Efficacy of an intratumoral controlled release formulation of clusterin antisense oligonucleotide complexed with chitosan containing paclitaxel or docetaxel in prostate cancer xenograft models.
| Title: | Efficacy of an intratumoral controlled release formulation of clusterin antisense oligonucleotide complexed with chitosan containing paclitaxel or docetaxel in prostate cancer xenograft models. |
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| Authors: | Springate CM; ARC Pharmaceuticals Inc, 102-2386 East Mall, Vancouver, BC, Canada, V6T 1Z3.; Jackson JK; Gleave ME; Burt HM |
| Source: | Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2005 Sep; Vol. 56 (3), pp. 239-47. Date of Electronic Publication: 2005 Apr 30. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0344-5704 (Print) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Berlin : Springer Verlag; Original Publication: Berlin, New York, Springer International. |
| MeSH Terms: | Adenocarcinoma/*drug therapy ; Antineoplastic Agents, Phytogenic/*pharmacology ; Chitosan/*administration & dosage ; Glycoproteins/*administration & dosage ; Molecular Chaperones/*administration & dosage ; Oligonucleotides, Antisense/*administration & dosage ; Prostatic Neoplasms/*drug therapy ; Taxoids/*administration & dosage; Adenocarcinoma/pathology ; Antineoplastic Agents, Phytogenic/chemistry ; Cell Line, Tumor/drug effects ; Chitosan/chemistry ; Glycoproteins/chemistry ; Molecular Chaperones/chemistry ; Oligonucleotides, Antisense/chemistry ; Paclitaxel/administration & dosage ; Paclitaxel/chemistry ; Prostatic Neoplasms/pathology ; Taxoids/chemistry ; Animals ; Chemistry, Pharmaceutical ; Clusterin ; Delayed-Action Preparations ; Docetaxel ; Drug Therapy, Combination ; Humans ; Injections, Intralesional ; Male ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Ointments ; Transplantation, Heterologous ; Xenograft Model Antitumor Assays |
| Abstract: | Purpose: To develop and evaluate an injectable, controlled release delivery system for a phosphorothioate antisense oligonucleotide (ASO) based on complexed ASO:chitosan dispersed in a biodegradable polymeric paste for intratumoral treatment of solid tumors.; Methods: Clusterin ASO was complexed with chitosan particles and incorporated into a paste based on a 60:40 blend of methoxy-poly(ethylene glycol) (MePEG) and triblock copolymer of poly(D: ,L: -lactic acid-co-caprolactone)-PEG-(D: ,L: -lactic acid-co-caprolactone). In vitro release profiles of clusterin ASO into phosphate-buffered saline at 37 degrees C were obtained under sink conditions and assayed by anionic exchange high-performance liquid chromatography. In vivo efficacy studies were carried out in human prostate PC-3 and LNCaP tumors grown subcutaneously in mice. Paste formulations of clusterin ASO with or without paclitaxel or docetaxel were injected intratumorally and tumor volumes and serum prostate specific antigen (PSA) levels were measured.; Results: Controlled release of clusterin ASO was obtained over several weeks. The rate and extent of ASO release was proportional to the ratio of ASO to chitosan in the paste. Treatment of mice bearing PC-3 tumors with clusterin ASO plus paclitaxel or docetaxel paste had reduced mean tumor volume by greater than 50% at 4 weeks. Treatment of mice bearing LNCaP tumors with clusterin ASO plus paclitaxel reduced mean tumor volume and serum PSA level by more than 50% and 70%, respectively.; Conclusions: Complexation of clusterin ASO with chitosan and incorporation into polymeric paste with paclitaxel or docetaxel produced in vitro controlled release of the ASO and in vivo efficacy over 4 weeks following a single intratumoral injection in solid human prostate tumors in mice. |
| Substance Nomenclature: | 0 (Antineoplastic Agents, Phytogenic); 0 (CLU protein, human); 0 (Clu protein, mouse); 0 (Clusterin); 0 (Delayed-Action Preparations); 0 (Glycoproteins); 0 (Molecular Chaperones); 0 (Ointments); 0 (Oligonucleotides, Antisense); 0 (Taxoids); 15H5577CQD (Docetaxel); 9012-76-4 (Chitosan); P88XT4IS4D (Paclitaxel) |
| Entry Date(s): | Date Created: 20050503 Date Completed: 20050816 Latest Revision: 20181201 |
| Update Code: | 20260130 |
| DOI: | 10.1007/s00280-004-0997-5 |
| PMID: | 15864591 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't