Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability.

Abstract

Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement is obtained in a more clinically relevant setting, we investigated PG-TXL effects on tumor cure. Mice bearing 7-mm-diameter ovarian carcinomas were treated with PG-TXL at an equivalent paclitaxel dose of 80 mg/kg, single dose or 5 daily fractions of radiation or both PG-TXL and radiation. Treatment endpoint was TCD(50) (radiation dose yielding tumor control in 50% of mice). Acute radioresponse of jejunum, skin, and hair was determined for all treatments. PG-TXL dramatically improved tumor radioresponse, reducing TCD(50) of single-dose irradiation from 53.9 (52.2-55.5) Gy to 7.5 (4.5-10.7) Gy, an enhancement factor (EF) of 7.2. The drug improved the efficacy of fractionated irradiation even more, reducing the TCD(50) of 66.6 (62.8-90.4) Gy total fractionated dose to only 7.9 (4.3-11.5) Gy, for an EF of 8.4. PG-TXL did not affect normal tissue radioresponse resulting from either single or fractionated irradiation. PG-TXL dramatically potentiated tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. To our knowledge, PG-TXL increased the therapeutic ratio of radiotherapy more than that previously reported for other taxanes, thus, PG-TXL has a high potential to improve clinical radiotherapy.