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Mitochondria and nuclei dual-targeted hollow carbon nanospheres for cancer chemo-photodynamic synergistic therapy.
Molecular Pharmaceutics 2019 March 22
Dual-targeted nanoparticles are gaining increasing importance as a more effective anticancer strategy by attacking double key sites of tumor cells, especially in chemo-photodynamic therapy. To retain the nuclei inhibition effect and enhance DOX-induced apoptosis by mitochondrial pathways simultaneously, we synthesized the novel nanocarrier (HKH) based on hollow carbon nitride nanosphere (HCNS) modified with hyaluronic acid (HA) and the mitochondrial localizing peptide D[KLAKLAK]2 (KLA). DOX-loaded HKH nanoparticles (HKHD) showed satisfactory drug loading efficiency, excellent solubility and very low hemolytic effect. HA/CD44 binding and electrostatic attraction between positively-charged KLA and A549 cells facilitated HKHD uptake via endocytosis mechanism. Acidic microenvironment, hyaluronidase and KLA-targeting altogether facilitate doxorubicin toward mitochondria and nuclei, resulting in apoptosis, DNA intercalating, cell-cycle arrested at S-phase and light-induced ROS production. Intravascular HKHD inhibited tumor growth in A549-implanted mice with good safety. The present study, for the first time, systemically reveals biostability, targetability, chemophotodynamics and safety of the functionalized novel HKHD.
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