Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39213, USA.
CytRx Corporation, 79104 Freiburg, Germany.
Int J Mol Sci. 2021 Jan 23;22(3):1126. doi: 10.3390/ijms22031126.
Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects. In this study, the ELP system was further modified with an enzyme-cleavable linker in order to release drugs within tumors. This system consists of an ELP, a matrix metalloproteinase (MMP) substrate, a cell-penetrating peptide (CPP), and a 6-maleimidocaproyl amide derivative of doxorubicin (Dox). This strategy shows up to a 4-fold increase in cell penetration and results in more death in breast cancer cells compared to ELP-Dox. Even in doxorubicin-resistant cells (NCI/ADR and MES-SA/Dx5), ELP-released cell-penetrating doxorubicin demonstrated better membrane penetration, leading to at least twice the killing of resistant cells compared to ELP-Dox and free Dox. MMP-digested CPP-Dox showed better membrane penetration and induced more cancer cell death in vitro. This CPP-complexed Dox released from the ELP killed even Dox-resistant cells more efficiently than both free doxorubicin and non-cleaved ELP-CPP-Dox.
弹性蛋白样多肽 (ELPs) 会对外界温度发生特征性的相转变。因此，它已被用作化疗药物的热敏载体，因为它可以用于靶向高热肿瘤。这种新策略为癌症治疗带来了前所未有的选择，减少了对副作用的担忧。在这项研究中，ELP 系统进一步用可酶切的连接子进行修饰，以便在肿瘤内释放药物。该系统由 ELP、基质金属蛋白酶 (MMP) 底物、穿透肽 (CPP) 和阿霉素 (Dox) 的 6-马来酰亚胺基己酰胺衍生物组成。与 ELP-Dox 相比，该策略使细胞穿透增加了 4 倍，导致乳腺癌细胞死亡增加了 4 倍。即使在多柔比星耐药细胞 (NCI/ADR 和 MES-SA/Dx5) 中，ELP 释放的穿透肽阿霉素表现出更好的膜穿透性，导致耐药细胞的杀伤率至少是 ELP-Dox 和游离 Dox 的两倍。经 MMP 消化的 CPP-Dox 显示出更好的膜穿透性，并在体外诱导更多的癌细胞死亡。从 ELP 释放的这种 CPP 复合的阿霉素甚至比游离多柔比星和非切割的 ELP-CPP-Dox 更有效地杀死多柔比星耐药细胞。
