Drug Resistance In Cancer Therapy

耐药性仍然是成功治疗许多癌症的主要障碍，因此开发新的策略来预防或克服它是一个重要的目标。这项新的R 01提案是基于先前资助的探索性R21赠款的结果，根据该赠款，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，用修饰的纳米颗粒递送药物可以显著克服耐药性。这从多柔比星在抗性细胞系中的功效的13倍增强和紫杉醇（PTX）的25倍增强以及基于单剂量静脉内施用负载PTX的修饰的NP与未修饰的NP或在Chremophore中的药物相比的持续肿瘤抑制中是明显的。我们的修饰的NP在体内的功效也可以部分归因于它们比未修饰的NP在肿瘤组织中更好的靶向和保留。我们推测NP界面处的表面改性剂的分子结构影响NP与细胞膜脂质的生物物理相互作用，然后影响包封治疗剂的细胞递送和体内肿瘤靶向。我们还推测，在修饰的NP中共递送去甲基化剂地西他滨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的功效的分子机制，并将纳米颗粒与脂质膜的生物物理相互作用与其治疗功效相关联。我们假设修饰的纳米颗粒的最佳组合可以完全逆转耐药性。具体目标是：目标1：研究修饰剂在NP界面处的分子结构对NP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; AIM 2：研究修饰的NP的生物分布和肿瘤特异性递送，并确定其体内生物相容性;以及AIM 3：证明优化的NP在乳腺癌异种移植小鼠模型中消退耐药肿瘤的疗效，并确定疗效机制。我们提出了一种克服癌症治疗耐药性的创新方法，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难治的癌症方面。此外，使用我们修饰的NP的有效疗法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.