Efficacy of an intratumoral controlled release formulation of clusterin antisense oligonucleotide complexed with chitosan containing paclitaxel or docetaxel in prostate cancer xenograft models.
OBJECTIVE
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.
Springate
Christopher M K
CM
ARC Pharmaceuticals Inc, 102-2386 East Mall, Vancouver, BC, Canada, V6T 1Z3.
Jackson
John K
JK
Gleave
Martin E
ME
Burt
Helen M
HM
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000008:administration & dosage* / Q000737:chemistry; D051152:Clusterin; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D006023:Glycoproteins / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000008:administration & dosage* / Q000737:chemistry; D009368:Neoplasm Transplantation; D009824:Ointments; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D003692:Delayed-Action Preparations; D006023:Glycoproteins; D018832:Molecular Chaperones; D009824:Ointments; D016376:Oligonucleotides, Antisense; D043823:Taxoids; D000077143:Docetaxel; D048271:Chitosan; D017239:Paclitaxel