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

Abstract

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 H 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 8.9×10mg/mL and 13.2×10mg/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.

Mucoadhesive nanostructured polyelectrolytes complexes modulate the intestinal permeability of methotrexate

“…Subsequently, the MTT solution was removed and DMSO was added to dissolve the formed formazan crystals, under shaking for 30 min in the dark. The absorbance was measured using a multimode plate reader (Biotek Synergy 2, Winooski, VT, USA) at 570 and 630 nm Silva et al, 2017). The viability percentage was calculated according the Eq.…”

“…Permeability studies of free MTX, NpHA-MTX and NpHP-MTX dispersions at concentration 100 μg/mL, were performed in triplicate during 4 h. At predetermined time intervals (5,15,30,45,60,120,180 and 240 min), aliquots of 200 μL were withdrawn from the basolateral chamber of the insert and immediately replaced with fresh HBSS. At the end of the experiment, an aliquot of the apical compartment medium was removed for the drug quantification Silva et al, 2017). After, the inserts were washed twice with HBSS and incubated for 30 min, at 37°C, to the layer equilibrium.…”

Dual Acting Polymeric Nano-Aggregates for Liver Cancer Therapy

“…However, because of its poor aqueous solubility, clinical use of PTX is often hindered [16]. As such, formulations of PTX using amphiphilic polymers have been heavily reported in the literature [17,18,19,20], with some nanoparticle formulations now available in the clinic for cancer therapy [21]. …”

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

“…Therefore, knowing how a drug carrier behaves for different types of chemotherapeutic agents, with different mechanisms of action and physicochemical properties, is an encouraging approach. The 3,6-O,O'-dimyristoyl chitosan derivative (DMCh) has been studied in our previous work for the encapsulation of paclitaxel (Silva et al, 2017). The promising results previously obtained motivated our research group to evaluate the ability of this new polymer to act as a drug delivery system for CPT.…”