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Mol Pharm. 2019 May 6;16(5):2235-2248. doi: 10.1021/acs.molpharmaceut.9b00259. Epub 2019 Apr 2.

Mitochondria and Nuclei Dual-Targeted Hollow Carbon Nanospheres for Cancer Chemophotodynamic Synergistic Therapy.

Author information

1
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy , Fuzhou University , Fuzhou , Fujian 350116 , China.
2
College of Pharmacy , Fujian Medical University , Fuzhou 350116 , China.
3
Institute of Oceanography , Minjiang University , Fuzhou , Fujian 350108 , China.
4
State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry , Fuzhou University , Fuzhou 350002 , China.

Abstract

Dual-targeted nanoparticles are gaining increasing importance as a more effective anticancer strategy by attacking double key sites of tumor cells, especially in chemophotodynamic therapy. To retain the nuclei inhibition effect and enhance doxorubicin (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 (HKHDs) 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 the endocytosis mechanism. Acidic microenvironment, hyaluronidase, and KLA targeting together facilitate doxorubicin toward the mitochondria and nuclei, resulting in apoptosis, DNA intercalation, cell-cycle arrest at the S phase, and light-induced reactive oxygen species 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.

KEYWORDS:

doxorubicin; dual-targeted nanoparticles; graphitic hollow carbon nitride nanosphere; mitochondria; photodynamic therapy

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