Development of drug carriers, which can chaperone xenobiotics directly to their site of action, is an essential step for the advancement of precision medicine. Cationic nanoparticles can be used as a drug delivery platform for various agents including chemotherapeutics, oligonucleotides, and antibodies. Self-assembly of short peptides facilitates the formation of well-defined nanostructures suitable for drug delivery, and varying the polarity of the self-assembly medium changes the nature of noncovalent interactions in such a way as to generate numerous unique nanostructures. Here, we have synthesized an ultrashort cell-penetrating tetrapeptide (sequence Lys-Val-Ala-Val), with Lys as a cationic amino acid, and studied the self-assembly property of the BOC-protected (L1) and -deprotected (L2) analogues. Spherical assemblies obtained from L1/L2 in a 1:1 aqueous ethanol system have the ability to encapsulate small molecules and successfully enter into cells, thus representing them as potential candidates for intracellular drug delivery. To verify the efficacy of these peptides in the facilitation of drug efficacy, we generated encapsulated versions of the chemotherapeutic drug doxorubicin (Dox). L1- and L2-encapsulated Dox (Dox-L1 and Dox-L2), similar to the unencapsulated drug, induced upregulation of regulator of G protein signaling 6 (RGS6) and Gβ5, the critical mediators of ATM/p53-dependent apoptosis in Dox-treated cancer cells. Further, Dox-L1/L2 damaged DNA, triggered oxidative stress and mitochondrial dysfunction, compromised cell viability, and induced apoptosis. The ability of Dox-L1 to mediate cell death could be ameliorated via knockdown of either RGS6 or Gβ5, comparable to the results obtained with the unencapsulated drug. These data provide an important proof of principle, identifying L1/L2 as drug delivery matrices.

中文翻译：

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通过细胞穿透四肽的自组装产生的超分子结构促进促凋亡化疗药物的细胞内递送

药物载体的开发，可以将异生素直接陪伴到它们的作用部位，是推进精准医学的重要一步。阳离子纳米粒子可用作包括化疗药物、寡核苷酸和抗体在内的各种药物的药物递送平台。短肽的自组装有助于形成适合药物递送的明确纳米结构，并且改变自组装介质的极性会改变非共价相互作用的性质，从而产生许多独特的纳米结构。在这里，我们合成了一种以Lys为阳离子氨基酸的超短细胞穿透四肽（序列Lys-Val-Ala-Val），并研究了BOC保护（L1）和去保护（L2）的自组装特性。 ) 类似物。在 1:1 水性乙醇系统中从 L1/L2 获得的球形组件能够封装小分子并成功进入细胞，因此代表它们作为细胞内药物递送的潜在候选者。为了验证这些肽在促进药物疗效方面的功效，我们生成了化疗药物阿霉素 (Dox) 的封装形式。L1 和 L2 封装的 Dox（Dox-L1 和 Dox-L2），类似于未封装的药物，诱导 G 蛋白信号转导 6（RGS6）和 Gβ5 的调节上调，这是 Dox 中 ATM/p53 依赖性细胞凋亡的关键介质处理过的癌细胞。此外，Dox- 为了验证这些肽在促进药物疗效方面的功效，我们生成了化疗药物阿霉素 (Dox) 的封装形式。L1 和 L2 封装的 Dox（Dox-L1 和 Dox-L2），类似于未封装的药物，诱导 G 蛋白信号转导 6（RGS6）和 Gβ5 的调节上调，这是 Dox 中 ATM/p53 依赖性细胞凋亡的关键介质处理过的癌细胞。此外，Dox- 为了验证这些肽在促进药物疗效方面的功效，我们生成了化疗药物阿霉素 (Dox) 的封装形式。L1 和 L2 封装的 Dox（Dox-L1 和 Dox-L2），类似于未封装的药物，诱导 G 蛋白信号转导 6（RGS6）和 Gβ5 的调节上调，这是 Dox 中 ATM/p53 依赖性细胞凋亡的关键介质处理过的癌细胞。此外，Dox-L1 / L2损伤 DNA，引发氧化应激和线粒体功能障碍，损害细胞活力，并诱导细胞凋亡。Dox-L1 介导细胞死亡的能力可以通过敲除 RGS6 或 Gβ5 来改善，与使用未封装药物获得的结果相当。这些数据提供了重要的原理证明，将 L1/L2 确定为药物递送基质。