Overcoming the Diffusion Barrier of Mucus and Absorption Barrier of Epithelium by Self-Assembled Nanoparticles for Oral Delivery of Insulin

Abstract

Nanoparticles (NPs) have demonstrated great potential for the oral delivery of protein drugs that have very limited oral bioavailability. Orally administered NPs could be absorbed by the epithelial tissue only if they successfully permeate through the mucus that covers the epithelium. However, efficient epithelial absorption and mucus permeation require very different surface properties of a nanocarrier. We herein report self-assembled NPs for efficient oral delivery of insulin by facilitating both of these two processes. The NPs possess a nanocomplex core composed of insulin and cell penetrating peptide (CPP), and a dissociable hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives. After systematic screening using mucus-secreting epithelial cells, NPs exhibit excellent permeation in mucus due to the "mucus-inert" pHPMA coating, as well as high epithelial absorption mediated by CPP. The investigation of NP behavior shows that the pHPMA molecules gradually dissociate from the NP surface as it permeates through mucus, and the CPP-rich core is revealed in time for subsequent transepithelial transport through the secretory endoplasmic reticulum/Golgi pathway and endocytic recycling pathway. The NPs exhibit 20-fold higher absorption than free insulin on mucus-secreting epithelium cells, and orally administered NPs generate a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Our study provides the evidence of using pHPMA as dissociable "mucus-inert" agent to enhance mucus permeation of NPs, and validates a strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and drug-loaded CPP-rich core.

Efficient mucus permeation and tight junction opening by dissociable “mucus-inert” agent coated trimethyl chitosan nanoparticles for oral insulin delivery

“…The ability of NPs to penetrate through human mucus was evaluated using Ussing chamber system [33]. A pair of polycarbonate filters (Merck Millipore, 2.0 μm) was fixed to the sliders, and then the gap between the filters was filled with 50 μl of human mucus.…”

Inhibitory effect of a new orally active cedrol-loaded nanostructured lipid carrier on compound 48/80-induced mast cell degranulation and anaphylactic shock in mice

“…82 Nanoparticles can be modified with specific stabilizers, such as vitamin E TPGS, Pluronic F127, and penetrating peptides; once modified, these nanoparticles can improve the oral bioavailability of drug by promoting cross static water level and cell membrane permeability. 83 In an allergic reaction, mast cells are the key effector cells. They release a number of mediators along with histamine when exposed to foreign elements that trigger allergic symptoms like wheezing and shortness of breath.…”

Nanotechnology for protein delivery: Overview and perspectives

“…In a similar manner, Shan et al developed self-assembled nanoparticles that permeate the mucus layer and are absorbed into the epithelial layer to deliver insulin orally by inducing phased change of the nanostructure [120]. Penetratin, one of the most promising CPPs, was mixed with negatively charged insulin to make nanocomplex (NC) cores (148 nm), which were spontaneously assembled with a dissociable hydrophilic N -(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives via electrostatic interaction to form the self-assembled nanoparticles (175 nm).…”