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

Abstract

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, ϳ110 nm) and nanocapsules (NC) with an oily core (diameter, ϳ250 nm). The amount of RU incorporated into NS and NC was ϳ33 vs. Key words: breast cancer; antiestrogen; drug delivery; nanoparticlesHormone therapy consists of the abrogation of signals carried by natural hormones in order to block their biologic effects. This type of therapy has been used as a treatment for hormone-dependent cancers for more than 30 years. Worldwide, close to 1 million women per year are diagnosed with breast cancer. 1 Of all breast cancer patients, about one-third respond to hormone therapy, and this response is unfortunately only transient with a median duration of about 18 months. 2 Endocrine therapy of hormone-dependent breast cancer consists of a variety of both medical and surgical ablative treatment modalities aiming at suppressing the mitogenic action of endogenous estradiol. 3 The classic mechanism by which estradiol exerts its effects is through binding to its intranuclear receptor (estradiol receptor (ER)) and the activation of target genes that promote cell cycle progression and tumor growth in breast cancer. A number of molecules displaying partial or total antagonistic activity have been synthesized. 3 However, the recent discovery of a second ER, ER␤, 4 has considerably complicated our understanding of the mechanism of action of estradiol and also of the pharmacology of these antiestrogenic molecules. 5 Tamoxifen (Nolvadex), delivered orally at 40 mg/day, is the most frequently used antiestrogen at the moment. Tamoxifen and its active metabolite 4-hydroxy-tamoxifen are mixed antagonists/agonists whose activity is determined by the nature of the promoter to which ER binds, the nature of the ER (␣ or ␤) predominantly present in the tissue and the cellular content in terms of the coactivator/coinhibitor ratio. 5 For example, tamoxifen acts as a strong antagonist in the breast, but behaves as a full agonist in the uterus where it can induce carcinomas. 3 Thus, tamoxifen appears as an archetypal selective estrogen receptor modulator (SERM), with several undesirable side effects (hot flashes, induction of uterine cancers), but also some beneficial effects in the skeleton (inhibitory of bone resorption) as well as in the cardiovascular and central nervous systems (decrease of the incidence of coronary heart disease, improvement of cognitive function and delay of the onset of Alzheimer's disease, respectively (see MacGregor and Jordan 3 and references cited therein). Unfortunately, tamoxifen resistance always occurs, and in that case, a blockade of E 2 synthesis by aromatase inhibitors is sometimes of benefit (see Simpson et al. 6 for a review). In other cases, there is no response to aromatase inhibitors. Thus, despite encouraging improvements...

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