N-(2-Hydroxy)-propyl-3-trimethylammonium, O-Mysristoyl Chitosan Enhances the Solubility and Intestinal Permeability of Anticancer Curcumin.

An amphiphilic derivative of chitosan containing quaternary ammonium and myristoyl groups, herein named as ammonium myristoyl chitosan (DMCat), was synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) and myristoyl chitosan (DMCh). The success of the modification was confirmed using Fourier-transform infrared spectroscopy (FTIR) and ¹H nuclear magnetic resonance (NMR) spectroscopy. The average degrees of alkylation and quaternization ( D Q ¯ ) were determined by using ¹H NMR and conductometric titration. The zeta potential of the micelles was higher than 28 mV while its average size and encapsulation efficiency ranged from 280 nm to 375 nm and 68% to 100%, respectively. The in vitro cytotoxicity of the unloaded and curcumin (CUR)-loaded micelles was tested against Caco-2 and HT29-MTX intestinal epithelial cell lines. The results showed no cytotoxic effect from loaded and unloaded micelles as compared to free CUR. In the permeability test, it was observed that both types of micelles, i.e., DMCh and DMCat, improved CUR permeability. Additionally, higher permeability was verified for both systems in Caco-2/HT29-MTX:Raji B because of the mucoadhesive character of chitosan and its ability to open tight junctions. The results indicated that DMCat micelles, due to the physico-chemical, improved characteristics may be a promising carrier to encapsulate CUR aiming cancer therapy.

Self-aggregates of 3,6-O,O'-dimyristoylchitosan derivative are effective in enhancing the solubility and intestinal permeability of camptothecin.

The aim of this work was to investigate the potential of a new 3,6-O,O'-dimyristoyl derivative amphiphilic chitosan (DMCh), in improving the solubility of camptothecin (CPT), a hydrophobic anticancer drug, and its potential oral delivery. FTIR, 1H NMR and solid-state 13C NMR spectroscopy were used to characterize DMCh and to determine its average degree of substitution (DS¯=6.8%). DMCh/CPT micelles size ranged from (281-357nm), zeta potential (+32-50mV) of encapsulation efficiency of 42-100%. The in vitro cell viability showed that DMCh/CPT micelles were able to reduce the toxicity of CPT. The in vitro permeability of CPT through Caco-2 and Caco-2/HT29-MTX intestinal models was increased up to ten fold when formulated into DMCh micelles, underlining the mucoadhesive properties of the nanocarrier. DMCh/CPT micelles are able to enhance CPT solubility and bioavailability while reduce its cytotoxicity, showing the great potential for intestinal delivery of hydrophobic drugs.

Synthesis and characterization of 3,6-O,O'- dimyristoyl chitosan micelles for oral delivery of paclitaxel.

The aim of the present study was to investigate the potential application of 3,6-O,O'- dimyristoyl chitosan DMCh, an amphiphilic derivative of chitosan, for improving the oral bioavailability of paclitaxel (PTX), a water insoluble anticancer drug. The O-acylation of chitosan with myristoyl chloride was carried out by employing high (≈13.3) or low (2.0) molar excess of chitosan to result in samples DMCh07 and DMCh12, respectively. The successful O-acylation of chitosan was confirmed by FTIR and 1H NMR spectroscopy, the latter allowing also the determination of average degree of substitution (DS). The critical aggregation concentration (CAC) of samples DMCh07 (DS≈6.8%) and DMCh12 (DS≈12.0%) were 8.9×10-3mg/mL and 13.2×103mg/mL, respectively. It was observed by TEM that the DMCh micelles showed spherical shape while DLS measurements allowed the determination of their average size (287nm-490nm) and zeta potential (+32mV to +44mV). Such DMCh micelles were able to encapsulate paclitaxel with high drug encapsulation efficiency (EE), as confirmed by HPLC analyses. Studies on the cytotoxicity of DMCh07 micelles toward Caco-2 and HT29-MTX cells showed that, regardless the PTX loaded, DMCh07 micelles slightly decreased cellular viability at low micelles concentration (≤1µg/mL) while at high concentration (>10µg/mL) PTX-loaded DMCh07 micelles were less toxic toward Caco-2 cells when compared to free PTX. The PTX permeation across Caco-2 monoculture and Caco-2/HT29-MTX co-culture model confirmed the potential of DMCh micelles in improving the intestinal absorption of PTX. These results suggest that DMCh micelles may be a promising carrier to encapsulate PTX aiming cancer therapy.