Functionalized Micellar Nanocarriers for Targeted Cancer Therapy

用于癌症靶向治疗的功能化胶束纳米载体

基本信息

批准号：
7980812
负责人：
Chalet Tan
金额：
$ 47.07万
依托单位：
MERCER UNIVERSITY MACON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7980812
关键词：
Advanced Malignant Neoplasm Amination Antineoplastic Agents Binding Biodistribution Biological Blood Circulation CD44 gene Cells Clinical Trials Cytotoxin Development Drug Delivery Systems Drug Formulations Drug Kinetics Drug resistance Drug toxicity Engineering Ensure Excipients Folate Folic Acid Generations Goals Growth HSP 90 inhibition Heat-Shock Proteins 90 Hepatotoxicity Human Hyaluronic Acid Intravenous Kinetics Ligands Link MCF7 cell Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Micelles Modeling Molecular Mus NMR Spectroscopy Organ Organic solvent product Outcome Ovarian Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase Polyethylene Glycol 2000 Polyethylene Glycols Population Process Property Recurrence Research Series Site Solid Neoplasm Specificity Succinates Surface Therapeutic Time Toxic effect Tumor Tissue Water Xenograft Model anticancer activity base cancer cell cancer stem cell cancer therapy cancer type cytotoxic cytotoxicity density design drug distribution expectation folate-binding protein improved in vivo inhibitor/antagonist intravenous administration malignant breast neoplasm nanocarrier nanomedicine neglect neoplastic cell novel overexpression programs public health relevance success surfactant targeted delivery tumor tumor xenograft tumorigenesis uptake zeta potential

项目摘要

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.

描述（由申请人提供）：分子靶向药物的选择性干扰某些癌症的标志，通常具有轻度的毒性。但是，这些药物通常对肿瘤组织具有不利的分布。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。我们的研究计划的长期目标是设计新颖的胶束纳米载体，其适用于肿瘤靶向药物的范围广泛。 17-丙酰氨基17-甲氧基甘露霉素（17-AAG）是一种有效的热休克蛋白90（HSP90）抑制剂，目前正在患有晚期癌症患者的I阶段I和II临床试验。由于其严重的肝毒性以及当前静脉内配方中使用的大量有毒有机赋形剂，因此17-AAG的治疗结果受到了阻碍。我们的初步研究表明，17-AAG被有效地加载并保留在聚乙烯乙二醇2000-二甲基二酰磷脂酰乙醇胺（PEG2000-DSPE）/ - 生育基因聚乙二醇1000琥珀酸酯1000琥珀酸1000（TPGS）的混合胶束中，没有任何有机溶剂。我们建议将这些混合胶束与叶酸或透明质酸（HA）官能化，以分别靶向FR-或过表达CD44的肿瘤细胞。该提议的中心假设是，叶酸或HA偶联的PEG2000-DSPE/TPGS胶束将在肿瘤组织中提高17-AAG水平，同时将药物分布减少到健康器官，并增强17-AAG的抗癌功效。该提案的具体目的是：（1）生成官能化的PEG2000-DSPE/TPGS胶束纳米载体，以靶向17-AAG；（2）表征17-AAG具有官能化PEG2000-DSPE/TPGS胶束纳米载体的物理化学特性；（3）检查肿瘤细胞中纳入17-AAG的摄取和抗癌活性；（4）评估17-AAG和具有人类肿瘤异种移植物的小鼠的药代动力学，药效学和抗癌功效。公共卫生相关性：该项目的成功完成将确定高效且安全的纳米载体，以针对肿瘤的17 AAG递送，从而大大提高了抗肿瘤功效并降低了药物的毒性。不包含任何有机溶剂，拟议的纳米载体将提供一个强大的纳米医学平台，用于向许多常见的癌症类型提供水溶性差的抗癌药物。重要的是，所提出的纳米载体还经过设计，可将抗癌药物输送到癌症细胞中，肿瘤中罕见的癌细胞群体群体众多，已知对药物治疗具有抗性并引起肿瘤复发。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multi-drug delivery to tumor cells via micellar nanocarriers.

DOI：
10.1016/j.ijpharm.2011.07.033
发表时间：
2011-10-31
期刊：
INTERNATIONAL JOURNAL OF PHARMACEUTICS
影响因子：
5.8
作者：
Katragadda, Usha;Teng, Quincy;Rayaprolu, Bindhu Madhavi;Chandran, Thripthy;Tan, Chalet
通讯作者：
Tan, Chalet

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