an anchoring portion, wherein the steric stabilising polymeric segment is different from the anchoring portion, and wherein the anchoring portion anchors the stabiliser to the particulate material. 
     
     
         4 . The method according to  claim 3 , wherein the steric stabilising polymeric segment comprises a terminal ionic functional group. 
     
     
         5 . The method according to  claim 4 , wherein the ionic functional group is a cation. 
     
     
         6 . The method according to  claim 3 , wherein the steric stabilising polymeric segment of the stabiliser comprises polymer selected from the group consisting of poly(acrylamide), poly(ethylene oxide), poly(hydroxyethylacrylate), poly(N-isopropylacrylamide), poly(dimethylaminoethyl methacrylate), poly(vinyl pyrrolidone), and copolymers thereof. 
     
     
         7 . The method according to  claim 1 , wherein the anchoring portion comprises one or more carboxylic acid groups, one or more phosphate groups, one or more phosphinate groups, one or more thiol groups, one or more thiocarbonylthio groups, one or more sulfonic acid groups, ethoxysilyl groups, or combinations thereof. 
     
     
         8 . The method according to  claim 1 , wherein the stabiliser is a steric stabiliser comprising a steric stabilising polymeric segment and an anchoring polymeric segment. 
     
     
         9 . The method according to  claim 8 , wherein one or both of the steric stabilising and anchoring polymeric segments comprise the polymerised residue of one or more ethylenically unsaturated monomers. 
     
     
         10 . The method according to  claim 1 , wherein the stabiliser has a number average molecular weight of less than about 30,000. 
     
     
         11 . The method according to  claim 1 , wherein the particulate material is selected from the group consisting of a metal, a metal alloy, a metal salt, a metal complex, a metal oxide, an inorganic oxide, a radioactive isotope, a polymer particle, and combinations thereof. 
     
     
         12 . The method according to  claim 1 , wherein the particulate material ranges in size from about 10 nm to about 350 nm. 
     
     
         13 . The method according to  claim 1 , wherein said particulate material is iron oxide ranging in size from about 10 nm to about 15 nm. 
     
     
         14 . The method according to  claim 1 , wherein said particulate material is gold ranging in size from about 10 nm to about 15 nm. 
     
     
         15 . The method according to  claim 1 , wherein said particulate material is silicon oxide ranging in size from about 10 nm to about 15 nm. 
     
     
         16 . The method or use according to  claim 1 , wherein said particulate material is silicon oxide ranging in size from about 30 nm to about 40 nm. 
     
     
         17 . The method according to  claim 1 , wherein said particulate material is polystyrene ranging in size from about 10 nm to about 15 nm. 
     
     
         18 . The method according to  claim 1 , wherein said solid tumour is benign. 
     
     
         19 . The method according to  claim 1 , wherein said solid tumour is malignant. 
     
     
         20 . The method according to  claim 19 , wherein said malignant solid tumour is metastatic. 
     
     
         21 . The method according to  claim 18 , wherein said solid tumour is a central nervous system tumour, retinoblastoma, neuroblastoma, paediatric tumour, head and neck cancer, such as squamous cell cancer, breast cancer, prostate cancer, lung cancer, kidney cancers, renal cell adenocarcinoma, oesophagogastric cancer, hepatocellular carcinoma, pancreaticobiliary neoplasia, adenocarcinomas, islet cell tumours, colorectal cancer, cervical cancer, anal cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, ureter cancer, bladder cancer, germ cell tumour, testicular germ cell tumour, ovarian germ cell tumour, ovarian cancer, ovarian epithelial cancer, carcinoma of unknown primary, human immunodeficiency associated malignancy, Kaposi's sarcoma, lymphoma, leukemia, malignant melanoma, sarcoma, endocrine tumour, thyroid gland tumour, mesothelioma, or other pleural tumour, peritoneal tumour, neuroendocrine tumour or carcinoid tumour. 
     
     
         22 . The method according to  claim 1 , wherein said cellular toxin is either a cytostatic or a cytocidal agent. 
     
     
         23 . The method according to  claim 22 , wherein said agent is selected from the group consisting of Actinomycin D, Adriamycin, Arsenic Trioxide, Asparaginase, Bleomycin, Busulfan, Camptosar, Carboplatinum, Carmustine, Chlorambucil, Cisplatin, Corticosteroids, Colicheamicin, Cyclophosphamide, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabina, Gemcitabine, Gemzar, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Melphalan, Mercaptomurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Platinol, Platinex, Procarbizine, Raltitrexeel, Rixin, Steroids, Streptozocin, Taxol, Taxotere, Thioguanine, Thiotepa, Tomudex, Topotecan, Treosulfan, Trihydrate, Vinblastine, Vincristine, Vindesine, Vinorelbina, Vinorelbine, duanomycin, dactinomysin, esorubisin, mafosfamide, cytosine arabinoside, bis-chloroethylnitrosurea, Mitomycin C, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, hexamethylmelamine, pentamethylmelamine, amsacrine, chlorambudil, methylcyclohexylnitrosurea, nitrogen mustards, Cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, deoxyco-formycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), colchicine, trimetrexate, teni-poside, and diethylstilbestrol. 
     
     
         24 . The method according to  claim 22 , wherein said agent is selected from the group consisting of a DNA damaging agent, nucleophosmin, agents which induce cellular damage as part of a synergistic process with another agent, a catalytic antibody, prodrugs, CHK1/2 inhibitor, CBP-501, AZD7762, histone deacetylase inhibitor, vorinostat, tumour necrosis factor related apoptosis inducing ligand, BH3 mimetic, ABT737, small molecule inhibitors, tyrosine kinase inhibitors, imatinib mesylate, gefitinib, erlotinib, monoclonal antibodies, rituximab and trastuzumab. 
     
     
         25 . The method according to  claim 22 , wherein said agent is a molecule which functions as an RNA interference mechanism. 
     
     
         26 . The method according to  claim 25  wherein said molecule is an RNA oligonucleotide. 
     
     
         27 . The method according to  claim 26 , wherein said RNA oligonucleotide is long double stranded RNA (dsRNA), hairpin double stranded RNA (hairpin dsRNA), short interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA/small temporal RNA (miRNA/stRNA), miRNAs which mediate spatial development (sdRNAs), the stress response (srRNAs) or cell cycle (ccRNAs), RNA oligonucleotides designed to hybridise and prevent the functioning of endogenously expressed miRNA or stRNA or exogenously introduced siRNA. 
     
     
         28 . The method according to  claim 1 , wherein said particle or stabiliser is coupled to a ligand, which ligand is directed to said tumour. 
     
     
         29 . The method according to  claim 1 , wherein said particulate material is administered prior to the cellular toxin. 
     
     
         30 . The method according to  claim 1 , wherein said particulate materials and said cellular toxin are administered simultaneously.