In vitro and in vivo biologic evaluation of long-circulating biodegradable drug carriers loaded with the pure antiestrogen RU 58668.

We have developed a parenteral delivery system for the administration of the highly promising pure antiestrogen RU 58668 (RU). Two types of nanoparticles (NP) made of biodegradable copolymers and coated with polyethylene-glycol (PEG) chains were prepared: nanospheres (NS) (diameter, approximately 110 nm) and nanocapsules (NC) with an oily core (diameter, approximately 250 nm). The amount of RU incorporated into NS and NC was approximately 33 vs. approximately 5 microg RU/mg of polymer, respectively. Coating with PEG chains prolonged the antiestrogenic potency of RU, as shown by a prolonged antiuterotrophic activity of encapsulated RU into PEG-poly(D,L lactic acid) (PLA) NS, as compared to that of conventional nonpegylated NS. In mice bearing MCF-7 estrogen-dependent tumors, free RU injected at 4.3 mg/kg/week by i.v. route slightly decreased the estradiol-promoted (0.5 mg/kg/week) tumor growth while RU-loaded PEG-PLA NS injected at the same dose strongly reduced it. Analysis of cell cycle parameters in tumors treated with RU indicated that RU-loaded PEG-PLA NS injected at 4.3 mg/kg/week in MCF-7 tumors decreased cyclin D(1) and cyclin E simultaneously, and increased p27. The antitumoral activity of RU encapsulated within pegylated NC was stronger than that of RU entrapped with pegylated NS loaded at an equivalent dose. Indeed, the former decreased the tumor size in nude mice transplanted with the estrogen receptor-positive but estrogen-independent MCF-7/Ras breast cancer cells at a concentration 2.5 times lower than that of the latter (0.4 mg/kg/week compared to 1 mg/kg/week). Empty PEG-PLA NS and NC were devoid of antiuterotrophic and antitumoral activities. Altogether, these results suggest that the incorporation of the pure antiestrogen RU into long-circulating NP could represent a novel antiestrogen drug delivery system for the parenteral route.