Anticancer activity of proapoptotic peptides is highly improved by thermal targeting using elastin-like polypeptides.

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.