Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs

Jinqiang Wang; Jicheng Yu; Yuqi Zhang; Xudong Zhang; Anna R Kahkoska; Guojun Chen; Zejun Wang; Wujin Sun; Lulu Cai; Zhaowei Chen; Chenggen Qian; Qundong Shen; Ali Khademhosseini; John B Buse; Zhen Gu

doi:10.1126/sciadv.aaw4357

Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs

Sci Adv. 2019 Jul 10;5(7):eaaw4357. doi: 10.1126/sciadv.aaw4357. eCollection 2019 Jul.

Authors

Jinqiang Wang^{1

2

3}, Jicheng Yu³, Yuqi Zhang³, Xudong Zhang^{1

2}, Anna R Kahkoska⁴, Guojun Chen^{1

2}, Zejun Wang^{1

2}, Wujin Sun^{1

5}, Lulu Cai^{1

2

6}, Zhaowei Chen³, Chenggen Qian⁷, Qundong Shen⁷, Ali Khademhosseini^{1

2

5

8

9}, John B Buse⁴, Zhen Gu^{1

2

3

5

10}

Affiliations

¹ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
² California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
³ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.
⁴ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁵ Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic, Science and Technology of China, Chengdu 611731, China.
⁷ Department of Polymer Science and Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
⁸ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Radiology, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.

Abstract

Glucose-responsive insulin delivery systems with robust responsiveness that has been validated in animal models, especially in large animal models, remain elusive. Here, we exploit a new strategy to form a micro-sized complex between a charge-switchable polymer with a glucose-sensing moiety and insulin driven by electrostatic interaction. Both high insulin loading efficiency (95%) and loading capacity (49%) can be achieved. In the presence of a hyperglycemic state, the glucose-responsive phenylboronic acid (PBA) binds glucose instantly and converts the charge of the polymeric moiety from positive to negative, thereby enabling the release of insulin from the complex. Adjusting the ratio of the positively charged group to PBA achieves inhibited insulin release from the complex under normoglycemic conditions and promoted release under hyperglycemic conditions. Through chemically induced type 1 diabetic mouse and swine models, in vivo hyperglycemia-triggered insulin release with fast response is demonstrated after the complex is administrated by either subcutaneous injection or transdermal microneedle array patch.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / drug effects
Diabetes Mellitus, Experimental / drug therapy
Drug Carriers / chemical synthesis
Drug Carriers / chemistry*
Drug Delivery Systems*
Insulin / administration & dosage*
Mice
Molecular Structure
Polymers / chemical synthesis
Polymers / chemistry*
Swine

Substances

Blood Glucose
Drug Carriers
Insulin
Polymers

Grants and funding

F30 DK113728/DK/NIDDK NIH HHS/United States