In the present study, cholesterol nanostructured lipid carriers with various oleic acid content loaded with paclitaxel (PTX) were prepared by solvent emulsification-diffusion method using a Taguchi design. Size, zeta potential, entrapment efficiency, drug loading, and release percent of NLCs were measured. The results indicated that the most effective factors on the size were oleic acid content and surfactant percent. Zeta potential was more affected by the drug content. Drug to-lipid weight ratio was the most effective factor on entrapment efficiency and drug release from NLC. In the present work, the effect of lyophilization on the particle size and release properties of NLCs was also evaluated. The results revealed no differences between the characteristics of NLCs before and after freeze drying by using 25% w/w sorbitol as cryoprotectant. Cytotoxicity studies indicate that PTX associated with the NLC is also effective in HT-29 cell lines and enters the cancer cells selectively through the LDL receptor endocytic pathway. The IC 50 values of free PTX solubilized in Cremophor EL and NLC-born PTX after 72 h exposure were 8.32 ± 1.35 ng/mL and 5.24 ± 0.96 ng/mL, respectively.
A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into noveltargeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax Õ in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC 50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 mM for Anzatax Õ and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax Õ . Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax Õ . Compared with Anzatax Õ , the V d , T 1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX.
KeywordsBiodistribution, in vivo anti-tumor effect, Paclitaxel, pharmacokinetics, targeted polymeric micelle History
The aim of this study was to develop chitosan derivative polymeric micelles for co-delivery of paclitaxel (PTX) and α-tocopherol succinate (α-TS) to the cancer cells to improve the therapeutic efficiency and reduce side effects of PTX. In this study, amphiphilic tocopheryl succinate-grafted chitosan oligosaccharide was synthesized and physically loaded by PTX and α-TS with entrapment efficiency of 67.9% and 73.2%, respectively. Physical incorporation of α-TS into the micelles increased the hydrophobic interaction between PTX and the micelles core, which improved micelle stability, reduced the micelle size and also sustained the PTX release from the micelles. The mean particle size and zeta potential of αTS/PTX-loaded micelles were about 133 nm and +25.2 mV, respectively, and PTX release was completed during 6-9 d from the micelles. Furthermore, the cytotoxicity of α-TS/PTX-loaded micelles against human ovarian cancer cell line cancer cell in vitro was higher than that of PTX-loaded micelles and the free drug solution. Half maximal inhibitory concentration values of PTX after 48-h exposure of the cells to the PTX-loaded micelles modified and unmodified with α-TS were 110 and 188 ng/ml, respectively.
The treatment of brain cancer remains one of the most difficult challenges in oncology. The purpose of this study was to develop transferrin-conjugated nanostructured lipid carriers (Tf-NLCs) for brain delivery of paclitaxel (PTX). PTX-loaded NLCs (PTX-NLCs) were prepared using solvent evaporation method and the impact of various formulation variables were assessed using Box-Behnken design. Optimized PTX-NLC was coupled with transferrin as targeting ligand and in vitro cytotoxicity of it was investigated against U-87 brain cancer cell line. As a result, 14.1 mg of cholesterol, 18.5 mg of triolein, and 0.5% poloxamer were used to prepare the optimal formulation. Mean particle size (PS), zeta potential (ZP), entrapment efficiency (EE), drug loading (DL), mean release time (MRT) of adopted formulation were confirmed to be 205.4 ± 11 nm, 25.7 ± 6.22 mV, 91.8 ± 0.5%, 5.38 ± 0.03% and 29.3 h, respectively. Following conjugation of optimized PTX-NLCs with transferrin, coupling efficiency was 21.3 mg transferrin per mmol of stearylamine; PS and MRT were increased while ZP, EE and DL decreased non-significantly. Tf-PTX-NLCs showed higher cytotoxic activity compared to non-targeted NLCs and free drug. These results indicated that the Tf-PTX-NLCs could potentially be exploited as a delivery system in brain cancer cells.
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