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Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control

Rehmani, Sahrish; McLaughlin, Christopher M.; Eltaher, Hoda M.; Moffett, R. Charlotte; Flatt, Peter R.; Dixon, James E.

Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control Thumbnail


Authors

Sahrish Rehmani

Christopher M. McLaughlin

R. Charlotte Moffett

Peter R. Flatt



Abstract

Insulin regulates blood glucose levels, and is the mainstay for the treatment of type-1 diabetes and type-2 when other drugs provide inadequate control. Therefore, effective oral Insulin delivery would be a significant advance in drug delivery. Herein, we report the use of the modified cell penetrating peptide (CPP) platform, Glycosaminoglycan-(GAG)-binding-enhanced-transduction (GET), as an efficacious transepithelial delivery vector in vitro and to mediate oral Insulin activity in diabetic animals. Insulin can be conjugated with GET via electrostatic interaction to form nanocomplexes (Insulin GET-NCs). These NCs (size and charge; 140 nm, +27.10 mV) greatly enhanced Insulin transport in differentiated in vitro intestinal epithelium models (Caco2 assays; >22-fold increased translocation) with progressive and significant apical and basal release of up-taken Insulin. Delivery resulted in intracellular accumulation of NCs, enabling cells to act as depots for subsequent sustained release without affecting viability and barrier integrity. Importantly Insulin GET-NCs have enhanced proteolytic stability, and retained significant Insulin biological activity (exploiting Insulin-responsive reporter assays). Our study culminates in demonstrating oral delivery of Insulin GET-NCs which can control elevated blood-glucose levels in streptozotocin (STZ)-induced diabetic mice over several days with serial dosing. As GET promotes Insulin absorption, transcytosis and intracellular release, along with in vivo function, our simplistic complexation platform could allow effective bioavailability of other oral peptide therapeutics and help transform the treatment of diabetes.

Citation

Rehmani, S., McLaughlin, C. M., Eltaher, H. M., Moffett, R. C., Flatt, P. R., & Dixon, J. E. (2023). Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control. Journal of Controlled Release, 360, 93-109. https://doi.org/10.1016/j.jconrel.2023.06.006

Journal Article Type Article
Acceptance Date Jun 4, 2023
Online Publication Date Jun 22, 2023
Publication Date 2023-08
Deposit Date Jun 23, 2023
Publicly Available Date Jun 28, 2023
Journal Journal of Controlled Release
Print ISSN 0168-3659
Electronic ISSN 1873-4995
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 360
Pages 93-109
DOI https://doi.org/10.1016/j.jconrel.2023.06.006
Keywords Oral insulin delivery; Glycosaminoglycan-GAG-binding enhanced transduction (GET); Cell penetrating peptides (CPPs); Transepithelial delivery; Transcytosis
Public URL https://nottingham-repository.worktribe.com/output/22184806
PMID 37315695
Additional Information This article is maintained by: Elsevier; Article Title: Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control; Journal Title: Journal of Controlled Release; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jconrel.2023.06.006; Content Type: article; Copyright: © 2023 The Authors. Published by Elsevier B.V.

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