Targeted Delivery of Estrogen in Menopause

更年期雌激素的靶向输送

• 批准号: 6485448
• 负责人: RAVI MT SUBBIAH
• 金额: $ 9.63万
• 依托单位: MOLECULAR DIAGNOSTICS LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6485448
• 关键词: atherosclerotic plaque; cardiovascular agents; cardiovascular pharmacology; coronary disorder; drug delivery systems; estrogen receptors; estrogens; ethanol; hormone related neoplasm /cancer; hormone therapy; intravenous administration; liposomes; low density lipoprotein; macrophage; menopause; topical drug application; vascular endothelium

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.

描述（由申请人提供）：绝经后妇女的冠状动脉 疾病（CAD）是导致死亡的主要原因。雌激素替代疗法 似乎可以为绝经后妇女提供相当大的预防 CAD 的保护作用。 然而，人们非常担心乳腺癌和子宫内膜癌的风险 这些女性长期使用雌激素后。雌激素的激活 受体和随后的细胞生长方面的基因组效应似乎 在雌激素相关的癌症发生中发挥重要作用。我们实验室有 对通过差异化实现雌激素的差异化作用感兴趣 输送至细胞。我们假设所需的心脏保护作用 雌激素（无致癌作用）可以通过以下方式获得： 巨噬细胞优先递送疏水性雌激素 乙酰化低密度脂蛋白 (ac-LDL) 复合物与动脉粥样硬化组织或 b) 将这些雌激素结合到脂质微球中或通过包被 脂蛋白/雌激素与功能化 (Fc) 葡聚糖的复合物，两者 已被用于内皮细胞的优先摄取。第一阶段将 确定 a) 是否静脉注射给予疏水性雌激素会关联 低密度脂蛋白； b) 组织分布和巨噬细胞靶向的可行性 疏水性（MT）和内皮靶向（ET）脂质体制剂 用于差异性递送至巨噬细胞或内皮细胞的雌激素衍生物 c) ET 和 MT 是否具有功能活性。第二阶段将处理他们的 对致动脉粥样硬化指数和合适的脂蛋白样载体的体内影响 和用作透皮贴剂的增强剂。