Su Hao, Zhang Pengcheng, Cheetham Andrew G, Koo Jin Mo, Lin Ran, Masood Asad, Schiapparelli Paula, Quiñones-Hinojosa Alfredo, Cui Honggang
1. Department of Chemical and Biomolecular Engineering, and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218 United States.
2. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, United States.
Theranostics. 2016 Apr 28;6(7):1065-74. doi: 10.7150/thno.15420. eCollection 2016.
Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment.
对小分子疏水药物进行化学修饰是一种经临床验证的策略，用于设计具有更高治疗效果的前药。虽然这种前药策略提高了母体药物的水溶性和药代动力学特征，但由于药物释放速率减慢和细胞摄取效率降低，它通常会损害药物对癌细胞的效力。在此，我们报告了自组装前药（SAPD）的超分子设计，其水溶性有了很大提高，同时对癌细胞保持高效力。我们发现，通过将两个喜树碱（CPT）分子连接到一个亲水片段上而产生的CPT前药在水中可以缔合形成丝状纳米结构。我们的结果表明，相对于临床上使用的CPT前药伊立替康，这些SAPD对原发性脑癌细胞具有更高的疗效。我们相信这些发现为合理设计用于癌症治疗的超分子前药开辟了一条新途径。
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