title: Preparation and optimization of N-trimethyl-O-carboxymethyl chitosan nanoparticles for delivery of low-molecular-weight heparin.
abstract: The aim of this study was preparation, optimization and in vitro characterization of nanoparticles composed of 6-[O-carboxymethyl]-[N,N,N-trimethyl] (TMCMC) for oral delivery of low-molecular-weight heparin. The chitosan derivative was synthesized. Nanoparticles were prepared using the polyelectrolyte complexation method. Box-Behnken response surface experimental design methodology was used for optimization of nanoparticles. The morphology of nanoparticles was studied using transmission electron microscopy. In vitro release of enoxaparin from nanoparticles was determined under simulated intestinal fluid. The cytotoxicity of nanoparticles on a Caco-2 cell line was determined, and finally the transport of prepared nanoparticles across Caco-2 cell monolayer was defined. Optimized nanoparticles with proper physico-chemical properties were obtained. The size, zeta potential, poly-dispersity index, entrapment efficiency and loading efficiency of nanoparticles were reported as 235 ± 24.3 nm, +18.6 ± 2.57 mV, 0.230 ± 0.03, 76.4 ± 5.43% and 12.6 ± 1.37%, respectively. Morphological studies revealed spherical nanoparticles with no sign of aggregation. In vitro release studies demonstrated that 93.6 ± 1.17% of enoxaparin released from nanoparticles after 600 min of incubation. MTT cell cytotoxicity studies showed no cytotoxicity at 3 h post-incubation, while the study demonstrated concentration-dependent cytotoxicity after 24 h of exposure. The obtained data had shown that the nanoparticles prepared from trimethylcarboxymethyl chitosan may be considered as a good candidate for oral delivery of enoxaparin.
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .|b School of Pharmacy , Hamedan University of Medical Sciences , Hamedan , Iran .
authors.forename: Reza
authors.initials: R
authors.lastname: Mahjub
authors.affiliation: b School of Pharmacy , Hamedan University of Medical Sciences , Hamedan , Iran .
authors.forename: Tavakol
authors.initials: T
authors.lastname: Heidari Shayesteh
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Moojan
authors.initials: M
authors.lastname: Radmehr
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Seyed Yaser
authors.initials: SY
authors.lastname: Vafaei
authors.affiliation: c Department of Medicinal Chemistry, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran , and.|d Drug Design and Development Research Center , Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amini
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Rasoul
authors.initials: R
authors.lastname: Dinarvand
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Farid Abedin
authors.initials: FA
authors.lastname: Dorkoosh
mesh_terms: D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D016503:Drug Delivery Systems / Q000379:methods*; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000138:chemical synthesis*; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size
chemical_list: D006495:Heparin, Low-Molecular-Weight; C118071:N-trimethyl chitosan chloride; C504164:O-carboxymethylchitosan; D048271:Chitosan
keywords: Low-molecular-weight heparin; nanoparticle; oral delivery; poly electrolyte complexation; trimethyl carboxymethyl chitosan