Small-molecular Assemblies Nanoparticle For Multiple Tumor Targeting And Imaging-guided Combined Chemo-photothermal Therapy

Due to high drug payload and minimized burden of foreign materials in the course of metabolism and excretion,carrier-free nanomedicine based on self-assembly of small-molecular therapeutic agents has attracted considerable attention in cancer therapy.However,obstacles still remained,such as lacking of targeting efficiency,poor physiological stability,and serious drug burst release.Herein we developed a new nano-delivery system by coupling methotrexate(MTX)and doxorubicin(DOX)via amide bond and ester bond to hyaluronic acid(HA)backbone which enveloped the small molecular drug DOX-ICG by ?-? stacking.With HA for CD44 targeting,MTX for folate targeting,this nanosystems has a dual-targeting effect which can be used for specific targeting.The chemical structures of DOX-HA-MTX prodrug conjugate were analyzed by 1H NMR,FTIR,and UV-vis spectroscopy.And DOX-ICG@DHM nanoparticles were characterized by transmission electron microscope(TEM)and the particle size of DOX-ICG@DHM was about 200 nm.Meanwhile,DOX-ICG@DHM had a good stability and Photothermal effect.In vitro release experiments,the nanosystems showed the rapid disassembly followed by the accelerated drug release upon the stimuli of acid.And both cell uptake and cytotoxicity experiments showed the dual-targeting system had the more significant advantage than non-targeting or single-targeting system.Further,in vivo fluorescence imaging and antitumor efficiency experiment was used to confirm the ability of our nanosystems.The results showed,the nanosystems remarkably enhanced the accumulation in the tumor regions by EPR effect and CD44/folate receptor-mediated endocytosis.And the nanosystems demonstrated highly efficient apoptosis in cancer cells and remarkable tumor ablation by synergy between chemotherapy and PTT upon the irradiation of near-infrared laser.In conclusion,this multifunctional nanosystems based on small-molecular theranostic assemblies could provide a promising potential in developing dual-targeting drug delivery and imaging-guided combinational therapy.