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.
College of Pharmacy , Fujian Medical University , Fuzhou 350116 , China.
Mol Pharm. 2019 May 6;16(5):2235-2248. doi: 10.1021/acs.molpharmaceut.9b00259. Epub 2019 Apr 2.
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 [KLAKLAK] (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.
双靶向纳米颗粒作为一种更有效的抗癌策略，通过攻击肿瘤细胞的两个关键部位，特别是在化学光动力治疗中，越来越受到重视。为了同时保留核抑制作用并增强线粒体途径诱导的阿霉素（DOX）凋亡，我们合成了基于中空碳氮纳米球（HCNS）的新型纳米载体（HKH），其用透明质酸（HA）和线粒体定位肽[KLAKLAK]（KLA）进行了修饰。载 DOX 的 HKH 纳米颗粒（HKHDs）表现出令人满意的载药效率、优异的溶解度和极低的溶血作用。HA/CD44 结合和带正电荷的 KLA 与 A549 细胞之间的静电吸引通过内吞作用机制促进了 HKHD 的摄取。酸性微环境、透明质酸酶和 KLA 靶向共同促进阿霉素向线粒体和细胞核的转移，导致细胞凋亡、DNA 插入、细胞周期停滞在 S 期以及光诱导的活性氧产生。血管内 HKHD 抑制了 A549 植入小鼠的肿瘤生长，具有良好的安全性。本研究首次系统地揭示了功能化新型 HKHD 的生物稳定性、靶向性、化学光动力学和安全性。
