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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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.
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°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.
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.
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.
KeywordsChitosan Clusterin antisense oligonucleotide Paclitaxel Docetaxel Prostate cancer Complex
Phosphorothioate antisense oligonucleotide
- CC paste
Formulations of an injectable polymeric paste loaded with chitosan complexes
Mismatch oligonucleotide phosphorothioate
Random poly(D,L-lactic acid-co-caprolactone) copolymer
Triblock copolymer of PLC and PEG in the form of PLC-PEG-PLC
Prostate specific antigen
Tris(hydroxymethyl) aminomethane hydrochloride
This work was funded by research funding from ARC Pharmaceuticals Inc. to H.M. Burt and a grant from the Terry Fox Program Project of the National Cancer Institute of Canada to M.E. Gleave. A technology grant from the Science Council of British Columbia to ARC Pharmaceuticals Inc. is gratefully acknowledged. We thank Virginia Yago for her excellent technical assistance.
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