Functionalized Micellar Nanocarriers for Targeted Cancer Therapy

描述（由申请人提供）：分子靶向药物通常具有轻微的毒性，因为它们选择性地干扰癌症的某些特征。然而，这些药物通常不利于肿瘤组织的分布。此外，严重的毒性可能与用于溶解高亲脂性药物分子的有机溶剂/表面活性剂有关。我们研究计划的长期目标是设计具有广泛适用性的新型胶束纳米载体，用于肿瘤靶向药物的递送。17-烯丙胺-17-demethoxygeldanamycin （17-AAG）是一种有效的热休克蛋白90 （Hsp90）抑制剂，目前正在进行晚期癌症患者的I期和II期临床试验。17-AAG的治疗效果由于其严重的肝毒性以及目前静脉制剂中使用的大量有毒有机赋形剂而受到阻碍。我们的初步研究表明，在没有任何有机溶剂的情况下，17-AAG在聚乙二醇2000-二硬脂酰磷脂酰乙醇胺(PEG2000-DSPE)/-生育酚基聚乙二醇1000 -琥珀酸酯（TPGS）混合胶束中有效地装载和保留。我们建议用叶酸或透明质酸（HA）功能化这些混合胶束，分别靶向FR-或cd44 -过表达的肿瘤细胞。本研究的中心假设是叶酸或ha偶联PEG2000-DSPE/TPGS胶束会增加肿瘤组织中17-AAG的水平，同时减少药物向健康器官的分布，从而增强17-AAG的抗癌功效。该提案的具体目标是：(1)生成功能化的PEG2000-DSPE/TPGS胶束纳米载体，用于靶向递送17-AAG；(2)表征了功能化PEG2000- DSPE/TPGS胶束纳米载体17- aag的理化性质；(3)检测17-AAG-结合功能化PEG2000-DSPE/TPGS混合胶束在肿瘤细胞中的摄取和抗癌活性；(4)评价含功能化PEG2000-DSPE/TPGS混合胶束的17- aag在人肿瘤移植小鼠体内的药代动力学、药效学和抗癌效果。

DESCRIPTION (provided by applicant): The molecularly targeted drugs often have mild toxicities because of their selective interfere with certain hallmarks of cancer. However, these agents commonly have unfavorable distribution to the tumor tissue. In addition, serious toxicities may be associated with the organic solvents/surfactants that are used to dissolve the highly lipophilic drug molecules. The long-term goal of our research program is to devise novel micellar nanocarriers with broad applicability for tumor- targeted drug delivery. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a potent heat shock protein 90 (Hsp90) inhibitor that is currently undergoing Phases I and II clinical trials in patients with advanced cancers. The therapeutic outcomes of 17-AAG have been hampered owing to its severe hepatotoxicity as well as the large amount of toxic organic excipients used in the current intravenous formulations. Our preliminary studies have demonstrated that 17-AAG is efficiently loaded and retained within polyethylene glycol 2000-distearoylphosphatidylethanolamine (PEG2000-DSPE)/- tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles without the inclusion of any organic solvents. We propose to functionalize these mixed micelles with folic acid or hyaluronic acid (HA), to target FR-- or CD44-overexpressing tumor cells, respectively. The central hypothesis of this proposal is that folate- or HA-conjugated PEG2000-DSPE/TPGS micelles will increase 17-AAG levels in the tumor tissue while reducing the drug distribution to the healthy organs, and enhance the anticancer efficacy of 17-AAG. The specific aims of the proposal are: (1) To generate the functionalized PEG2000-DSPE/TPGS micellar nanocarriers for the targeted delivery of 17-AAG; (2) To characterize the physicochemical properties of 17-AAG-incorporating functionalized PEG2000- DSPE/TPGS micellar nanocarriers; (3) To examine the uptake and anticancer activity of 17-AAG- incorporating functionalized PEG2000-DSPE/TPGS mixed micelles in tumor cells; and (4) To evaluate the pharmacokinetics, pharmacodynamics and anticancer efficacy of 17-AAG-incorporating functionalized PEG2000-DSPE/TPGS mixed micelles in mice bearing human tumor xenografts. PUBLIC HEALTH RELEVANCE: The successful completion of this project will identify highly effective and safe nanocarriers for tumor-targeted delivery of 17-AAG, significantly enhancing the antitumor efficacy and reducing the toxicities of the drug. Without the inclusion of any organic solvents, the proposed nanocarriers will provide a robust nanomedicine platform for delivering poorly water-soluble anticancer drugs to many common cancer types. Importantly, the proposed nanocarriers are also engineered to delivery anticancer drugs into cancer stem cells, a rare population of cancer cells in the tumor which are known to be resistant to drug therapy and cause tumor recurrence.