Nanoparticles based on N-trimethylchitosan: evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models.
Among the chitosan derivatives, trimethylchitosan (TMC) has been shown to have penetration enhancement properties also in intestinal environment. In addition, the use of nanoparticulate systems has the advantage of protecting peptidic drugs from intestinal degradations, due to internalisation behaviour. Therefore, the aim of this paper was to evaluate nanoparticulate systems based on TMC. In particular the mucoadhesive and absorption enhancement properties of nanoparticles based on TMC with different quaternization degree (QD) intended for the intestinal administration of macromolecules (peptides) have been evaluated. Comparison with chitosan (CS.HCl) nanoparticles was made. The nanoparticles were loaded with fluorescein isothiocyanate dextran (FD4, MW 4400 Da), used as the model macromolecule. The intestinal penetration enhancement properties of nanoparticles were investigated in an in vitro Caco-2 cell model and an ex vivo rat jejunum model. The mucoadhesion of the nanosystems was evaluated using excised rat jejunum. All of the nanoparticulate systems interacted with the Caco-2 cells decreasing the transepithelial electric resistance (TEER) and increasing Lucifer Yellow (LY) Papp (paracellular pathway marker). All the nanosystems improved FD4 Papp, with the exception of the nanoparticles based on TMC with the highest QD. In this case an entrapment of nanoparticles into Caco-2 cells was supposed. Analogous results were obtained using the excised rat jejunum model. The increase in QD of TMC was seen to favour the mucoadhesion, resulting in a prolonged residence time on intestinal mucosa. The nanoparticle penetration into excised rat jejunum tissue, observed by means of CLSM, suggested that the mucoadhesive properties delayed the absorption of nanoparticles, however they produced an increase in the contact time with intestinal epithelium, offering a better chance for internalisation. The improvement of mucoadhesion and of nanoparticle internalisation with respect to chitosan nanosystems makes the TMCs nanosystems suitable carriers for the intestinal absorption of peptides.
Sandri
Giuseppina
G
Department of Pharmaceutical Chemistry, University of Pavia, Pavia, Italy.
Bonferoni
Maria Cristina
MC
Rossi
Silvia
S
Ferrari
Franca
F
Gibin
Sara
S
Zambito
Ylenia
Y
Di Colo
Giacomo
G
Caramella
Carla
C
D000268:Adhesiveness; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry / Q000378:metabolism*; D003911:Dextrans / Q000378:metabolism; D004337:Drug Carriers; D017097:Electric Impedance; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007546:Isoquinolines; D007583:Jejunum / Q000378:metabolism*; D018613:Microscopy, Confocal; D009077:Mucins / Q000378:metabolism; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D013997:Time Factors
D003911:Dextrans; D004337:Drug Carriers; D005456:Fluorescent Dyes; D007546:Isoquinolines; D009077:Mucins; C118071:N-trimethyl chitosan chloride; C015219:fluorescein isothiocyanate dextran; D048271:Chitosan; C017475:lucifer yellow; D016650:Fluorescein-5-isothiocyanate