Studies On Construction And Antitumor Efficacy Of Dual-targeted Nanocarrier Modified With PBA/FA

Currently,the integration of nanotechnology and biomedicine into a targeting therapy platform endows a new hope for the treatment of tumors.Targeting drug delivery could improve the efficacy of antitumor drugs and reduce the side effects of drugs on the system.Passive targeting mediated by the enhanced permeability and retention(EPR)effect could increase the aggregation of nanocarriers at the tumor sites.And active targeting induced by specific ligands could increase the enrichment of nanocarriers in tumor cells.Moreover,the co-modification of two specific ligands could play a synergistic targeting function and further enhance the endocytosis of tumor cells.Thus,in order to achieve an excellent antitumor efficacy and low side effects,the present aims to construct a new type of nanocarrier that possesses both passive targeting and dual active targeting capabilities.Biodegradable dendrigraft poly-L-lysine(DGL)was selected as the core of the nanocarrier.PEG and targeting ligands including phenylboronic acid(PBA)and folic acid(FA)were covalently conjugated to DGL by the amidation reaction.The morphologies,particle size distributions,composition,and surface charges of nanocarrier were characterized.The results of physicochemical characterization showed that DGL-PEG-PBA/FA was spherical nanoparticles,the particle size was42.4±0.25 nm and zeta potential was 6.91±0.87 m V.The nanocarrier could be used to load doxorubicin(DOX)and the drug loading content was 21.13±0.67%.Then,in vitro release experiment found that this nano-system loaded with DOX possessed sustaining release performance.The cumulative release rate reached 69.95% within 48 hours.Hep G2 and HL-7702 were selected as model cells.The in vitro targeting and cytotoxicity of end product DGL-PEG-PBA/FA-DOX nanoparticles against the two kinds of cells were studied by laser confocal microscopy,flow cytometry and MTT assay.The results indicated that Hep G2 cells showed enhanced cellular uptake and cytotoxicity to DGL-PEG-PBA/FA-DOX nanoparticles,while HL-7702 cells displayed lower cellular uptake and cytotoxicity.The mouse hepatoma H22 tumor-bearing Balb/c mice model was chosen to further investigate in vivo the targeting and antitumor efficacy of DGL-PEG-PBA/FA-DOX nanoparticles.The in vivo imaging in mice demonstrated that Cy5.5-labeled DGL-PEG-PBA/FA nanocarriers could preferentially accumulate at tumor sites.Pharmacodynamic experiments showed that DGL-PEGPBA/FA-DOX displayed excellent antitumor efficacy with a tumor inhibition rate of74.8%.In short,these results have showed that the dual-targeting DGL-PEG-PBA/FA nanocarrier had excellent physicochemical characteristics and biocompatibility,it could act as safe drug delivery vehicle.Moreover,it can specifically target tumor cells through the synergistic action of PBA and FA to achieve efficient drug delivery,improve antitumor efficacy and reduce systemic toxicity.