Drug self-delivery systems represent an important approach to enhance the therapeutic efficacy for cancer therapy. We report the design, synthesis and characterization of a new amphiphilic small molecule prodrug based on two types of anticancer drugs, the hydrophilic gemcitabine and hydrophobic camptothecin, linked by a disulfide bond and abbreviated as GT–CPT. The obtained amphiphilic prodrug conjugates self-assembled into nanoparticles in water and showed strong micellar stability and excellent blood compatibility in vivo. The GT–CPT prodrug conjugates could realize precise drug loading as high as ∼75 wt% demonstrating a carrier-free model for efficient drug delivery. Furthermore, the reduction-responsive disulfide bond enabled controlled drug release in the presence of tumour-specific microenvironment. It was found that each of these hybrid drug components (CPT and GT) not only showed enhanced cytotoxicity individually but also exhibited a prominent synergistic effect on HeLa and MCF-7 cancer cells. This study demonstrated the promising potential of this stimuli-responsive hybrid prodrug conjugate for highly efficient co-delivery of multiple anticancer chemotherapeutics, which could inspire further applications using such hybrid prodrug conjugates for combination cancer chemotherapy.

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吉西他滨-喜树碱偶联物：用于控制药物释放和协同治疗的杂合前药

药物自我传递系统代表了一种增强癌症治疗疗效的重要方法。我们报告了一种基于两类抗癌药物，亲水性吉西他滨和疏水性喜树碱的新型两亲小分子前药的设计，合成和表征，该药物通过二硫键连接，缩写为GT-CPT。所获得的两亲前药缀合物在水中自组装成纳米颗粒，并显示出强大的胶束稳定性和出色的体内血液相容性。GT-CPT前药偶联物可以实现高达约75 wt％的精确载药量，证明了无载体模型可以有效地进行药物输送。此外，在肿瘤特异性微环境的存在下，还原反应性二硫键能够控制药物的释放。发现这些杂种药物成分（CPT和GT）不仅单独显示出增强的细胞毒性，而且还对HeLa和MCF-7癌细胞表现出显着的协同作用。这项研究证明了这种刺激应答混合杂药前体在多种抗癌化学治疗药物的高效共输送方面的潜在潜力，这可能会激发使用此类混合杂药前体在癌症联合治疗中的进一步应用。