Glucose-responsive complex micelles for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo

作者:Wu, G (Wu, Gang)^{[ 1 ]} ; Li, C (Li, Chang)^{[ 1 ]} ; Liu, XY (Liu, Xiaoyu)^{[ 1 ]} ; Lv, J (Lv, Juan)^{[ 1 ]} ; Ding, YX (Ding, Yuxun)^{[ 1 ]} ; Liu, Y (Liu, Yong)^{[ 1 ]} ; Liu, Y (Liu, Ying)^{[ 1 ]} ; Huang, F (Huang, Fan)^{[ 3,4 ]} ; Shi, LQ (Shi, Linqi)^{[ 1,2 ]} ; An, YL (An, Yingli)^{[ 1 ]} ; Ma, RJ (Ma, Rujiang)^{[ 1 ]}

COLLOIDS AND SURFACES B-BIOINTERFACES, 2019, 180: 376-383

DOI: 10.1016/j.colsurfb.2019.05.003

摘要

Large amounts of insulin-loaded glucose-responsive micelles based on poly(amino acid)s have been developed for diabetes treatment over last decades, but most of them could not effectively protect insulin from enzymatic degradation in vivo because the micellar core was biodegradable and lacked protective structure for insulin, which would lower the efficacy of insulin to a large extent. In this study, we fabricated a new type of insulin-loaded glucose-responsive complex micelles (CMs), which were self-assembled by a phenylboronic acid (PBA)modified block copolymer PEG-b-P(Asp-co-AspPBA) and a glucosamine (GA)/nitrilotriacetic acid (NTA)-functionalized block copolymer PNIPAM-b-P(Asp-co-AspGA-co-AspNTA), for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo. The CMs possessed mixed shell of PEG/PNIPAM and cross-linked core of PBA/GA complex, which could be disintegrated under the condition of high glucose concentration (5 g/L) while maintaining stable at low glucose concentration (1 g/L). The NTA groups of CMs greatly improved the loading content of insulin by specifically bind insulin via the chelated zinc ions. More importantly, PNIPAM chains in the mixed shell would collapse under 37 degrees C and form hydrophobic domains around the micellar core, which could significantly protect the micellar core as well as the encapsulated insulin from attacking by external proteases. In a murine model of type 1 diabetes, the CMs with insulin chelated by NTA showed a long hypoglycemic effect, which is superior to insulin-loaded simple micelles without PNIPAM and insulin in PBS buffer (pH 7.4). Therefore, this kind of CMs could be a potential candidate for insulin delivery in diabetes therapy.