Department of Biomaterials, College of Materials, Research Center of Biomedical Engineering of Xiamen & Key Laboratory of Biomedical Engineering of Fujian Province & Fujian Provincial Key Laboratory for Soft Functional Materials Research, Xiamen University, Xiamen 361005, China.
State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry & Chemical Engineering, Xiamen University, Xiamen 361005, China.
J Mater Chem B. 2020 Mar 4;8(9):1922-1934. doi: 10.1039/d0tb00049c.
Carrier-free nanoparticles (NPs) via chemotherapeutic drug-drug conjugate assembly are a promising alternative for tumor chemotherapy. However, these NPs are still hindered via their nonspecific internalization into certain healthy cells and tissues. Herein, dual-acting methotrexate (MTX) and mannose (MAN) were conjugated via a hydrolyzable ester bond to synthesize a MTX-MAN conjugate as one molecule, which could be directly self-assembled into stimulus-responsive carrier-free NPs (MTX-MAN NPs) in aqueous solution. Such carrier-free MTX-MAN NPs with an accurate drug to sugar ratio could achieve on-demand drug release by dual stimuli of lysosomal acidity and esterase. Besides, MTX-MAN NPs could be dual-recognized by tumor cells in vitro and specifically by tumors in vivo. Moreover, the large proportion of MAN located on the NPs' surface could exert a shielding effect to avoid phagocytosis of macrophages, leading to long blood circulation. Therefore, the MTX-MAN NPs sharply reduced the drug dosage and decreased the toxicity to normal cells and tissues. Further in vitro and in vivo studies consistently confirmed that the MTX-MAN NPs exhibited superior tumor accumulation and highly synergistic chemotherapeutic effects. Furthermore, we found for the first time that MAN could enhance the antitumor activity of MTX. Considering that bi-functional MTX and MAN are approved via the FDA, and MAN is highly biosafe, the dual-self-recognizing, stimulus-responsive, and carrier-free MTX-MAN NPs might be a simple, selective, and safe chemotherapeutic strategy.
通过化疗药物偶联物组装无载体纳米颗粒 (NPs) 是肿瘤化疗的一种很有前途的替代方法。然而，这些 NPs 仍然受到其非特异性内化到某些健康细胞和组织的限制。在此，通过可水解酯键将甲氨蝶呤 (MTX) 和甘露糖 (MAN) 双功能化来合成 MTX-MAN 缀合物作为一个分子，该分子可以在水溶液中直接自组装成响应刺激的无载体 NPs (MTX-MAN NPs)。这种具有准确药物与糖比的无载体 MTX-MAN NPs 可以通过溶酶体酸度和酯酶的双重刺激实现按需药物释放。此外，MTX-MAN NPs 可以在体外被肿瘤细胞双重识别，并可以在体内特异性识别肿瘤。此外，位于 NPs 表面的大量 MAN 可以发挥屏蔽作用，避免巨噬细胞的吞噬作用，从而延长血液循环时间。因此，MTX-MAN NPs 大大降低了药物剂量，并降低了对正常细胞和组织的毒性。进一步的体外和体内研究一致证实，MTX-MAN NPs 表现出优异的肿瘤积累和高度协同的化疗效果。此外，我们首次发现 MAN 可以增强 MTX 的抗肿瘤活性。鉴于双功能 MTX 和 MAN 已通过 FDA 批准，且 MAN 具有高度生物安全性，因此双自识别、响应刺激和无载体的 MTX-MAN NPs 可能是一种简单、选择性和安全的化疗策略。
