School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, China.
School of Mechanical & Automotive Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China.
J Control Release. 2019 Dec 28;316:208-222. doi: 10.1016/j.jconrel.2019.10.052. Epub 2019 Nov 2.
The clinical treatment of melanoma continues to present many challenges including poor prognosis because neither monotherapy nor combination therapies have shown maximal treatment efficacy. In this study, an enzyme-responsive nanoparticle was designed for tumor subtypes with the high expression of heparanase-1, since highly metastatic tumors such as melanoma generally express significant levels of heparanase-1. PTX-DOTAP@alloferon-1-heparin/protamine, an enzyme-responsive nanoparticle, has a particle size of 106.1 ± 1.113 nm and a ζ-potential of -45.1 ± 0.455 mV, which enables enrichment in the tumor site by passive targeting. Subsequently, heparanase-1, which is highly expressed in the extracellular matrix, rapidly recognizes and degrades heparin in the outer layer of the nanoparticle and releases encapsulated alloferon-1 by ion diffusion to activate inhibited NK cells in the tumor microenvironment. The size of the smart nanoparticle will eventually decrease to 59.30 ± 0.783 nm and the ζ-potential will reverse to 25.4 ± 0.257 mV, which is beneficial for deep penetration and tumor cell uptake (due to the high negative charge on the tumor cell surface) of PTX-DOTAP cores. Paclitaxel is released in the cytoplasm, and the tumor cells are arrested in the G2/M phase. The nanoparticle characterization experiment demonstrated that in vivo drug delivery could be completed. In subsequent cell and animal experiments, the experimental data demonstrated the efficient therapeutic effects of the nanoparticle. This study provides an excellent template nanoparticle for the treatment of highly metastatic tumors to enhance future prognosis.
黑色素瘤的临床治疗仍然存在许多挑战，包括预后不良，因为无论是单药治疗还是联合治疗都没有显示出最大的治疗效果。在这项研究中，设计了一种针对肝素酶-1高表达的肿瘤亚型的酶响应纳米粒子，因为高转移性肿瘤，如黑色素瘤通常表达高水平的肝素酶-1。PTX-DOTAP@alloferon-1-heparin/protamine，一种酶响应纳米粒子，粒径为 106.1±1.113nm，ζ-电位为-45.1±0.455mV，能够通过被动靶向富集在肿瘤部位。随后，在肿瘤微环境中高度表达的细胞外基质中的肝素酶-1迅速识别并降解纳米粒子外层的肝素，并通过离子扩散释放包裹的 alloferon-1，以激活被抑制的 NK 细胞。智能纳米粒子的大小最终将减小到 59.30±0.783nm，ζ-电位将反转至 25.4±0.257mV，这有利于 PTX-DOTAP 核的深穿透和肿瘤细胞摄取（由于肿瘤细胞表面带高负电荷）。紫杉醇在细胞质中释放，肿瘤细胞被阻滞在 G2/M 期。纳米粒子表征实验表明可以完成体内药物递送。在随后的细胞和动物实验中，实验数据证明了纳米粒子的高效治疗效果。这项研究为治疗高转移性肿瘤提供了一种优秀的模板纳米粒子，以提高未来的预后。
