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Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres
Published on: November 5, 2016
A bioinspired polymeric membrane-enclosed insulin crystal achieves long-term, self-regulated drug release for type 1
Jianchang Xu1,2, Yang Zhang1,2, Sheng Zhao1,2
1State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Abstract:
The nuclear envelope serves as a highly regulated gateway for macromolecule exchange between the nucleus and cytoplasm in eukaryotes. Here we have developed a cell nucleus-mimicking polymeric membrane-enclosed system for long and self-regulated therapy. A polymeric nano-membrane with nanopores is conformally synthesized in situ on the surface of each insulin crystal, ensuring sustained, adjustable and zero-order drug release kinetics. Glucose- and β-hydroxybutyrate-dually sensitive microdomains are integrated into the nano-membranes. Under a normal state, the microdomains are uncharged and the channel is narrow enough to block insulin outflow. Under hyperglycaemia and ketonaemia, microdomains convert the high glucose and β-hydroxybutyrate concentration signals to the negative electric potential of membranes, widening the nanopores with rapid insulin outflow. In type 1 diabetic mice and minipigs, this system can maintain normoglycaemia for longer than 1 month and 3 weeks, respectively, with validated glucose- and β-hydroxybutyrate-triggered insulin release. Such membrane-enclosed drug crystal/powder formulation provides a broad platform for long-acting controlled release.
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