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 tumour 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 tumours.

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  or the use according to  claim 2 , 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 or use according to  claim 3 , wherein the steric stabilising polymeric segment comprises a terminal ionic functional group. 
     
     
         5 . The method or use according to  claim 4 , wherein the ionic functional group is a cation. 
     
     
         6 . The method or use according to any one of  claims 3  to  5 , wherein the steric stabilising polymeric segment of the stabiliser comprises polymer selected from poly(acrylamide), poly(ethylene oxide), poly(hydroxyethylacrylate), poly(N-isopropylacrylamide), poly(dimethylaminoethyl methacrylate), poly(vinyl pyrrolidone), and copolymers thereof. 
     
     
         7 . The method or use according to any one of  claims 1  to  6 , wherein the anchoring portion comprising 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 or use according to any one of  claims 1  to  7 , wherein the stabiliser is a steric stabiliser comprising a steric stabilising polymeric segment and an anchoring polymeric segment. 
     
     
         9 . The method or use 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 or use according to any one of  claims 1  to  9 , wherein the stabiliser has a number average molecular weight of less than about 30,000. 
     
     
         11 . The method or use according to any one of  claims 1  to  10 , wherein the particulate material is selected from 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 or use according to any one of  claims 1  to  11 , wherein the particulate material ranges in size from about 10 nm to about 350 nm. 
     
     
         13 . The method or use according any one of  claims 1  to  12 , wherein said particulate material is iron oxide ranging in size from about 10 nm to about 15 nm. 
     
     
         14 . The method or use according any one of  claims 1  to  12 , wherein said particulate material is gold ranging in size from about 10 nm to about 15 nm. 
     
     
         15 . The method or use according any one of  claims 1  to  12 , wherein said particulate material is silicon oxide ranging in size from about 10 nm to about 15 nm. 
     
     
         16 . The method or use according any one of  claims 1  to  12 , wherein said particulate material is silicon oxide ranging in size from about 30 nm to about 40 nm. 
     
     
         17 . The method or use according any one of  claims 1  to  12 , wherein said particulate material is polystyrene ranging in size from about 10 nm to about 15 nm. 
     
     
         18 . The method or use according to any one of  claims 1  to  17 , wherein said solid tumour is benign. 
     
     
         19 . The method or use according to any one of  claims 1  to  17 , wherein said solid tumour is malignant. 
     
     
         20 . The method or use according to  claim 19 , wherein said malignant solid tumour is metastatic. 
     
     
         21 . The method or use according to any one of  claims 18 - 20 , wherein said solid tumour is a central nervous system tumour, retinoblastoma, neuroblastoma, paediatric tumour, head and neck cancer such as squamous cell cancer, breast and prostate cancer, lung cancer, kidney cancers, such as renal cell adenocarcinoma, oesophagogastric cancer, hepatocellular carcinoma, pancreaticobiliary neoplasia, such as adenocarcinomas and islet cell tumours, colorectal cancer, cervical cancer, anal cancer, uterine or other reproductive tract cancer, urinary tract cancer, such as of the ureter or bladder, germ cell tumour such as a testicular germ cell tumour or ovarian germ cell tumour, ovarian cancer, such as an ovarian epithelial cancer, carcinoma of unknown primary, human immunodeficiency associated malignancy, such as Kaposi's sarcoma, lymphoma, leukemia, malignant melanoma, sarcoma, endocrine tumour, such as of the thyroid gland, mesothelioma or other pleural or peritoneal tumour, neuroendocrine tumour or carcinoid tumour. 
     
     
         22 . The method or use according to any one of  claims 1  to  21 , wherein said cellular toxin is either a cytostatic or a cytocidal agent. 
     
     
         23 . The method or use according to  claim 22 , wherein said agent is selected from 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 or use according to  claim 22 , wherein said agent is selected from a DNA damaging agent (eg. nucleophosmin or agents which induce cellular damage as part of a synergistic process with another agent), a catalytic antibody, prodrugs, CHK1/2 inhibitor (e.g. CBP-501 or AZD7762), histone deacetylase inhibitor (e.g. vorinostat), tumour necrosis factor related apoptosis inducing ligand or BH3 mimetic (e.g. ABT737), small molecule inhibitors such as the tyrosine kinase inhibitors imatinib mesylate, gefitinib, erlotinib, and monoclonal antibodies (e.g. rituximab or trastuzumab). 
     
     
         25 . The method or use according to  claim 22 , wherein said agent is a molecule which functions as an RNA interference mechanism. 
     
     
         26 . The method or use according to  claim 25  wherein said molecule is an RNA oligonucleotide. 
     
     
         27 . The method or use 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 or use according to any one of  claims 1  to  27 , wherein said particle or stabiliser is coupled to a ligand, which ligand is directed to said tumour. 
     
     
         29 . The method or use according to any one of  claims 1  to  28 , wherein said particulate material is administered prior to the cellular toxin. 
     
     
         30 . The method or use according to any one of  claims 1  to  28 , wherein said particulate materials and said cellular toxin are administered simultaneously.