Biodistribution of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor

Purpose: Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a water-soluble pacli taxel (TXL) conjugate made by conjugating TXL to poly(L-glutamic; acid) via ester bonds. In preclinical studies, PG-TXL has shown significant antitumo r activity against a variety of solid tumors. To elucidate the relationship between tissue distribution and antitumor efficacy of PG-TXL, we studied a nd compared the biodistribution of PG-TXL and TXL. Methods: Female C3Hf/Kam mice bearing syngeneic ovarian OCa-1 tumors were injected with either [H-3 ]TXL or PG-[H-3]TXL at an equivalent TXL dose of 20 mg/kg. Mice were killed at various times after drug injection, and samples of blood, spleen, liver , kidney, lung, heart, muscle, brain, fat, and tumor were removed and the r adioactivity counted. In addition. concentrations of free [H-3]TXL released from PG[H-3]TXL in the spleen, liver, kidney, and tumor were analyzed by u sing high-performance liquid chromatography (HPLC). Whole-body autoradiogra phs of mice killed 1 day and 6 days after administration of PG-[H-3]TXL wer e obtained to study the intratumoral distribution of PG-TXL. Results: When [H-3]TXL was conjugated to polymer, the biodistribution pattern of PG-[H-3] TXL differed from that of [H-3]TXL. Based on area under the tissue concentr ation-time curve (AUC) values, tumor exposure to [H-3]TXL was five times gr eater when administered as PG-TXL than as TXL formulated in Cremophor EL/al cohol vehicle. Furthermore, concentrations of free paclitaxel released from PG-[H-3]TXL remained relatively constant in tumor tissue, being 489, 949 a nd 552 ng/g tumor tissue at 5, 48 and 144 h after dosing, respectively. Aut oradiographic images of mice injected with PG-[H-3]TXL revealed that radioa ctivity was primarily located in the periphery of the tumor on day 1 after drug administration and was homogeneously diffused into the center of the t umor by day 6. Over the 144-h study period, [H-3]TXL concentrations, predom inantly as the inactive conjugate, were higher in tissues with a more abund ant reticular endothelial system (i.e, liver, kidney, spleen, lung) than in tissues with less abundant or lacking RE systems (i.e. muscle, rat, brain) . Both [H-3]TXL and PG [H-3]TXL were excreted primarily through the hepatob iliary route, with a small fraction of each drug (5% and 8.7%, respectively ) excreted into the urine within 48 h. Conclusions: This study indicates th at the distribution to tumor tissue was enhanced when [H-3]TXL was administ ered as a macromolecular conjugate, and that free TXL was released and main tained within the tumor for a prolonged period. Thus, the antitumor activit y of PG-TXL observed in preclinical studies may be attributed in part to en hanced tumor uptake of PG-TXL.