# Efficient Oral Insulin Delivery Through Thiolated Trimethyl Chitosan-Grafted β-Cyclodextrin Nanoparticles

## TL;DR

This paper introduces a new nanoparticle system that improves oral insulin delivery by protecting insulin from degradation and enhancing its absorption in the gut.

## Contribution

A novel thiolated trimethyl chitosan-grafted β-cyclodextrin nanoparticle system is developed for efficient oral insulin delivery.

## Key findings

- NCT nanoparticles showed mucus adhesion, permeability, and pH sensitivity in the gastrointestinal tract.
- Insulin/NCT nanoparticles reduced blood glucose levels to 39% of initial levels after 5 hours and increased insulin bioavailability to 12.58%.
- The nanoparticles effectively protected insulin from degradation and improved intestinal retention time.

## Abstract

Background: Oral insulin improves compliance and convenience in patients with diabetes who require regular needle injections. However, the clinical application of oral insulin preparations has been limited due to instability and inefficient permeation through the gastrointestinal tract. In this study, a novel cationic polysaccharide nanodrug delivery platform was designed for efficient oral insulin delivery. Methods: The innovative thiolated trimethyl chitosan-grafted β-cyclodextrin (NCT) was synthesized by utilizing N-trimethyl chitosan (TMC) as the polymer backbone. This involved modifying TMC with thiol group-containing N-acetylcysteine and carboxymethyl-β-cyclodextrin that possesses hydrophobic cavities via an amide condensation reaction. Subsequently, this polymer was employed to construct the NCT nanoparticle system using an ionic cross-linking method. The physicochemical properties of the NCT nanoparticles were systematically analyzed, and their therapeutic efficacy was comprehensively evaluated in streptozotocin (STZ)-induced animal models. Results: The NCT nanoparticles demonstrated mucus adhesion, permeability, and pH sensitivity, which facilitated a slow and controlled release within the gastrointestinal microenvironment due to both ionic electrostatic interactions and disulfide bonding interactions. The experiments revealed in vivo that insulin/NCT nanoparticles extended the retention time of insulin in the small intestine. Blood glucose levels decreased to approximately 39% of the initial level at 5 h post-administration while exhibiting smooth hypoglycemic efficacy. Simultaneously, insulin bioavailability increased to 12.58%. Conclusions: The NCT nanoparticles effectively protect insulin from degradation in the gastrointestinal microenvironment while overcoming intestinal barriers, thereby providing a promising approach to oral biomolecule delivery.