posted on 2019-03-21, 00:00authored byRuizhi Xie, Shu Lian, Huayi Peng, Changhe OuYang, Shuhui Li, Yusheng Lu, Xuning Cao, Chen Zhang, Jianhua Xu, Lee Jia
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.