Engineering Dual-Targeted Nanoplatforms to Effectively Treat NSCLC.

摘要 纳米医学为解决以前被认为是 临床医生无法解决的问题。其中一个问题是非小细胞肺癌(NSCLC)的耐药性。 使用小分子抑制剂试图克服耐药性，但未能恢复药物敏感性。 替代的补偿生存途径出现，以允许肿瘤的重新生长。为了减轻肿瘤 在生长过程中，我们需要抑制不止一条生存途径，副作用最小或没有。纳米颗粒 具有选择性地同时阻止多种生存途径以控制其生长的能力 肿瘤。然而，纳米颗粒协同击倒多个交叉连接的生存通路还没有得到 还没探索过。我们最近发现了两个目标Ax1和FN14，并证明了 这些标记与EGFR突变体NSCLC的抗性有关。随后，我们设计了纳米颗粒 同时共敲除肿瘤中的Ax1和FN14，干扰串扰，并成功 克服了小鼠模型的耐药性。合乎逻辑的下一步是验证这些发现在临床上的相关性 动物模型和病人样本。同样重要的是进一步优化纳米颗粒的大小以 以良好的体内特性最大限度地传递深层肿瘤。因此，在这项建议中，我们将 合成不同大小的NP，了解它们穿透肿瘤深处以完全恢复药物的能力 对长期治疗反应的敏感性。我们将使用患者组织，患者衍生的有机化合物，药物- 耐药细胞系、原位动物模型和患者来源的异种移植 纳米平台。这些数据将验证我们的新纳米颗粒平台是一种有前途的打击毒品的策略 在非小细胞肺癌中的耐药性，并催化未来的临床试验。

ABSTRACT Nanomedicine provides new opportunities to solve medical problems that were previously perceived as unsolvable by clinicians. One such problem is drug resistance in Non-Small Cell Lung Cancer (NSCLC). Attempts to overcome the resistance using small molecule inhibitors have failed to restore the drug sensitivity. Alternative compensation survival pathways emerge to allow the regrowth of the tumor. To abate the tumor growth, we need to suppress more than one survival pathway with minimal or no side effects. Nanoparticles possess the ability to selectively and simultaneously arrest multiple survival pathways to control the growth of the tumor. However, nanoparticles to co-knockdown multiple cross-linked survival pathways have not been explored yet. We recently identified two targets AXL and FN14 and demonstrated that the cross-talk between these markers is responsible for resistance in EGFR mutant NSCLC. Subsequently, we designed nanoparticles to simultaneously co-knockdown both AXL and FN14 in the tumor, disrupted the cross-talk, and successfully overcame drug resistance in murine models. The logical next step is to validate the findings in clinically relevant animal models and patient samples. It is equally important to optimize the size of nanoparticles further to maximize deep tumor delivery with favorable in vivo characteristics. Therefore, in this proposal, we will synthesize different sizes of NP, understand their ability to penetrate deep inside the tumor to fully restore drug sensitivity for a long-lasting therapeutic response. We will use patient tissues, patient-derived organoids, drug- resistant cell lines, orthotopic animal models, and patient-derived xenografts to establish the efficacy of the nanoplatform. The data will validate our new nanoparticle platform, as a promising strategy to combat drug resistance in NSCLC and catalyze clinical trials in the future.