Drug Resistance In Cancer Therapy

癌症治疗中的耐药性

基本信息

批准号：
8239465
负责人：
VINOD D LABHASETWAR
金额：
$ 39.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2010-05-10 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239465
关键词：
Acetates Address Affect Animals Antineoplastic Agents Apoptosis Atomic Force Microscopy Binding Biodistribution Biology Cancer Patient Cell Line Cell membrane Cells Charge Clinical Cremophor DDAB DNA DNA Methylation Data Decitabine Dose Doxorubicin Drug Delivery Systems Drug Formulations Drug resistance Dyes Emulsions Encapsulated Ensure Enzymes Equilibrium Exocytosis Funding Grant Health Image Image Analysis In Vitro Intravenous Length Lipids Liver Location MCF7 cell Malignant Neoplasms Medicine Membrane Membrane Lipids Microscopic Modeling Modification Molecular Molecular Conformation Molecular Structure Monitor Mus NIH Program Announcements Nanotechnology Neoplasm Metastasis Normal Cell Normal tissue morphology Outcome Outcome Study Oxidative Stress Paclitaxel Pathway interactions Penetration Pharmaceutical Preparations Pharmacotherapy Phosphatidylserines Polymers Polyvinyl Alcohol Polyvinyls Refractory Research Resistance Risk Role Saline Serum Solutions Solvents Surface System Techniques Testing Therapeutic Time Tissues Toxic effect Treatment Efficacy Tumor Tissue Vesicle Water Xenograft procedure ammonium bromide anti-cancer therapeutic antiproliferative agents base biomaterial compatibility cancer cell cancer therapy cytokine demethylation design drug efficacy effective therapy efficacy testing evaporation hexadecyltrimethylammonium bromide in vivo innovation intravenous administration intravenous injection malignant breast neoplasm membrane model mouse model nanoparticle nanoscience neoplastic cell optical imaging prevent programs response surfactant tumor tumor growth tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Drug resistance remains a major obstacle to the successful treatment of many cancers, and hence developing new strategies to prevent or overcome it is an important objective. This new R01 proposal is based on results of the previously funded exploratory R21 grant, under which we tested the efficacy of surface-modified biodegradable nanoparticles (NPs) to overcome drug resistance. Our data demonstrated that drug delivery with modified NPs can significantly overcome drug resistance. This was evident from a 13-fold enhancement in efficacy of doxorubicin and 25-fold of paclitaxel (PTX) in a resistant cell line and sustained tumor inhibition based on a single-dose intravenous administration of the PTX-loaded modified NPs vs. unmodified NPs or drug in Chremophore". The efficacy of our modified NPs in vivo could in part also be due to their better targeting and retention in tumor tissue than unmodified NPs. We speculate that the molecular structure of the surface-modifying agent at the NP interface influences the biophysical interactions of NPs with cell-membrane lipids, which then affect the cellular delivery of the encapsulated therapeutics and tumor targeting in vivo. We also speculate that co-delivery of a demethylating agent, decitabine in modified NPs would further reverse drug resistance. The overall objective of our study is to elucidate the molecular mechanisms of efficacy of the surface-modified NPs and to correlate the biophysical interactions of NPs with lipid membrane to their therapeutic efficacy. We hypothesize that an optimal combination of modified NPs can completely reverse drug resistance. The specific aims are: AIM 1: To study the effects of the molecular structure of a modifying agent at the NP interface on biophysical interactions of NPs with lipid membranes and correlate these interactions with drug efficacy in vitro, particularly in overcoming drug resistance; AIM 2: To study the biodistribution and tumor- specific delivery of modified NPs and determine their biocompatibility in vivo; and AIM 3: To demonstrate the efficacy of the optimized NPs in regressing drug-resistant tumors in a xenograft mouse model of breast cancer and to determine the mechanisms of efficacy. We propose an innovative approach to overcoming drug resistance in cancer therapy, the successful outcome of which will have significant clinical benefits, particularly in treating cancers that are refractory to normal drug therapy. Furthermore, an effective therapy with our modified NPs might prevent the cancer from developing drug resistance. PUBLIC HEALTH RELEVANCE: The risk of tumors' acquiring resistance to cancer chemotherapeutics remains the major obstacle to successful treatment of many cancers. We propose an innovative approach to overcoming drug resistance in cancer therapy, the successful outcome of which will have significant clinical benefits, particularly in treating cancers that are refractory to normal drug therapy. Furthermore, our approach might also prevent the cancer from developing drug resistance, thus providing an effective therapy for the treatment of cancer patients.

描述（由申请人提供）：耐药性仍然是成功治疗许多癌症的主要障碍，因此开发新策略来预防或克服它是一个重要目标。这项新的 R01 提案基于之前资助的探索性 R21 资助的结果，在该资助下，我们测试了表面改性的可生物降解纳米颗粒 (NP) 克服耐药性的功效。我们的数据表明，修饰纳米粒子的药物输送可以显着克服耐药性。与未修饰的 NP 相比，单剂量静脉注射负载 PTX 的修饰 NP 后，阿霉素和紫杉醇 (PTX) 在耐药细胞系中的功效分别提高了 13 倍和紫杉醇 (PTX) 的 25 倍，并且持续抑制肿瘤，这一点显而易见。或 Chremophore 中的药物”。我们的修饰纳米粒子在体内的功效部分也可能是由于它们比未修饰的纳米粒子更好地靶向和保留在肿瘤组织中。我们推测纳米粒子界面处的表面改性剂的分子结构影响纳米粒子与细胞膜脂质的生物物理相互作用，从而影响封装治疗剂的细胞递送和体内肿瘤靶向。去甲基化剂地西他滨在修饰的纳米颗粒中的作用将进一步逆转耐药性，我们研究的总体目标是阐明表面修饰的纳米颗粒功效的分子机制。将纳米粒子与脂质膜的生物物理相互作用与其治疗功效相关联。我们假设修饰纳米粒子的最佳组合可以完全逆转耐药性。具体目标是：目标 1：研究纳米粒子界面处修饰剂的分子结构对纳米粒子与脂质膜的生物物理相互作用的影响，并将这些相互作用与体外药物功效相关联，特别是在克服耐药性方面；目标2：研究修饰纳米粒子的生物分布和肿瘤特异性递送并确定其体内生物相容性；目标 3：证明优化的纳米颗粒在乳腺癌异种移植小鼠模型中消退耐药肿瘤的功效，并确定功效机制。我们提出了一种克服癌症治疗中耐药性的创新方法，其成功结果将具有显着的临床益处，特别是在治疗对正常药物治疗无效的癌症方面。此外，使用我们修饰的纳米粒子进行有效治疗可能会防止癌症产生耐药性。公共卫生相关性：肿瘤对癌症化疗药物产生耐药性的风险仍然是成功治疗许多癌症的主要障碍。我们提出了一种克服癌症治疗中耐药性的创新方法，其成功结果将具有显着的临床益处，特别是在治疗对正常药物治疗无效的癌症方面。此外，我们的方法还可以防止癌症产生耐药性，从而为癌症患者的治疗提供有效的疗法。