Engineered insulin-polycation complexes for glucose-responsive delivery with high insulin loading

被引:19
作者
Volpatti, Lisa R. [1 ,2 ,6 ]
Burns, Delaney M. [1 ]
Basu, Arijit [2 ]
Langer, Robert [1 ,2 ,3 ,4 ,5 ]
Anderson, Daniel G. [1 ,2 ,3 ,4 ,5 ]
机构
[1] MIT, Dept Chem Engn, Cambridge, MA 02139 USA
[2] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA
[3] Boston Childrens Hosp, Dept Anesthesiol, Boston, MA 02115 USA
[4] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA 02139 USA
[5] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA
[6] Univ Chicago, Pritzker Sch Mol Engn, Chicago, IL 60637 USA
关键词
glucose-responsive; electrostatic complex; insulin; polycation; nanoparticle; SENSITIVE HYDROGELS; CIRCULAR-DICHROISM; CONCANAVALIN-A; RELEASE; OXIDASE; COMPLICATIONS; HYPOGLYCEMIA; MORTALITY; SYSTEM; PH;
D O I
10.1016/j.jconrel.2021.08.017
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Glucose-responsive insulin delivery systems have the potential to improve quality of life for individuals with diabetes by improving blood sugar control and limiting the risk of hypoglycemia. However, systems with desirable insulin release kinetics and high loading capacities have proven difficult to achieve. Here, we report the development of electrostatic complexes (ECs) comprised of insulin, a polycation, and glucose oxidase (GOx). Under normoglycemic physiological conditions, insulin carries a slight negative charge and forms a stable EC with the polycation. In hyperglycemia, the encapsulated glucose-sensing enzyme GOx converts glucose to gluconic acid and lowers the pH of the microenvironment, causing insulin to adopt a positive charge. Thus, the electrostatic interactions are disrupted, and insulin is released. Using a model polycation, we conducted molecular dynamics simulations to model these interactions, synthesized ECs with > 50% insulin loading capacity, and determined in vitro release kinetics. We further showed that a single dose of ECs can provide a glycemic profile in streptozotocin-induced diabetic mice that mimics healthy mice over a 9 h period with 2 glucose tolerance tests.
引用
收藏
页码:71 / 79
页数:9
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