Targeted Delivery of Estrogen in Menopause

描述（由申请人提供）：在绝经后女性中，冠状动脉 疾病（CAD）是导致死亡的主要原因。雌激素替代疗法 似乎对绝经后妇女的CAD提供了相当大的保护。 然而，人们非常关注乳腺癌和子宫内膜癌的风险 在这些妇女长期使用雌激素后。雌激素的激活 受体和随后在细胞生长方面的基因组效应似乎 在雌激素相关的致癌作用中起重要作用。本实验室 一直有兴趣实现差异的影响雌激素的差异， 递送至细胞。我们假设， 雌激素（无致癌作用）可以通过以下两种方式获得： 选择性释放疏水性雌激素的巨噬细胞 乙酰化LDL（ac-LDL）复合物与动脉粥样硬化组织或B）通过 将这些雌激素结合到脂质微球中或通过包被 脂蛋白/雌激素复合物与功能化的（Fc）葡聚糖，两者都 已经用于内皮细胞的优先摄取。一期将 确定a）静脉内施用的疏水性雌激素是否将与 B）组织分布和巨噬细胞靶向治疗的可行性 (MT)和内皮靶向（ET）的疏水脂质体制剂 用于差异递送至巨噬细胞或内皮细胞的雌激素衍生物 和c）ET和MT是否具有功能活性。第二阶段将处理他们的 对动脉粥样硬化指数和合适的脂蛋白样载体的体内作用 和用作透皮贴剂的增强剂。

DESCRIPTION (provided by applicant): In postmenopausal women, coronary artery disease (CAD) is the leading cause of death. Estrogen replacement therapy appears to offer considerable protection against CAD in postmenopausal women. However, there is great concern about risk for breast and endometrial cancer after long-term estrogen use in these women. The activation of estrogen receptors and subsequent genomic effects in terms of cell growth appears to play a significant role in estrogen-related carcinogenesis. Our laboratory has been interested in achieving a differential effect of estrogens by differential delivery to cells. We hypothesize that desired cardioprotective benefits of estrogens (without carcinogenic effects) can be achieved either through a) macrophages targeted for preferential delivery of hydrophobic estrogen acetylated LDL (ac-LDL) complexes to atherosclerotic tissues or b) by conjugating these estrogens into lipid microspheres or by coating lipoprotein/estrogen complexes with functionalized (Fc) dextran, both of which have been used for preferential uptake by endothelial cells. Phase I will determine a) whether i.v. administered hydrophobic estrogens will associate with LDL; b) tissue distribution and the feasibility of macrophage-targeted (MT) and endothelium-targeted (ET) liposomal preparation of hydrophobic estrogen derivatives for differential delivery to macrophages or endothelium and c) whether ET and MT are functionally active. Phase II will deal with their in vivo effects on atherogenic indices and suitable lipoprotein-like carriers and enhancers for use as transdermal patch.