Department of Biomaterials, College of Materials, Research Center of Biomedical Engineering of Xiamen & Key Laboratory of Biomedical Engineering of Fujian Province, Xiamen University, Xiamen 361005, China.
Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, China.
J Mater Chem B. 2020 May 6;8(17):3829-3841. doi: 10.1039/d0tb00468e.
Carrier-free nanodrugs, generated via the straightforward small-molecule self-assembly of anticancer drugs, provide a promising route for cancer chemotherapy. However, their low structural stability, lack of targeting specificity, and poor stimulus responsiveness are still limiting their therapeutic effect. Inspired by Watson-Crick G[triple bond, length as m-dash]C base pairing, the FDA-approved chemo-drug methotrexate (MTX, which can bind with folate receptors) and 5-fluorouracil (5-FU, a DNA/RNA synthetase inhibitor) were adopted for direct assembly into self-recognizing MTX-5-FU nanoparticles via "Watson-Crick-like base pairing"-driven precise supramolecular assembly. Sequentially, our synthesized weak acidity-responsive polyethylene glycol (PEG) was inserted onto the nanoparticle surface to temporarily shield the self-targeting function of MTX and prolong the blood circulation time. Once PEG-MTX-5-FU nanoparticles reached the weakly acidic tumor microenvironment, the PEG corona could be cleaved from their surface and then MTX could be re-exposed to recover its self-recognition ability and significantly elevate tumor cell uptake; furthermore, the de-PEGylated MTX-5-FU nanoparticles could respond to the stronger acidity of lysosome, triggering core disassembly and thus the burst release of both MTX and 5-FU. Further in vitro and in vivo studies consistently confirmed that the nanodrugs exhibited preferable accumulation at the tumor sites with highly synergistic chemotherapeutic effects. The supramolecular recognition-inspired, cascade-triggered self-targeting and controlled release of nanodrugs could be a promising strategy to improve synergistic chemotherapy.
无载体纳米药物通过抗癌药物的简单小分子自组装生成，为癌症化疗提供了有前途的途径。然而，它们的结构稳定性低、缺乏靶向特异性和较差的刺激响应性仍然限制了它们的治疗效果。受 Watson-Crick G[三重键，长度为 m-dash]C 碱基配对的启发，采用已获得 FDA 批准的化疗药物甲氨蝶呤（MTX，可与叶酸受体结合）和 5-氟尿嘧啶（5-FU，一种 DNA/RNA 合成酶抑制剂），通过“Watson-Crick 样碱基配对”驱动的精确超分子组装，直接组装成自识别的 MTX-5-FU 纳米颗粒。随后，我们合成的弱酸性响应性聚乙二醇（PEG）被插入到纳米颗粒表面，以暂时屏蔽 MTX 的自靶向功能并延长血液循环时间。一旦 PEG-MTX-5-FU 纳米颗粒到达弱酸性肿瘤微环境，PEG 冠层可以从其表面被切割，然后 MTX 可以重新暴露以恢复其自识别能力，并显著提高肿瘤细胞摄取率；此外，去 PEG 化的 MTX-5-FU 纳米颗粒可以响应溶酶体更强的酸度，触发核心解体，从而导致 MTX 和 5-FU 的爆发释放。进一步的体外和体内研究一致证实，纳米药物在肿瘤部位表现出更好的积累，并具有高度协同的化疗效果。基于超分子识别的级联触发自靶向和控制释放纳米药物可能是提高协同化疗效果的有前途的策略。
