Permeability of Novel Chitosan-g-Poly(Methyl Methacrylate) Amphiphilic Nanoparticles in a Model of Small Intestine In Vitro.

Imrit Noi,Murali Kumarasamy,Inbar Schlachet,Alejandro Sosnik

doi:10.3390/polym10050478

Abstract

Engineering of drug nanocarriers combining fine-tuned mucoadhesive/mucopenetrating properties is currently being investigated to ensure more efficient mucosal drug delivery. Aiming to improve the transmucosal delivery of hydrophobic drugs, we designed a novel nanogel produced by the self-assembly of amphiphilic chitosan graft copolymers ionotropically crosslinked with sodium tripolyphosphate. In this work, we synthesized, for the first time, chitosan-g-poly(methyl methacrylate) nanoparticles thiolated by the conjugation of N-acetyl cysteine. First, we confirmed that both non-crosslinked and crosslinked nanoparticles in the 0.05–0.1% w/v concentration range display very good cell compatibility in two cell lines that are relevant to oral delivery, Caco-2 cells that mimic the intestinal epithelium and HT29-MTX cells that are a model of mucin-producing goblet cells. Then, we evaluated the effect of crosslinking, nanoparticle concentration, and thiolation on the permeability in vitro utilizing monolayers of (i) Caco-2 and (ii) Caco-2:HT29-MTX cells (9:1 cell number ratio). Results confirmed that the ability of the nanoparticles to cross Caco-2 monolayer was affected by the crosslinking. In addition, thiolated nanoparticles interact more strongly with mucin, resulting in a decrease of the apparent permeability coefficient (Papp) compared to the pristine nanoparticles. Moreover, for all the nanoparticles, higher concentration resulted in lower Papp, suggesting that the transport pathways can undergo saturation.

Highlights

Oral administration of medication is the most popular and preferred method for patients and physicians [1]
Aiming to physically stabilize amphiphilic nanocarriers by means of drug-compatible chemical pathways, we recently introduced a novel mucoadhesive nanogel produced by the self-assembly of amphiphilic chitosan (CS) graft copolymers synthesized by the hydrophobization of the side-chain with oligo(N-isopropylacrylamide) (oligo(NiPAAm)) blocks and non-covalent crosslinking with sodium tripolyphosphate (TPP) [26]
The reaction product was purified by dialysis against distilled water using a regenerated cellulose dialysis membrane with molecular weight cut-off (MWCO) of 12–14 kDa (Spectra/Por® 4 nominal flat width of 75 mm, diameter of 48 mm and volume/length ratio of 18 mL/cm, Spectrum Laboratories, Inc., Rancho Dominguez, CA, USA) for at

Summary

Introduction

Oral administration of medication is the most popular and preferred method for patients and physicians [1]. It is painless, safe, and enables self-administration. The most relevant are low physicochemical stability in the gastrointestinal tract and the presence of a mucus layer that reduces the drug absorption rate and extent into the systemic circulation [2]. Mucus is a viscoelastic gel mainly formed by water and the glycoprotein mucin that covers all the exposed epithelial surfaces in the body that are not covered by skin such as the respiratory system, the gastrointestinal tract, the vagina, and the eye. Mucus is a porous and semipermeable barrier that enables exchange of nutrients, water, and gases while being almost impenetrable to most pathogens and protecting the epithelium from chemical, physical, and mechanical insults [3]

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Results

Conclusion