Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province, School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, PR China.
Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University; Shenzhen second people's hospital, Shenzhen, Guangdong, China.
Biomater Sci. 2019 Oct 1;7(10):4218-4229. doi: 10.1039/c9bm00907h. Epub 2019 Aug 7.
As a significant part of molecular-targeted therapies, small-molecule agents (SMAs) have been increasingly used for cancer treatment. Nevertheless, most SMAs are currently administered orally due to their poor solubility, resulting in a low bioavailability and unavoidable side effects. Herein, we proposed a promising SMA delivery strategy using a biocompatible and redox-responsive nanoparticle (NP) delivery system to improve their bioavailability, alleviate side effects and enhance therapeutic performance. To demonstrate the feasibility of this strategy, a type of cysteine-based hydrophobic polymer was employed to construct a redox-sensitive nanoplatform for the delivery of various hydrophobic oral SMAs. These SMA-loaded nanoparticles (SMA-NPs) all have a small particle size and good drug-loading capacity. Particularly, lapatinib-loaded nanoparticles (LAP-NPs) with a minimal particle size (79.71 nm) and an optimal drug-loading capacity (12.5%) were utilized as a model to systemically explore the in vitro and in vivo anticancer potential of SMA-NPs. As expected, the LAP-NPs exhibited rapid redox-responsive drug release, enhanced in vitro cytotoxicity and cell apoptosis, and demonstrated notable anti-metastasis ability and desirable intracellular localization. Additionally, the in vivo results demonstrated the preferential accumulation of LAP-NPs in tumor tissues and the significant suppression of tumor growth. Therefore, the generated SMA-NP delivery system shows great SMA delivery potential for advanced molecular-targeted therapies.
作为分子靶向治疗的重要组成部分，小分子药物（SMAs）越来越多地用于癌症治疗。然而，由于其溶解度差，大多数 SMA 目前只能口服给药，导致生物利用度低和不可避免的副作用。在此，我们提出了一种有前途的 SMA 递药策略，使用生物相容性和氧化还原响应性纳米颗粒（NP）递药系统来提高其生物利用度、减轻副作用并增强治疗效果。为了证明这种策略的可行性，我们采用了一种基于半胱氨酸的疏水性聚合物来构建氧化还原敏感的纳米平台，用于递送各种疏水性口服 SMA。这些载有 SMA 的纳米颗粒（SMA-NPs）均具有较小的粒径和良好的载药能力。特别是，具有最小粒径（79.71nm）和最佳载药能力（12.5%）的拉帕替尼载药纳米颗粒（LAP-NPs）被用作模型，系统地研究了 SMA-NPs 的体外和体内抗癌潜力。正如预期的那样，LAP-NPs 表现出快速的氧化还原响应性药物释放、增强的体外细胞毒性和细胞凋亡，并表现出显著的抗转移能力和理想的细胞内定位。此外，体内结果表明 LAP-NPs 优先在肿瘤组织中积累，并显著抑制肿瘤生长。因此，所产生的 SMA-NP 递药系统显示出用于先进的分子靶向治疗的 SMA 递药的巨大潜力。
