UBC Theses and Dissertations
An intratumoral controlled release formulation of clusterin antisense oligonucleotide and paclitaxel or docetaxel for treatment of prostate tumors Springate, Christopher Michael Kevin
The localized controlled delivery of both phosphorothioated clusterin antisense oligonucleotide (clusterin ASO) and paclitaxel or docetaxel to prostate tumors to maintain therapeutic concentrations of the agents at the target disease site was investigated in this work. The primary objectives were to develop and characterize the physicochemical properties, drug release profiles and efficacy in prostate cancer models, of intratumoral, controlled release polymeric paste formulations of clusterin ASO and paclitaxel or docetaxel. A solvent loading process was used to complex polyanionic clusterin ASO with polycationic chitosan microparticles (microparticulate CC complexes). CC complexes were incorporated into an injectable, biodegradable paste based on a 40/60 blend of triblock copolymer poly(D,L-lactide-co-caprolactone)-block-poly(ethylene glycol)-block-(D,L-lactide-cocaprolactone) and methoxy-poly(ethylene glycol) (CC paste). CC paste formed a semi-solid implant when injected into aqueous media or tissue. Physicochemical characterization of CC complexes showed that the amount of clusterin ASO complexed with chitosan was dependent on the ASO:chitosan ratio and the pH. In vitro release of ASO from CC paste in phosphate buffered saline (PBS) at 37°C was assayed by HPLC and showed that the release of ASO was influenced by ASO:chitosan ratios, pH, phosphate ion concentration and the presence or absence of polymer paste. Increasing the amount of chitosan or decreasing the pH resulted in slower ASO release rates as a result of the increased number of positively charged amine groups within the chitosan available forcomplexation with ASO. In vitro release of clusterin ASO and its 20-, 19- and 18-mer degradation products from CC paste into human plasma at 37°C was assayed by capillary gel electrophoresis (CGE). The data showed that degradation of 21-mer clusterin ASO occurred in the plasma and suggested that the polymer paste protected ASO from nuclease degradation. Treatment of mice bearing human prostate PC-3 or LNCaP tumors with an intratumoral injection of CC pastes loaded with clusterin ASO plus paclitaxel or docetaxel reduced mean tumor volumes and serum PSA levels 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 agents and in vivo efficacy over four weeks following a single intratumoral injection in solid human prostate tumors in mice.
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