Drug Resistance In Cancer Therapy

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，因此开发新的策略来预防或克服它是一个重要的目标。这项新的R01提案是基于先前资助的探索性R21资助的结果，在该资助下，我们测试了表面修饰的可生物降解纳米颗粒（NPs）克服耐药性的功效。我们的数据表明，通过修饰的NPs给药可以显著克服耐药性。这从多柔比星和紫杉醇（PTX）在耐药细胞系中的疗效提高13倍和25倍以及基于单剂量静脉给药PTX负载的修饰NPs与未修饰NPs或Chremophore药物的持续肿瘤抑制可见一斑。”我们改良的NPs在体内的有效性部分也可能是由于它们比未改良的NPs在肿瘤组织中具有更好的靶向性和保留性。我们推测，NP界面表面修饰剂的分子结构会影响NP与细胞膜脂质的生物物理相互作用，进而影响包封治疗药物的细胞递送和体内肿瘤靶向。我们还推测，在修饰的NPs中共同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NPs的分子机制，并将NPs与脂膜的生物物理相互作用与其治疗效果联系起来。我们假设改良NPs的最佳组合可以完全逆转耐药性。目的1：研究修饰剂在NP界面上的分子结构对NP与脂质膜生物物理相互作用的影响，并将这些相互作用与体外药物疗效，特别是克服耐药性的作用联系起来；目的2：研究修饰NPs的生物分布和肿瘤特异性递送，并确定其体内生物相容性；目的3：验证优化后的NPs在乳腺癌异种移植小鼠模型中对耐药肿瘤的消退效果，并确定其作用机制。我们提出了一种创新的方法来克服癌症治疗中的耐药性，其成功的结果将具有显着的临床效益，特别是在治疗常规药物治疗难治的癌症方面。此外，利用我们改良的NPs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.