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Remodeling Tumor‐Associated Macrophages and Neovascularization Overcomes EGFRT790M‐Associated Drug Resistance by PD‐L1 Nanobody‐Mediated Codelivery
Small ( IF 13.3 ) Pub Date : 2018-10-11 , DOI: 10.1002/smll.201802372
Weimin Yin 1, 2 , Xiaolu Yu 1, 3 , Xuejia Kang 1, 4 , Yuge Zhao 1, 2 , Pengfei Zhao 1, 2 , Hongyue Jin 1, 3 , Xuhong Fu 1, 2 , Yakun Wan 1 , Chengyuan Peng 1 , Yongzhuo Huang 1, 3
Affiliation  

Precision medicine has made a significant breakthrough in the past decade. The most representative success is the molecular targeting therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non‐small‐cell lung cancer (NSCLC) with oncogenic drivers, approved by the US Food and Drug Administration (FDA) as first‐line therapeutics for substituting chemotherapy. However, the rapidly developed TKI resistance invariably leads to unsustainable treatment. For example, gefitinib is the first choice for advanced NSCLC with EGFR mutation, but most patients would soon develop secondary EGFRT790M mutation and acquire gefitinib resistance. TKI resistance is a severe emergency issue to be solved in NSCLC, but there are a few investigations of nanomedicine reported to address this pressing problem. To overcome EGFRT790M‐associated drug resistance, a novel delivery and therapeutic strategy is developed. A PD‐L1 nanobody is identified, and first used as a targeting ligand for liposomal codelivery. It is found that simvastatin/gefitinib combination nanomedicine can remodel the tumor microenvironment (e.g., neovascularization regulation, M2‐macrophage repolarization, and innate immunity), and display the effectiveness of reversing the gefitinib resistance and enhancing the EGFRT790M‐mutated NSCLC treatment outcomes. The novel simvastatin‐based nanomedicine provides a clinically translatable strategy for tackling the major problem in NSCLC treatment and demonstrates the promise of an old drug for new application.

中文翻译:

通过PD-L1纳米抗体介导的Codelivery重构肿瘤相关的巨噬细胞和新血管形成克服了EGFRT790M相关的耐药性

在过去的十年中,精密医学取得了重大突破。最有代表性的成功是在表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)的分子靶向治疗中,使用具有致癌作用的非小细胞肺癌(NSCLC),获得了美国食品药品监督管理局(FDA)的批准替代化疗的一线治疗药物。然而,快速发展的TKI抗药性总是导致不可持续的治疗。例如,吉非替尼是具有EGFR突变的晚期NSCLC的首选,但大多数患者很快会发展成继发性EGFR T790M突变并获得吉非替尼耐药性。TKI耐药性是NSCLC中亟待解决的严重紧急问题,但是据报道,有一些针对纳米医学的研究可以解决这一紧迫问题。为了克服与EGFR T790M相关的耐药性,开发了一种新颖的递送和治疗策略。鉴定出PD-L1纳米抗体,它首先用作脂质体代码传递的靶向配体。发现辛伐他汀/吉非替尼联合纳米药物可以重塑肿瘤微环境(例如,新生血管调节,M2巨噬细胞复极和先天免疫),并显示出逆转吉非替尼耐药性和增强EGFR T790M的有效性。突变的NSCLC治疗结果。基于辛伐他汀的新型纳米药物为解决NSCLC治疗中的主要问题提供了可临床翻译的策略,并证明了将旧药用于新用途的希望。
更新日期:2018-10-11
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