NANOTHERAPEUTIC STRATEGY FOR MULTIDRUG RESISTANT TUMORS

多重耐药肿瘤的纳米治疗策略

基本信息

批准号：
7127627
负责人：
Mansoor M Amiji
金额：
$ 36.05万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2009-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The development of multi-drug resistance (MDR) is a major cause of failure in chemotherapeutic management of cancer. In breast cancer, for instance, more than 50% of the patients relapse due to acquired resistance to standard chemotherapy regimens. Novel strategies to overcome MDR in a clinically meaningful way that does not expose the patients to significant toxicity are urgently needed. In the proposed study, our strategy to overcome MDR in vivo relies on a multifunctional approach to optimize delivery of pro-apoptotic drugs to the tumor mass, increase the intracellular drug concentrations, and reverse cellular resistance by modulating ceramide levels. The preliminary studies show that we can prepare tumor-targeted biodegradable polymer-based engineered nanocarriers (PENS) for encapsulation of hydrophobic pro-apoptotic drugs, like paclitaxel. We have also found that increasing intracellular ceramide concentrations by delivery from exogenous source or inhibiting the metabolism results in significant enhancement of cytotoxicity in sensitive and resistant tumor cells. C6-ceramide and tamoxifen, a potent inhibitor of ceramide metabolism, were co-administered with paclitaxel for synergistic activity in tumor cells and in vivo. Based on these preliminary findings, we are confident that PENS, developed using engineering design criteria, can be made to efficiently deliver multiple therapeutic agents to the tumor mass. The specific aims of the proposal are: (1) to develop, characterize, and optimize long-circulating, biodegradable polymeric nanocarriers with encapsulated paclitaxel, ceramide, and tamoxifen, either alone or in combination, (2) to evaluate the uptake, distribution, intracellular concentrations of paclitaxel, ceramide, and tamoxifen, cytotoxicity, and apoptotic activity in culture of sensitive and resistant tumor cells, (3) to examine the biodistribution and pharmacokinetic profiles of drugs administered in the control and nanocarrier formulations in sensitive and resistant xenograft tumor models established in nude mice, (4) to determine the antitumor efficacy of single and combination therapy in PENS in sensitive and resistant xenograft models, and (5) use mathematical modeling to improve the design of nanocarriers for tumor-targeted delivery of single and combination drug therapy. The results of this study would be extremely valuable in the treatment of refractory tumors using a multifunctional nanotherapeutic approach that efficiently delivers the drug and can overcome cellular resistance. The multimodal nanocarrier strategy proposed here would provide a translatable approach to overcome MDR in cancer patients.

描述（由申请人提供）：多药耐药性（MDR）的发展是癌症化疗失败的主要原因。例如，在乳腺癌中，超过 50% 的患者由于对标准化疗方案产生耐药性而复发。迫切需要以具有临床意义的方式克服 MDR 的新策略，且不会使患者暴露于显着的毒性。在拟议的研究中，我们克服体内多药耐药的策略依赖于多功能方法来优化促凋亡药物向肿瘤块的递送，增加细胞内药物浓度，并通过调节神经酰胺水平逆转细胞耐药性。初步研究表明，我们可以制备肿瘤靶向的可生物降解聚合物基工程纳米载体（PENS），用于封装疏水性促凋亡药物，如紫杉醇。我们还发现，通过外源递送或抑制代谢来增加细胞内神经酰胺浓度会导致敏感和耐药肿瘤细胞的细胞毒性显着增强。 C6-神经酰胺和他莫昔芬（神经酰胺代谢的有效抑制剂）与紫杉醇共同给药，以在肿瘤细胞和体内发挥协同活性。基于这些初步发现，我们相信使用工程设计标准开发的 PENS 可以有效地将多种治疗药物递送至肿瘤块。该提案的具体目标是：(1) 开发、表征和优化长循环、可生物降解的聚合物纳米载体，其中包含单独或组合的封装紫杉醇、神经酰胺和他莫昔芬，(2) 评估其吸收、分布、敏感和耐药肿瘤细胞培养物中紫杉醇、神经酰胺和他莫昔芬的细胞内浓度、细胞毒性和凋亡活性，(3) 检查在裸鼠建立的敏感和耐药异种移植肿瘤模型中，对照和纳米载体制剂中施用的药物的生物分布和药代动力学特征，（4）确定PENS中单一和联合疗法在敏感和耐药异种移植模型中的抗肿瘤功效，以及（5 ）使用数学模型来改进纳米载体的设计，用于肿瘤靶向递送单一和组合药物治疗。这项研究的结果对于使用多功能纳米治疗方法治疗难治性肿瘤非常有价值，该方法可以有效地输送药物并克服细胞耐药性。这里提出的多模式纳米载体策略将提供一种可转化的方法来克服癌症患者的多药耐药性。