Oral delivery of peptide drugs using nanoparticles self-assembled by poly(gamma-glutamic acid) and a chitosan derivative functionalized by trimethylation.
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.
Department of Biotechnology, Vanung University, Chungli, Taoyuan, ROC.
Fwu-Long
FL
Mi
Yong-Yi
YY
Wu
Yu-Hsin
YH
Lin
Kiran
K
Sonaje
Yi-Cheng
YC
Ho
Chiung-Tong
CT
Chen
Jyuhn-Huarng
JH
Juang
Hsing-Wen
HW
Sung
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D017097:Electric Impedance; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility
D004337:Drug Carriers; D007328:Insulin; D011108:Polymers; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D048271:Chitosan