The suppression of human prostate tumor growth in mice by the injection ofa slow-release polymeric paste formulation of paclitaxel

Most patients that present in the clinic with prostate cancer have either l ocalized 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 formu lation of paclitaxel for intratumoral injection into nonmetastatic human pr ostate tumors grown s.c. in mice. Paclitaxel was dissolved (10% w/w) in a b lend of a biodegradable triblock copolymer of a random copolymer of D,L-lac tide and epsilon-caprolactone (PLC) with poly(ethyleneglycol) [PEG; PLC-PEG -PLC] blended with methoxypoly(ethylene glycol) in a 40:60 ratio. Human pro state LNCaP tumors grown s.c. in castrated athymic male mice were injected with 100 mu l of this paste at room temperature. Changes in tumor progressi on were assessed using both serum prostate-specific antigen (PSA) levels an d tumor size. Paclitaxel inhibited LNCaP cell growth in vitro in a concentr ation-dependent fashion with an IC50 of 1 nM. Apoptosis was documented usin g DNA fragmentation analysis. The paste formulation solidified over a perio d of 1 h both in vivo and in aqueous media at 37 degrees C as the methoxypo ly(ethylene glycol) component partitioned out of the insoluble PLC-PEG-PLC/ paclitaxel matrix. The semisolid implant released drug at a rate of about 1 00 mu g/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 60-2 92 ng/ml (mean, 181 +/- 88 ng/ml), and tumor volume increased from 30 to 10 00 mm(3). In mice treated with a single 100-mu l injection 3 weeks after ca stration (early-phase treatment group), tumors decreased in volume from a m ean of 43 +/- 19 mm(3) 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 mm(3) to non palpable, 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 needl e injection site in paclitaxel-treated mice only. The controlled-release fo rmulation can be injected via 22-gauge needles and is effective in inhibiti ng 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 t umors who are not candidates for radical treatment.