RESUMO
In this study, a novel oral drug delivery system based on linolenic acid-modified chitosan (CS-LA) micelle was developed to improve the oral bioavailability of doxorubicin (DOX), which was proven by its in vivo intestinal absorption in rats. The DOX-loaded CS-LA micelles (CS-LA@DOX) were prepared by the dialysis method. The synthesized micelle material was identified by proton nuclear magnetic resonance spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy (FT-IR). A series of the micelle properties, including particle size distribution, zeta potential, encapsulation efficiency (EE), drug loading (DL), micromorphology, polymorphy, and critical micelle concentration (CMC) were characterized or tested. The in vitro release of micelles was observed by the dialysis method, and the absorption-promoting effect of micelles was investigated by intestinal circulation experiments in rats. The animal welfare and experimental procedures were in accordance with the regulations of the Animal Ethics Committee of Guilin Medical University. The results of 1H-NMR and FT-IR showed that CS and LA were covalently bound via an amide linkage. The DOX encapsulated in the micelle core was in an amorphous state. The as-prepared micelles in the transmission electron microscope (TEM) image showed regular spherical shapes and uniform sizes with a series of excellent characteristics including (119.2 ± 2.1) nm of mean particle size [polymer dispersity index (PDI), 0.190 ± 0.08], +12.1 mV of zeta potential, (70.23 ± 0.74) % of EE, (8.77 ± 0.02) % of DL and 51.75 μg·mL-1 of CMC. Compared with the reference, DOX hydrochloride, the proposed micelle drug delivery system showed an obvious sustained-release effect in vitro release; and enhanced drug absorption in the small intestine of rats.
RESUMO
Chitosan(CS)surface was modified with hydrophobic octyl groups to prepare N-octyl chitosan(nitro-gen-octyl chitosan;OC).Then hydrophilic group carboxyl-polyethylene glycol-amino (PEG);tumor-targeting lig-and D-glucosamine(DG);and membrane-penetrating peptide 9-D-arginine(9R)were linked to OC successively. Then the DG and 9R modified chitosan micelle (DG/9R-PEG-OC)with tumor-targeting and transmembrane effect was prepared.By hydrogen nuclear magnetic resonance spectrometer (1 H NMR)and sodium dodecyl sul-fate polyacryl amide gel electrophoresis(SDS-PAGE);the successful formation of DG/9R-PEG-OC was certified;with particle size of 151.8 nm and Zeta potential of 16.5 mV.The morphology of chitosan micelle observed by transmission electron microscope was homogeneous spherical structure.The drug loading content (DLC)(using fluorescein as a model drug)and encapsulation efficiency (EE)were about 28.2% and 75.0% measured by UV-visible spectrophotometer.Meanwhile;the drug showed a controlled releasing profile out of the micelle.Cellu-lar uptake experiments indicated DG/9 R-PEG-OC micelle had a significant tumor-tageting and transmembrane effects;especially on HepG2 cells;which exbihited high expression of the glucose transporter.Thus DG/9R-PEG-OC micelle could be a promising drug targeted delivery system of hydrophobic antitumor drugs.