Study On Hepatic Targeting Vector Based On Chitosan And

Arsenic trioxide (As2O3) is extracted from Chinese medicine arsenic. It was first reported to induce complete remission in patients with acute promyelocytic leukemia (APL) in 1970. Further, the anti-cancer effects of As2O3 are not restricted to APL, but have also been observed in other solid tumors. But a previous pharmacokinetic study has shown that plasma arsenic eliminates rapidly and the elimination half-life of As2O3 in plasma is very short after intravenous administration. Besides, high doses of As2O3 are usually accompanied by severe side effects, including peripheral neuropathies, liver failure and cardiac toxicity. Therefore, it is necessary to develop an effective delivery system which could increase the drug accumulation at tumor sites, diminish off-target toxicity and extend the circulation time of the drug in bloodIn this work, poly (ethylene glycol)/lactobionic acid-grafted chitosan (PLC) was prepared as an anti-liver cancer drug delivery since lactobionic acid can be effectively recognized by the hepatocytes and PEG can specifically avoid recognition by cells of the mononuclear phagocyte system (MPS). The structure of the (PLC) was characterized by Fourier transform infrared spectrometry and elemental analysis. The self-assembly behaviors of the PLC were monitored by steady-state fluorescence spectroscopy and electronic transmission microscope. The protein adsorption of the PI C was detected with bovine serum albumin (BSA) by electrochemical impedance spectroscopy. Besides, to study the effects of PLC on the structure of BSA, the interactions between the PLC and BSA were detected by ultraviolet spectrum, fluorescence spectrum, and circular dichroism. The hemocompatibility of PLC was investigated by observing the effects of PLC on the hemolysis rate and the plasma recalcification time (PRT). The results showed that mPEG and LA could grafted chitosan successfully and the total substitution of mPEG and LA is 11.73%, and the PLC almost did not adsorb protein. Besides, the data shows that BSA maintained its original folded confirmation in PLC solution. PLC shows perfect hemocompatibility that the PRT was prolonged greatly and the hemolysis rate was less than 5%.With good biodegradation and biocompatibility, Poly (lactic-co-glycolic acid) (PLGA) was selected as materials for drug loading, and the As2O3-PLGA/PLC NPs were prepared by the W/O/W method and optimized by orthogonal experimental with several factors. The optimal preparation conditions obtained as follows:oil-water ratio of 20:1; PLGA concentration of 30 mg/mL; PLC concentration of 1 mg/mL; Poloxamer (9%, w/v) as emulsifier. The optimized As2O3-PLGA/PLC NPs presented suitable physical stability, favorable size of 187.2 ± 10.6 nm (PDI,0.197 ± 0.008; Zeta potential,28.9± 0.3 mV), spherical shape, high encapsulation efficiency (91.68 ± 1.42%) and high drug loading (72.0 ± 1.24%). The cumulative release of the drug is 72.83% when drug release 5 days in PBS.To evaluate the anti-tumor efficacy of As2O3-PLGA/PLC NPs, we investigate the anti-tumor efficacy in vitro and in vivo. In vitro, the antitumor efficacy against SMMC-7721 cells and LO2 cells were studied by CCK method. The result indicated that the As2O3-PLGA/PLC NPs had good blood compatibility and obvious inhibitory effect against SMMC-7721 cells, and these inhibitory effect enhanced with the extension time and concentration of drug increased. And the 50% inhibition concentration (IC50) of these nanoparticles was 0.47 ±0.017 μg As2O3/mL at 72 h, which was far below the IC50 of free As2O3 (0.96 ± 0.033μg As2O3/mL). We next investigated the in vivo anti-tumor efficacy of As2O3-PLGA/PLC NPs in the BALB/c mouse model bearing subcutaneous human HEPG-2 cells. As2O3-PLGA/PLC NPs also showed high tumor growth inhibition effect on liver tumor in vivo. After one period of treatment, the tumor volumes of mice receiving As2O3-PLGA/PLC NPs (1.602 ± 0.524 mm3) were significantly smaller than that of the mice receiving normal saline (2.262 ± 0.546 mm3, P<0.001). In addition, these nanoparticles did not present toxic effects on kidney and liver.