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The Suppression of Human Prostate Tumor Growth in Mice by the Intratumoral Injection of a Slow-Release Polymeric Paste Formulation of Paclitaxel¹

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada [J. K. J., H. M. B.]; Cancer Endocrinology, British Columbia Cancer Agency, Prostate Cancer Research Group, Jack Bell Research Centre, Vancouver, British Columbia, V6M 3Z6 Canada [M. E. G., V. Y., E. B.]; and Angiotech Pharmaceuticals, Inc., University of British Columbia, Vancouver, British Columbia, V6T 1Z4 Canada [W. L. H.]

Most patients that present in the clinic with prostate cancer have either localized or recurrent postradiotherapy therapy tumors that may be amenable to injectable treatments using slow-release cytotoxic drugs. The objective of this preclinical study was to design an injectable polymeric paste formulation of paclitaxel for intratumoral injection into nonmetastatic human prostate tumors grown s.c. in mice. Paclitaxel was dissolved (10% w/w) in a blend of a biodegradable triblock copolymer of a random copolymer of D,L-lactide and -caprolactone (PLC) with poly(ethyleneglycol) [PEG; PLC-PEG-PLC] blended with methoxypoly(ethylene glycol) in a 40:60 ratio. Human prostate LNCaP tumors grown s.c. in castrated athymic male mice were injected with 100 µl of this paste at room temperature. Changes in tumor progression were assessed using both serum prostate-specific antigen (PSA) levels and tumor size. Paclitaxel inhibited LNCaP cell growth in vitro in a concentration-dependent fashion with an IC₅₀ of 1 nM. Apoptosis was documented using DNA fragmentation analysis. The paste formulation solidified over a period of 1 h both in vivo and in aqueous media at 37°C as the methoxypoly(ethylene glycol) component partitioned out of the insoluble PLC-PEG-PLC/paclitaxel matrix. The semisolid implant released drug at a rate of about 100 µg/day in vitro. In control mice treated with paste without paclitaxel, serum PSA levels increased from 2–8 ng/ml (mean, 4.3 ± 2 ng/ml) to 60–292 ng/ml (mean, 181 ± 88 ng/ml), and tumor volume increased from 30 to 1000 mm³. In mice treated with a single 100-µl injection 3 weeks after castration (early-phase treatment group), tumors decreased in volume from a mean of 43 ± 19 mm³ to nonpalpable, and PSA levels decreased from a mean of 22 ± 8 to 2 ± 1 ng/ml by 8 weeks after castration. In mice treated 5 weeks after castration (androgen-independent tumors; late-phase treatment group), tumors decreased in volume from a mean of 233 ± 136 mm³ to nonpalpable, and serum PSA decreased from 24 ± 8 to 9 ± 4 ng/ml. Observed side effects of the treatment were limited to minor ulceration at the needle injection site in paclitaxel-treated mice only. The controlled-release formulation can be injected via 22-gauge needles and is effective in inhibiting LNCaP tumor growth and PSA levels in mice bearing multiple nonmetastatic tumors. Paclitaxel may be an effective therapy for patients with localized tumors recurring after radiotherapy and for some patients with localized tumors who are not candidates for radical treatment.

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