Wei Weijia, Zhang Xiujuan, Chen Xianfeng, Zhou Mengjiao, Xu Ruirui, Zhang Xiaohong
Functional Nano & Soft Materials Laboratory (FUNSOM) and Technology Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
School of Chemistry and Forensic Sciences, Faculty of Life Sciences, University of Bradford, BD7 1DP, UK.
Nanoscale. 2016 Apr 21;8(15):8118-25. doi: 10.1039/c5nr09167e.
Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future.
许多药物分子可直接用作纳米药物，无需任何无机或有机载体，如二氧化硅和脂质体纳米结构。这种新型的无载体药物纳米颗粒（NPs）因其超高的药物负载能力和生物可降解性在临床治疗中具有巨大潜力。对于实际应用而言，此类纳米药物在血液循环过程中具备强大的稳定性以及治疗分子的最小过早释放至关重要。为满足这一要求，在此我们开发了谷胱甘肽响应性且可交联的两亲性聚乙二醇（PEG）分子来修饰无载体药物纳米颗粒。这些PEG分子可在纳米颗粒表面交联，赋予它们更高的稳定性，并且该交联对细胞内环境敏感，以实现生物响应性药物释放。通过这种巧妙的设计，我们的实验结果表明，阿霉素从交联PEG纳米颗粒中的释放比从非交联PEG纳米颗粒中的释放显著更慢，并且可以通过调节还原剂的浓度来控制阿霉素的释放曲线，以破坏PEG分子之间的交联。更重要的是，体内研究表明，交联PEG纳米颗粒表现出良好的血液循环半衰期（>4小时）以及在肿瘤区域的强烈积累，从而实现有效的抗癌治疗。我们期望这项工作将为稳定无载体纳米药物提供一种有力策略，并为其未来成功的临床应用铺平道路。
