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
Background and purpose: Reactive oxygen species (ROSs) are continuously produced as byproducts of cell metabolism. Free radicals are an unstable form of ROSs with the tendency to react readily with biomolecules such as amino acids, lipids and DNA. These reactions lead to oxidative damages to the cell. Oxidative stress occurs when the concentration of the ROSs exceeds the capacity of antioxidative protection systems of the body. 5-Hydroxypyridin-4-one derivatives can chelate Fe 2+ and Fe 3+ due to their α-hydroxyketone moiety. Also, tautomerism in hydroxypyridinone ring leads to enough level of aromaticity resulting in a catechol-like behavior that provides them with good chelating and radical scavenging properties. Experimental approach: Different compounds were synthesized with 5-hydroxypyridine-4-one moiety as the core. The antioxidant properties of molecules were evaluated experimentally by DPPH scavenging method and theoretically using DFT/B3LYP with a 6-31++G (d,p) basis set. Electronic properties were investigated using frontier molecular orbital theory calculations. Furthermore, global descriptive parameters were obtained to find the chemical reactivity of molecules. The natural bond orbital analysis was performed to investigate charge distribution and hydrogen bonding. Findings/Results: Structures of the synthesized compounds were confirmed using IR, 1 H-NMR, and 13 C-NMR spectral analyses. Among all the synthesized compounds, Va and Vb showed the best antioxidant effect experimentally and computationally. Conclusion and implications: Results of this study were valuable in terms of synthesis, in silico , and in vitro antioxidant evaluations and can be useful for future investigations about the design of novel 5-hydroxypyridin- 4-one derivatives possessing iron-chelating and radical scavenging abilities.
The novel amphiphilic derivatives of Methotrexate-chitosan oligosaccharide (MTX-CHO) with different molar feeding ratios of MTX were synthesized. The degree of MTX substitution ranged from 4.47 to 13.5%. MTX-CHO copolymer formed micelles with an average size of 134.6±14.52 to 236.6±30.01 nm, and zeta potential of 20±5 to 16.8±7.74 mV. The critical micelle concentration was found to range from 125 to 0.56 mg/l. Analysis of micelles with different degree of substitutions (DSs) revealed that the size of micelles decreased by increasing DS while zeta potential was reduced. Release study indicated that drug content had effect on the release rate. With increasing amount of loaded drug in the micelle, release rate was decreased. Drug loaded and unloaded MTX-CHO micelles showed significant cytotoxicity on MDA-MB-231. Loaded micelle was more effective than unloaded one which indicated that conjugation could reduce efficacy of MTX. The viability of MDA-MB-231 in presence of drug loaded micelles was significantly decreased and cell viability at 1 µg/ml was 45.17±9% while the viability of unloaded micelles was 91.86±9.88. These phenomena make MTX-CHO micelles as a good candidate for hydrophobic anticancer drug carrier.
To develop an effective therapeutic treatment, the potential of poly (lactic-co-glycolic acid)-polyethylene glycol-retinoic acid (PLGA-PEG-RA) polymeric micelles for targeted delivery of irinotecan to hepatocellular carcinoma (HepG2) and colorectal cancer cell lines (HT-29) was evaluated. PLGA-PEG-RA was synthesized by amide reaction of PLGA with NH2-PEG-NH and then PLGA-PEG-NH with RA and confirmed by FTIR and H NMR spectroscopy. Irinotecan-loaded nanomicelles were prepared using thin-film hydration method and the impact of various formulation variables on their particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), and mean release time (MRT) were assessed using a Taguchi design. TEM was used to observe morphology of the nanomicelles and the CMC was determined by fluorescence spectroscopy. Adopted PLGA-PEG-RA nanomicelle exhibited PS of 160 ± 9.13 nm, PDI of 0.20 ± 0.05, ZP of -24.9 ± 4.03 mV, EE of 83.9 ± 3.61%, MRT of 3.28 ± 0.35 h, and CMC value of 25.7 μg/mL. Cytotoxicity of the targeted nanomicelles on HepG2 and HT-29 cell lines was significantly higher than that of non-targeted nanomicelles and the free drug. These results suggest that PLGA-PEG-RA nanomicelles could be an efficient delivery system of irinotecan for targeted therapy of colorectal cancer and hepatocellular carcinoma.
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