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 °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.