Targeted Delivery of Estrogen in Menopause

描述(申请人提供)：绝经后女性的冠状动脉 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冠心病有相当大的保护作用。 然而，乳腺癌和子宫内膜癌的风险是非常令人担忧的。 在这些女性长期使用雌激素后。雌激素的激活作用 受体和随后的基因组效应在细胞生长方面似乎 在雌激素相关的致癌过程中起着重要作用。我们的实验室有 我有兴趣通过不同的方式来实现雌激素的不同效果 传送到细胞。我们假设，预期的心脏保护益处 雌激素(无致癌作用)可通过以下两种途径获得： 以巨噬细胞为靶点优先输送疏水性雌激素 乙酰化低密度脂蛋白(Ac-LDL)复合体与动脉粥样硬化组织或b)通过 将这些雌激素结合成脂质微球或包衣 脂蛋白/雌激素与官能化(Fc)葡聚糖的复合体，两者都 已被用于内皮细胞的优先摄取。第一阶段将 确定a)静脉注射是否服用疏水性雌激素会使 与低密度脂蛋白；b)组织分布和巨噬细胞靶向的可行性 (MT)和内皮靶向(ET)疏水性脂质体的制备 雌激素衍生物对巨噬细胞或内皮细胞的差异性递送 以及c)ET和MT是否在功能上有效。第二阶段将处理他们的 体内对动脉粥样硬化指标的影响及合适的脂蛋白样载体 以及用作透皮贴剂的促进剂。

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.