Small Molecular Theranostic Assemblies\nFunctionalized by Doxorubicin–Hyaluronic Acid–Methotrexate\nProdrug for Multiple Tumor Targeting and Imaging-Guided Combined Chemo-Photothermal\nTherapy

Abstract

Because\nof high drug payload and minimized burden of foreign materials in\nthe course of metabolism and excretion, carrier-free nanomedicine\nbased on self-assembly of small-molecule therapeutic agents has attracted\nconsiderable attention in cancer therapy. However, obstacles still\nremained, such as lack of targeting efficiency, poor physiological\nstability, and serious drug burst release. Herein, we developed a\nself-dual-targeting prodrug conjugate by coupling methotrexate (MTX)\nand doxorubicin (DOX) to a hyaluronic acid (HA) backbone which enveloped\nthe small molecular drug coassemblies of DOX and indocyanine green\nfor specific targeting and imaging-guided chemo-photothermal therapy\n(PTT). The constructed nanosystems exhibited a diameter of ∼200\nnm, superior physiological stability, and improved photothermal effect.\nTaking advantage of functionality of MTX–HA–DOX conjugate,\nthe nanosystems remarkably enhanced the accumulation in the tumor\nregions by enhanced penetration and retention effect and CD₄₄/folate receptor-mediated endocytosis. Upon the stimuli of acid,\nthe nanosystems showed the rapid disassembly followed by the accelerated\ndrug release. Consequently, the nanosystems demonstrated highly efficient\napoptosis in cancer cells and remarkable tumor ablation by synergy\nbetween chemotherapy and PTT upon the irradiation of near-infrared\nlaser. The multifunctional nanosystems based on small molecular theranostic\nassemblies could provide a promising potential in developing dual-targeting\ndrug delivery and imaging-guided combinational therapy.