Thermal targeting of an acid-sensitive doxorubicin conjugate of elastin-like polypeptide enhances the therapeutic efficacy compared with the parent compound in vivo.
Thermal targeting of an acid-sensitive doxorubicin conjugate of elastin-like polypeptide enhances the therapeutic efficacy compared with the parent compound in vivo.
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DOI：
10.1158/1535-7163.mct-11-0998
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发表时间：
2012-07
影响因子：
5.7
通讯作者：
Raucher D
中科院分区：
文献类型：
--
作者：
Moktan S;Perkins E;Kratz F;Raucher D
弹性蛋白样多肽（ELP）聚集在轻度高温反应，但在正常生理条件下保持可溶性。ELP大分子可在实体瘤中蓄积，这是因为其具有增强的渗透性和滞留效应。ELP的肿瘤保留可以通过局部加热肿瘤引起的高血压诱导的ELP聚集而进一步增强。我们评估了ELP在E0771同基因小鼠乳腺癌模型中递送多柔比星（Dox）的治疗潜力。ELP-Dox缀合物由在N-末端的细胞穿透肽和在ELP的C-末端的多柔比星的6-马来酰亚胺己酰腙衍生物组成。酸敏感性腙接头确保在药物缀合物的细胞摄取后Dox在溶酶体/内体中的释放。以5 mg Dox当量/kg给药的ELP-Doxo将Dox的血浆半衰期延长至5.5小时。此外，当应用热疗时，ELP-Dox的肿瘤摄取增加2倍，并且与游离Dox相比也增强。尽管在用游离Dox处理的动物的心脏中发现高水平的Dox，但在ELPDox处理的动物中未发现可检测水平的Dox，表明肿瘤靶向与ELP-Dox的潜在心脏毒性的降低之间的相关性。在12 mg Dox当量/kg的最佳剂量下，ELP-Dox联合热疗诱导完全肿瘤生长抑制，这明显上级仅中度抑制肿瘤生长的游离药物。总之，我们的研究结果表明，ELP的热靶向增加了阿霉素的效力，这是利用ELP提高传统抗癌药物治疗效果的潜力的基础。
Elastin-like polypeptides (ELP) aggregate in response to mild hyperthermia, but remain soluble under normal physiological conditions. ELP macromolecules can accumulate in solid tumors because of the enhanced permeability and retention effect. Tumor retention of ELPs can be further enhanced through hyperthermia-induced aggregation of ELPs by local heating of the tumor. We evaluated the therapeutic potential of ELPs in delivering doxorubicin (Dox) in the E0771 syngeneic mouse breast cancer model. The ELP-Dox conjugate consisted of a cell penetrating peptide at the N-terminus and the 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensured release of Dox in the lysosomes/endosomes after cellular uptake of the drug conjugate. ELP-Doxo dosed at 5 mg Dox equivalent/kg, extended the plasma half-life of Dox to 5.5 hours. Additionally, tumor uptake of ELP-Dox increased 2-fold when hyperthermia was applied, and was also enhanced compared to free Dox. Although high levels of Dox were found in the heart of animals treated with free Dox, no detectable levels of Dox were found in ELPDox treated animals indicating a correlation between tumor targeting and reduction of potential cardiac toxicity of ELP-Dox. At an optimal dose of 12 mg Dox equivalent/kg, ELP-Dox in combination with hyperthermia induced a complete tumor growth inhibition, which was distinctly superior to free drug which only moderately inhibited tumor growth. In summary, our findings demonstrate that thermal targeting of ELP increases the potency of doxorubicin underlying the potential of exploiting ELPs to enhance the therapeutic efficacy of conventional anticancer drugs.