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Chitosan Based Nanocarrier Systems for Tumor Targeting

Author: LiJing
Tutor: ChenXiGuang
School: Ocean University of China
Course: Marine biology
Keywords: Chitosan Targeting Glucose transporter1 Nanoparticles Cancer therapy
CLC: R94
Type: PhD thesis
Year: 2012
Downloads: 832
Quote: 2
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Abstract

At present，cancer has become one of the factors that endanger human health. The keyto cancer therapy is targeting treatment. Receptor-Ligand mediated tumor activetargeting technology in combination with nanotechnology, and the use of naturalbiodegradable materials as anti-cancer carriers, will be an effective approach forcancer therapy.The overexpression of Glucose transporter protein1(GLUT1) in malignant cellsfacilitated the Receptor-Ligand (GLUT1-Glucose) mediated tumor targeting.Glucose-conjugated water soluble chitosan (GSC) nanoparticle was developed fortargeted breast cancer therapy. GSC polysaccharide was synthesized using succinicacid as linker between glucosamine and water soluble chitosan (WSC), confirmed byfourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonancespectroscopy (NMR), thermal gravimetric analysis (TG) and elemental analysis. Thecritical aggregation concentration (CAC) of GSC was0.021mg/ml, determined byfluorescence spectroscopy using pyrene as a fluorescence probe. FITC was covalentlylinked with GSC for futher fluorescence localization. The fluorescent labelingefficiency of FWSC and FGSC was1.39%and1.23%, respectively.WSC NPs was prepared by ionic crosslinking method. GSC, FWSC and FGSCcould form self-assembled nanoparticles under ultrasonication. The nanoparticleswere characterized by dynamic light scattering, the zeta potential of WSC NPs, GSCNPs, FWSC NPs and FGSC NPs was11.5mV,23.9mV,25.8mV and19.5mV, withtheir average size of185.5nm,89.3nm,92.9nm and100.8nm, respectively. WSCNPs and GSC NPs observed by transmission electron microscope exhibited sphericalmorphology. WSC NPs and GSC NPs showed low hemolysis rate (﹤5%) and BSAadsorption rate. MTT assay showed that GSC NPs and FGSC NPs were nontoxic andbiocompatible to MEFs, MCF-7and4T1cells.A model hydrophobic anticancer drug, doxorubicin (DOX) was efficiently entrapped in the nanoparticles, the loading capacity and encapsulation efficiency ofDOX-FWSC NPs was12.53%and40.37%, the loading capacity and encapsulationefficiency of DOX-FGSC NPs was20.1%and64.81%. Drug release of DOX-FWSCNPs and DOX-FGSC NPs was studied by the dynamic dialysis method, the result ofwhich indicated that the drug loaded nanoparticles exhibited pH controlled andsustained-release behavior in PBS buffer solution.In vitro cellular uptake study showed that the phagocytosis of FGSC NPsdepended on not only the electrostatic interaction between the nanoparticles surfaceswith the cell membrane, but also the targeting groups modified on the surface ofnanoparticles. Both the fluorescence microscopy and quantitative determinationshowed that the FGSC NPs was easier to be endocytosed by cells than FWSC NPs.Besides, the antitumor activity of DOX-FGSC NPs was more effective in4T1cellkilling than that of DOX-FWSC NPs. Under the drug concentration of2μg/ml, thecell growth inhibitory effect order was: DOX-FGSC NPs＞ADR＞DOX-FWSC NPs,the result of which indicated that DOX-FGSC NPs had better tumor cell growthinhibitory effect than ADR at low drug concentrations. The in vitro experimentalresults demonstrated that GSC NPs was favorable for tumor cell phagocytosis,initially showed targeting effect to tumor cells.The in vivo antitumor effect of ADR, DOX-FWSC NPs and DOX-FGSC NPswere studied in4T1bearing mice after i.v. injection. DOX-FGSC NPs couldobviously inhibit the growth of tumor and deduce the side effects of DOX to normaltissues. The hydrophilic shell and small particle size of DOX-FGSC NPs facilitatedthe passive targeting to tumor tissues. Meanwhile, the surface modifications oftargeting group enabled the nanocarriers to active targeting to tumor tissue, as well asreduce the accumulation in other organs. The concentration of GLUT1in varioustissues of tumor bearing mice was measured by ELISA. GLUT1was overexpressed intumor, which was consistent with the drug distribution, further confirmed thatDOX-FGSC NPs could active targeting to GLUT1.Our results showed that nanoparticles decorated with glucose have specific reorganization and interaction with GLUT1over-expressed by tumor cells, whichrenders GSC NPs a promising anticancer drug delivery carrier for targeted cancertherapy.

Chitosan Based Nanocarrier Systems for Tumor Targeting

Abstract

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