Paclitaxel in tyrosine-derived nanospheres as a potential anti-cancer agent: In vivo evaluation of toxicity and efficacy in comparison with paclitaxel in Cremophor

摘要

Paclitaxel (PTX) has gained widespread clinical use yet its administration is associated with significant toxicity. In the present study, the toxicity and anti-tumor efficacy of tyrosine-derived nanospheres (NSP) for the delivery of PTX was compared to a clinical formulation of PTX in PBS-diluted Cremophor^® EL (PTX–CrEL-D). Maximum tolerated dose was determined using a concentration series of PTX in NSP and CrEL-D, with toxicity assessed by measuring changes in body weight. Healthy mice administered PTX–NSP continued to gain weight normally while treatment with PTX–CrEL-D resulted in significant weight loss that failed to recover following treatment. Even at the dose of 50 mg/kg, PTX–NSP showed better tolerance than 25 mg/kg of PTX–CrEL-D. Xenograft studies of breast cancer revealed that the anti-tumor efficacy of PTX–NSP was equal to that of PTX–CrEL-D in tumors originating from both MDA-MB-435 and ZR-75-1 cancer lines. Larger volume of distribution and longer half-life were measured for PTX–NSP administration compared to those reported in the literature for a CrEL formulation. This trend suggests the potential for improved therapeutic index of PTX when administered via NSP. The findings reported here confirm that the NSP formulation is an efficient method for PTX administration with significant increase in maximum tolerated dose, offering possible clinical implications in the treatment of breast tumors.