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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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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°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.

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Abbreviations

ASO:

Phosphorothioate antisense oligonucleotide

CC:

Chitosan complexes

CC paste:

Formulations of an injectable polymeric paste loaded with chitosan complexes

MePEG:

Methoxy-poly(ethylene glycol)

MMO:

Mismatch oligonucleotide phosphorothioate

PEG:

Poly(ethylene glycol)

PLC:

Random poly(D,L-lactic acid-co-caprolactone) copolymer

PLC-PEG-PLC:

Triblock copolymer of PLC and PEG in the form of PLC-PEG-PLC

PSA:

Prostate specific antigen

Trizma:

Tris(hydroxymethyl) aminomethane hydrochloride

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Acknowledgements

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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Authors and Affiliations

  1. ARC Pharmaceuticals Inc, 102-2386 East Mall, Vancouver, BC, Canada, V6T 1Z3

    Christopher M. K. Springate

  2. Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada, V6T 1Z4

    Christopher M. K. Springate, John K. Jackson & Helen M. Burt

  3. The Prostate Centre, Vancouver General Hospital, Division of Urology, The University of British Columbia, Vancouver, BC, Canada, V6H 3Z3

    Martin E. Gleave

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  1. Christopher M. K. Springate
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  2. John K. Jackson
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  4. Helen M. Burt
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Correspondence to Helen M. Burt.

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Springate, C.M.K., Jackson, J.K., Gleave, M.E. et al. Efficacy of an intratumoral controlled release formulation of clusterin antisense oligonucleotide complexed with chitosan containing paclitaxel or docetaxel in prostate cancer xenograft models. Cancer Chemother Pharmacol 56, 239–247 (2005). https://doi.org/10.1007/s00280-004-0997-5

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