MMP-2 sensitive poly(malic acid) micelles stabilized by π-π stacking enable high drug loading capacity

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Materials for biology and medicine, 2020-09, Vol.8 (37), p.8527-8535
• Main Authors: Qiao, Youbei, Zhan, Chunjing, Wang, Chaoli, Shi, Xuetao, Yang, Jingcheng, He, Xin, Ji, Erlong, Yu, Zhe, Yan, Changjiao, Wu, Hong
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Biocompatibility; Biological activity; Cell Line, Tumor; Computer simulation; Doxorubicin; Doxorubicin - chemistry; Doxorubicin - therapeutic use; Drug carriers; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Drug delivery; Drug Liberation; Female; Free energy; Gelatinase A; Humans; Internalization; Malate; Matrix metalloproteinase; Matrix metalloproteinases; Metalloproteinase; Mice, Inbred BALB C; Micelles; Neoplasms - drug therapy; Neoplasms - pathology; Oligopeptides - chemistry; Peptides; Polyester resins; Polyesters; Polyesters - chemical synthesis; Polyesters - chemistry; Polyethylene glycol; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Polymalic acid; Polymers; Stacking; Static Electricity; Toxicity; Xenograft Model Antitumor Assays
• ISSN: 2050-750X; 2050-7518
• DOI: 10.1039/d0tb01682a

Poly(β- l -malic acid) (PMLA) together with its derivatives is an aliphatic polyester with superior bio-properties for anti-tumor drugs. In order to surmount the obstacles of low drug loading and rapid premature release during the circulation of polyester-based micelles, micelles based on poly(β-benzyl malate)- b -polyethylene glycol (PBM-PEG) were developed in this study. The micelles had high drug loading capacity (>20 wt%) and held robust stability, owing to the π-π stacking interactions between polymer chains, and between the polymer and drug. Computer simulation also confirmed that there was the strongest binding free energy between PBMs, and PBM and doxorubicin (DOX), compared with other polyesters. A cell-penetrating moiety (TAT) was employed, and furthermore, a protective outer shell (PEG 5k ) was also introduced via a matrix metalloproteinase-2 (MMP-2) cleavable peptide. Before reaching the tumor site, the TAT peptide was shielded by long chain PEG, and the micelles showed low bioactivity. While at the tumor tissues where MMP-2 was highly expressed, the cleavage of the linker leads to the exposure of TAT, thus enhancing the cellular internalization. The desired therapeutic consequent was also observed, with no accompanying systemic toxicity detected. Our findings indicated that this MMP-2 sensitive PBM polymeric micelle would be a promising antitumor drug carrier with enhanced therapeutic effects. Poly(β- l -malic acid) (PMLA) together with its derivatives is an aliphatic polyester with superior bio-properties for anti-tumor drugs.