Jiang Zhongyu, Feng Xiangru, Zou Haoyang, Xu Weiguo, Zhuang Xiuli
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, 96 Jinzhai Road, Hefei, 230026, P. R. China.
Bioact Mater. 2021 Feb 13;6(9):2688-2697. doi: 10.1016/j.bioactmat.2021.01.034. eCollection 2021 Sep.
PEGylation has been widely applied to prolong the circulation times of nanomedicines the steric shielding effect, which consequently improves the intratumoral accumulation. However, cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG, which limits their therapeutic effect. To this end, we designed and prepared two kinds of poly(l-glutamic acid)-cisplatin (PLG-CDDP) nanoformulations with detachable PEG, which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization. The extracellular pH (pH)-responsive cleavage 2-propionic-3-methylmaleic anhydride (CDM)-derived amide bond and matrix metalloproteinases-2/9 (MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG, yielding pH-responsive PEG- -PLG and MMP-sensitive PEG--PLG. The corresponding smart nanoformulations PEG- -PLG-Pt and PEG--PLG-Pt were then prepared by the complexation of polypeptides and cisplatin (CDDP). The circulation half-lives of PEG- -PLG-Pt and PEG--PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt, respectively. Upon reaching tumor tissue, PEG on the surface of nanomedicines was detached as triggered by pH or MMP, which increased intratumoral CDDP retention, enhanced cell uptake, and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer (HGSOC) mouse model, indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.
聚乙二醇化已被广泛应用于延长纳米药物的循环时间，这是通过空间位阻屏蔽效应实现的，从而提高了肿瘤内的蓄积。然而，聚乙二醇化纳米制剂的细胞摄取总是受到聚乙二醇空间排斥的阻碍，这限制了它们的治疗效果。为此，我们设计并制备了两种具有可裂解聚乙二醇的聚（L-谷氨酸）-顺铂（PLG-CDDP）纳米制剂，其对特定肿瘤组织微环境有响应，以延长循环时间并增强细胞内化。利用细胞外pH（pH）响应性裂解的2-丙酸-3-甲基马来酸酐（CDM）衍生的酰胺键和基质金属蛋白酶-2/9（MMP-2/9）敏感的可降解肽PLGLAG来连接PLG和PEG，得到pH响应性的PEG- -PLG和MMP敏感性的PEG--PLG。然后通过多肽与顺铂（CDDP）的络合制备相应的智能纳米制剂PEG- -PLG-Pt和PEG--PLG-Pt。PEG- -PLG-Pt和PEG--PLG-Pt的循环半衰期分别比对照PLG-Pt高约4.6倍和4.2倍。到达肿瘤组织后，纳米药物表面的聚乙二醇在pH或MMP的触发下被裂解，这增加了肿瘤内顺铂的滞留，增强了细胞摄取，并提高了对致命性高级别浆液性卵巢癌（HGSOC）小鼠模型的抗肿瘤疗效，表明可裂解聚乙二醇化纳米制剂具有广阔的临床应用前景。
