Inducing apoptosis in cancer cells is an effective strategy for cancer therapy. The cationic α-helix forming KLAKLAKKLAKLAK peptide (KLAK) has been known to induce apoptosis by disrupting the mitochondria. In the present study, we have designed a thermally targeted KLAK peptide by genetically engineering the KLAK sequence to the carboxy terminus of the heat responsive biopolymer elastin-like polypeptide (ELP). The cellular internalization of ELP-KLAK was made possible by engineering a cell penetrating peptide sequence (SynB1) to the amino terminus of ELP. The SynB1-ELP1-KLAK fusion polypeptide was cytotoxic against both estrogen receptor positive and negative human breast cancer cell lines. The potency of SynB1-ELP1-KLAK was further enhanced when mild hyperthermia was added to the treatment. In response to hyperthermia, SynB1-ELP1-KLAK selectively triggered apoptosis, which was associated with disruption of the mitochondria. The thermally responsive SynB1-ELP-KLAK polypeptide can have improved tumor targeting by the application of mild hyperthermia. Furthermore, the pharmacokinetic properties of ELP can prevent degradation of KLAK in vivo, and the use of SynB1 can mediate tumor cell uptake, thereby augmenting the effect of KLAK.

中文翻译：

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通过使用弹性蛋白样多肽的热靶向，可以大大提高促凋亡肽的抗癌活性。

诱导癌细胞凋亡是癌症治疗的有效策略。已知形成 KLAKLAKKLAKLAK 肽 (KLAK) 的阳离子 α-螺旋通过破坏线粒体来诱导细胞凋亡。在本研究中，我们通过将 KLAK 序列基因工程到热响应性生物聚合物弹性蛋白样多肽 (ELP) 的羧基末端，设计了一种热靶向 KLAK 肽。通过将细胞穿透肽序列 (SynB1) 设计到 ELP 的氨基末端，使 ELP-KLAK 的细胞内化成为可能。SynB1-ELP1-KLAK 融合多肽对雌激素受体阳性和阴性人乳腺癌细胞系均具有细胞毒性。当温和的热疗加入治疗时，SynB1-ELP1-KLAK 的效力进一步增强。为了应对高温，SynB1-ELP1-KLAK 选择性地触发细胞凋亡，这与线粒体的破坏有关。热响应性 SynB1-ELP-KLAK 多肽可以通过应用温和的热疗改善肿瘤靶向。此外，ELP 的药代动力学特性可以防止 KLAK 在体内的降解，使用 SynB1 可以介导肿瘤细胞摄取，从而增强 KLAK 的作用。