Oral Delivery of Peptide Drugs Using Nanoparticles Self-Assembled by Poly(γ-glutamic acid) and a Chitosan Derivative Functionalized by Trimethylation

Abstract

In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(gamma-glutamic acid) (gamma-PGA, TMC/gamma-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/gamma-PGA NPs were 73.8 +/- 2.9% and 23.5 +/- 2.1%, respectively. TMC/gamma-PGA NPs had superior stability in a broader pH range to CS/gamma-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/gamma-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/gamma-PGA NPs was significantly reduced. At pH 7.4, TMC/gamma-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/gamma-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/gamma-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the p K a of CS. In contrast, TMC40/gamma-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.

Chitosan/Fucoidan pH Sensitive Nanoparticles for Oral Delivery System

“…[7][8][9][10][11][12] Hence, chitosan has been used to improve or control drug release through the oral route. 13,14 Chitosan expresses positive charges as a physiological medium because of its pKa value at 6.5. This property makes it suitable for interacting with negatively charged fucoidan to form nanoparticles (NP).…”

Drug Delivery Applications of Chitosan and its Derivatives

“…The nanocomplex exhibited good stability and enhanced uptake of Caco-2 cells by endocytosis (Mao et al 2005(Mao et al , 2006. Except for enhanced stability, trimethyl chitosan -poly glutamic acid nanoparticles also exhibited better swollen property than that of chitosan and can release insulin for 12 days (Mi et al 2008). Thiolated chitosan based nanoparticles were prepared for intranasal delivery of insulin.…”

Nanoparticles Based on Chitosan Derivatives

“…To this purpose N-carboxymethyl chitosan, poly(γ-glutamic acid), poly(aspartic acid) and hyaluronic acid were used as polyanions, while TMC and glycidyl trimethyl ammonium chitosan were the polycations [24][25][26][27]. In a case both the polyanion (hyaluronic acid) and the polycation (TMC) were thiolated and the nanoparticles were stabilized by the formation of interchain disulfide bonds [28].…”

“…Poly(γ-glutamic acid) was used by Mi et al [25] as the anionic polyelectrolyte complexing agent to prepare nanoparticles from TMC by the PEC method, for the oral delivery of insulin. According to the authors insulin was transported across the Caco-2 cell in vitro model of GI epithelium via the paracellular route.…”