| Recently,more and more studies have focused on amphiphilic conjugates,which can self-assemble into nanoparticles for drug delivery systems.Usually,the designed amphiphilic conjugates have many advantages,such as good biocompatibility,biodegradability,and non-toxic side effects.In addition,the nanoparticles with small size can accumulate at the tumor site via enhance the permeability and retention(EPR)effect.At present,the focus of research is the introduction of targeted ligands,as well as the bonds that will be decomposed in the tumor environment,when the amphiphilic conjugates are synthetized.So that the self-assembled nanoparticles have the targeting function and can stimulate the response to drug release.Methotrexate,a kind of antitumor drug,can specifically bind to the folic acid receptor overexpressed on the surface of the tumor cells,thus achieving active targeting effects.Hyaluronic acid is a natural polymer that can specifically bind to the CD44 receptor which is overexpressed on the surface of tumor cells.In this paper,a nano dual drug delivery system with dual targeting function was designed,combining methotrexate and hyaluronic acid,and its properties were also studied.The main contents are as follows:(1)HA-OCA was prepared by a covalent connection between HA and OCA through an amide reaction,and then the MTX-HA-OCA was prepared via a esterification reaction between the carboxyl group of MTX and the hydroxyl group on HA of HA-OCA.HA-OCA and MTX-HA-OCA were characterized by Fourier transform infrared spectrometer,X-ray diffraction analyzer,NMR spectroscopy and UV-vis spectrophotometer respectively,and the connection between HA and OCA,MTX and HA-OCA was discussed.(2)The HA-OCA conjugates and MTX-HA-OCA conjugates could self-assemble into nanoparticles via ultrasonic method-combined self-assembly technology,and CUR was encapsulated into the nanoparticles.The particle size,potential and morphology of the CUR-loaded HA-OCA nanoparticles(HA-OCA/CUR NPs)and CUR-loaded MTX-HA-OCA nanoparticles(MTX-HA-OCA/CUR NPs)were characterized.The release of CUR from HA-OCA/CUR NPs and MTX-HA-OCA/CUR NPs in different PBS solution of pH 7.4 and 5.7 was also explored.The morphology characterization results showed that both HA-OCA/CUR NPs and MTX-HA-OCA/CUR NPs were spherical,and the particle sizes were 90 ~140 nm and 60 ~100 nm,respectively.Both Zeta potentials were about-25 mV.The release of CUR in MTX-HA-OCA/CUR NPs in PBS solution of pH 5.7 was significantly higher than that in PBS solution of pH 7.4.The HA-OCA/CUR NPs showed the same release behavior.(3)In vitro cellular uptake of HA-OCA/CUR NPs and MTX-HA-OCA/CUR NPs was studied using HeLa cells and MCF-7 cells as cell models.MTT method was used to study the anti-tumor ability of HA-OCA/CUR NPs and MTX-HA-OCA/CUR NPs.Finally,the HeLa-tumor bearing mice were used as animal models,and the distribution of HA-OCA/CUR NPs and MTX-HA-OCA/CUR NPs in mice was studied by in vivo fluorescence imaging.The results showed that MTX-HA-OCA/CUR NPs could be selectively absorbed by tumor cells with the CD44 receptor and folate receptor over-expressed via the receptor-ligand mediated endocytosis.Dual targeting ligands made MTX-HA-OCA/CUR NPs more capable of internalizing cells,thereby the concentration of intracellular drugs could be increased.Moreover,MTX-HA-OCA/CUR NPs contained two kinds of antineoplastic drugs,the combination of which could play a stronger role in killing tumor cells.The in vivo imaging in mice showed that MTX-HA-OCA/CUR NPs had stronger tumor targeting ability and more accumulation in tumor sites. |
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