Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science , Soochow University , Suzhou 215123 , People's Republic of China.
Mol Pharm. 2018 Nov 5;15(11):4854-4861. doi: 10.1021/acs.molpharmaceut.8b00498. Epub 2018 Sep 27.
Monomethyl auristatin E (MMAE) is an extremely potent peptide drug that is currently used in the form of antibody drug conjugates (ADCs) for treating different cancers. ADCs are, however, associated with low drug conjugation, immunogenicity, small scale production, and high costs. Here, cRGD-functionalized polylipopeptide micelles (cRGD-Lipep-Ms) were explored for enhanced loading and targeted delivery of MMAE to HCT-116 colorectal tumor xenografts. Interestingly, cRGD-Lipep-Ms achieved an MMAE loading content of 5.5 wt %, which was 55-fold higher than that of poly(ethylene glycol)- b-poly(d,l-lactide) micelles. MMAE-loaded cRGD-Lipep-Ms (MMAE-cRGD-Lipep-Ms) showed a small hydrodynamic size of 59 nm, minimal drug leakage in 10% FBS, and efficient uptake and superb antiproliferative activity in αβ-overexpressing HCT-116 tumor cells. Remarkably, MMAE-cRGD-Lipep-Ms displayed over 10-fold better toleration than free MMAE in mice and completely suppressed growth of HCT-116 colorectal tumor xenografts. These polylipopeptide micelles have appeared to be an attractive alternative to ADCs for targeted delivery of potent peptide drugs.
单甲基澳瑞他汀 E（MMAE）是一种极其有效的肽类药物，目前以抗体药物偶联物（ADC）的形式用于治疗不同的癌症。然而，ADC 存在药物偶联率低、免疫原性、小规模生产和高成本等问题。在这里，研究了 cRGD 功能化聚脂肽胶束（cRGD-Lipep-Ms），以增强 MMAE 对 HCT-116 结直肠肿瘤异种移植物的负载和靶向递送。有趣的是，cRGD-Lipep-Ms 实现了 5.5wt%的 MMAE 载药含量，比聚乙二醇-b-聚（d,l-丙交酯）胶束高 55 倍。载 MMAE 的 cRGD-Lipep-Ms（MMAE-cRGD-Lipep-Ms）表现出 59nm 的小水动力粒径，在 10%FBS 中最小的药物泄漏，以及在 αβ 过表达的 HCT-116 肿瘤细胞中的高效摄取和优异的抗增殖活性。值得注意的是，与游离 MMAE 相比，MMAE-cRGD-Lipep-Ms 在小鼠中表现出超过 10 倍的耐受性，并完全抑制了 HCT-116 结直肠肿瘤异种移植物的生长。这些聚脂肽胶束似乎是一种有吸引力的替代 ADC 的方法，可用于靶向递送强效肽类药物。
