Functionalized Micellar Nanocarriers for Targeted Cancer Therapy

描述(申请人提供)：分子靶向药物通常有轻微的毒性，因为它们选择性地干扰癌症的某些特征。然而，这些药物通常对肿瘤组织有不利的分布。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，用于肿瘤靶向药物输送。17-烯丙氨基-17-去甲氧基格尔达那霉素(17-AAG)是一种有效的热休克蛋白90(Hsp90)抑制剂，目前正在晚期癌症患者中进行I期和II期临床试验。由于17-AAG的严重肝毒性以及目前静脉注射制剂中使用的大量有毒有机辅料，其治疗结果受到了阻碍。我们的初步研究表明，17-AAG在聚乙二醇2000-二硬脂酰磷脂酰乙醇胺(PEG2000-DSPE)/-生育酚聚乙二醇1000琥珀酸酯(TPGS)混合胶束中被有效地负载和保留，而不需要任何有机溶剂。我们建议用叶酸或透明质酸(HA)对这些混合胶束进行功能化，以分别靶向FR-或CD44高表达的肿瘤细胞。这一建议的中心假设是，叶酸或HA偶联的PEG2000-DSPE/TPGS胶束将增加肿瘤组织中17-AAG的水平，同时减少药物向健康器官的分布，并增强17-AAG的抗癌效果。该建议的具体目的是：(1)制备靶向递送17-AAG的功能化PEG2000-DSPE/TPGS胶束纳米载体；(2)表征17-AAG掺入功能化PEG2000-DSPE/TPGS胶束纳米载体的理化性质；(3)检测17-AAG掺入功能化PEG2000-DSPE/TPGS混合胶束在肿瘤细胞中的摄取及抗癌活性；(4)评价17-AAG掺入功能化PEG2000-DSPE/TPGS混合胶束在荷瘤小鼠体内的药代动力学、药效学和抗癌效果。 与公共卫生相关：该项目的成功完成将为肿瘤靶向传递17-AAG寻找高效和安全的纳米载体，显著提高抗肿瘤疗效并降低药物的毒性。在不包含任何有机溶剂的情况下，所提议的纳米载体将提供一个强大的纳米药物平台，用于向许多常见的癌症类型输送难溶于水的抗癌药物。重要的是，被提议的纳米载体还被设计成将抗癌药物输送到癌症干细胞中，癌症干细胞是肿瘤中一种罕见的癌细胞群体，已知它们对药物治疗具有耐药性，并导致肿瘤复发。

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.