Drug Resistance In Cancer Therapy

描述(申请人提供)：耐药性仍然是许多癌症成功治疗的主要障碍，因此开发新的策略来预防或克服它是一个重要的目标。这一新的R01提案是基于之前资助的探索性R21拨款的结果，在该拨款下，我们测试了表面修饰的可生物降解纳米颗粒(NPs)克服耐药性的有效性。我们的数据表明，修饰纳米粒的药物传递可以显著地克服耐药性。阿霉素和紫杉醇(PTX)在耐药细胞系中的疗效分别提高了13倍和25倍，基于单剂静脉注射PTX修饰的NPs与未修饰的NPs或药物的持续肿瘤抑制，这一点是显而易见的。我们的修饰纳米粒在体内的疗效也可能部分归因于它们比未经修饰的纳米粒更好地靶向性和在肿瘤组织中保留。我们推测，NP界面表面修饰剂的分子结构会影响NPs与细胞-膜脂的生物物理相互作用，从而影响包埋的治疗药物的细胞递送和体内的肿瘤靶向。我们还推测，在修饰的纳米粒中联合传递去甲基化药物地西他滨将进一步逆转耐药性。本研究的总体目标是阐明表面修饰纳米颗粒的分子作用机制，并将纳米颗粒与脂膜的生物物理相互作用与其治疗效果联系起来。我们假设，一种最佳的修饰纳米粒组合可以完全逆转耐药性。其具体目的是：目的1：研究纳米粒界面修饰分子的分子结构对纳米粒与脂膜的生物物理相互作用的影响，以及这些相互作用与体外药效，特别是在克服耐药性方面的相关性；目的2：研究修饰纳米粒的生物分布和肿瘤特异性递送，并测定其体内生物相容性；目的3：验证优化后的纳米粒对乳腺癌移植瘤耐药肿瘤的逆转作用，并确定其作用机制。我们提出了一种克服癌症治疗中耐药的创新方法，其成功的结果将带来显著的临床好处，特别是在治疗常规药物治疗难治的癌症方面。此外，用我们的修饰纳米粒进行有效的治疗可能会防止癌症产生耐药性。

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.