Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
ACS Appl Mater Interfaces. 2016 Sep 14;8(36):23568-79. doi: 10.1021/acsami.6b08239. Epub 2016 Sep 6.
Advances in active targeting drug delivery system (DDS) have revolutionized glioma diagnosis and therapy. However, the lack of the sufficient targets on glioma cells and limited penetration capability of DDS have significantly compromised the treatment efficacy. In this study, by taking advantages of the abundant extracellular matrix-derived heparan sulfate proteoglycan (HSPG) and enhanced tumor penetration ability mediated by neuropilin-1 (NRP-1) protein, we reported the ATWLPPR and CGKRK peptide dual-decorated nanoparticulate DDS (designated AC-NP) to achieve angiogenic blood vessels and tumor microenvironment dual-targeting effect. The resulted AC-NP displayed the particle size of 123 ± 19.47 nm. Enhanced cellular association of AC-NP was achieved on HUVEC cells and U87MG cells. AC-NP was internalized via caveolin- and lipid raft-mediated mechanism with the involvement of energy and lysosome in HUVEC cells and via caveolin- and lipid raft-mediated pathway with the participation of energy, microtubulin, and lysosome in U87MG cells. After loading with anticancer drug, paclitaxel (PTX), the enhanced apoptosis induction and antiproliferative activity were achieved by AC-NP. Furthermore, in vitro U87MG tumor spheroids assays showed a deeper penetration and an enhanced inhibitory effect against the U87MG tumor spheroids achieved by AC-NP. In vivo animal experiment showed that decoration of AC peptide on the nanoparticulate DDS resulted in extensive accumulation at glioma site and improved anti-glioma efficacy. Collectively, the results suggested that AC-NP holds great promise to serve as an effective tumor blood vessel and tumor microenvironment dual-targeting DDS with enhanced penetration capability, holding great potential in improving anti-glioma efficacy.
主动靶向药物传递系统（DDS）的进展彻底改变了神经胶质瘤的诊断和治疗。然而，由于神经胶质瘤细胞上缺乏足够的靶点以及 DDS 的穿透能力有限，极大地限制了治疗效果。在这项研究中，我们利用丰富的细胞外基质衍生的硫酸乙酰肝素蛋白聚糖（HSPG）和神经纤毛蛋白-1（NRP-1）蛋白介导的增强肿瘤穿透能力的优势，报告了 ATWLPPR 和 CGKRK 肽双重修饰的纳米颗粒 DDS（命名为 AC-NP），以实现血管生成和肿瘤微环境的双重靶向作用。得到的 AC-NP 的粒径为 123±19.47nm。AC-NP 增强了与 HUVEC 细胞和 U87MG 细胞的细胞关联。AC-NP 通过网格蛋白和脂筏介导的机制，通过能量和溶酶体在 HUVEC 细胞中内化，通过网格蛋白和脂筏介导的途径，通过能量、微管蛋白和溶酶体在 U87MG 细胞中内化。载有抗癌药物紫杉醇（PTX）后，AC-NP 增强了细胞凋亡诱导和抗增殖活性。此外，在体外 U87MG 肿瘤球体实验中，AC-NP 显示出更深的穿透性和对 U87MG 肿瘤球体的增强抑制作用。体内动物实验表明，AC 肽在纳米颗粒 DDS 上的修饰导致在神经胶质瘤部位的广泛积累，提高了抗神经胶质瘤疗效。总之，这些结果表明，AC-NP 有望成为一种有效的肿瘤血管和肿瘤微环境双重靶向 DDS，具有增强的穿透能力，在提高抗神经胶质瘤疗效方面具有巨大潜力。
