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Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption in non-small cell lung cancer
Biomaterials ( IF 12.8 ) Pub Date : 2021-08-21 , DOI: 10.1016/j.biomaterials.2021.121078
Christopher M Baehr 1 , Lu Zhang 1 , Yi Wu 2 , Andras Domokos 3 , Wenwu Xiao 1 , Lei Wang 4 , Kit S Lam 1
Affiliation  

Non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug-resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial which is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, which leads to the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range and it synergized cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low dose cisplatin chemotherapy. This is the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy.



中文翻译:

用于非小细胞肺癌溶酶体破坏的可转化淀粉样蛋白-β 模拟肽两亲物

非小细胞肺癌 (NSCLC) 是美国癌症死亡率的最大贡献者。传统的化学疗法具有毒性并且容易产生耐药性。最近,几种候选药物被证明可以在侵袭性癌症中诱导溶酶体膜透化 (LMP)。这导致人们对溶酶体失调作为治疗靶点的兴趣增加。然而,需要一些方法来克服当前溶酶体抑制剂的两个局限性:低特异性和效力。在这里,我们报告了一种可变形纳米材料的开发它被触发以诱导 NSCLC 中溶酶体的 LMP。纳米材料由肽两亲物组成,它们自组装成纳米颗粒,与溶酶体共定位,并由于溶酶体 pH 值的变化而改变构象为纳米原纤维,从而导致溶酶体的破坏、细胞死亡和顺铂致敏。我们发现这种可穿透细胞的可转化肽纳米颗粒 (CPTNP)在低微摩尔范围内对 NSCLC 细胞产生细胞毒性,并且它使顺铂的细胞毒性增效四倍。此外,我们证明了 CPTNP 在小鼠异种移植模型中与低剂量顺铂化疗联合使用时具有有限毒性的有前途的抗肿瘤作用。这是通过可转化肽纳米材料增强 LMP 的第一个例子,并为癌症治疗提供了一个有前途的新策略。

更新日期:2021-08-27
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