Lin Ziqi, Wang Yuequan, Li Wenwen, Sun Fei, Lv Qingzhi, Zhang Shenwu, Liu Xiaohong, Qin Feng, Luo Cong
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Pharmacy, Binzhou Medical University, Yantai 264003, China.
Asian J Pharm Sci. 2024 Aug;19(4):100892. doi: 10.1016/j.ajps.2024.100892. Epub 2024 Feb 28.
Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery. However, prodrug activation remains a rate-limiting step for exerting therapeutic actions, which requires to quickly reach the minimum valid concentrations of free drugs. Fortunately, we find that a natural compound (BL-193) selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin (PPT) at ineffective dose concentrations. Based on this, we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of PPT. Specifically, a redox-sensitive prodrug (PSSF) of PPT is synthesized by coupling 9-fluorenyl-methanol (Fmoc-OH) with PPT linked via disulfide bond. Intriguingly, PSSF with a π-conjugated structure readily co-assembles with BL-193 into stable nanoassembly. Significantly, BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic window for PPT. Moreover, prodrug design and precise hybrid nanoassembly well manage off-target toxicity. As expected, such a BL-193-empowered prodrug nanoassembly elicits potent antitumor responses. This study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.
小分子前药纳米组装技术在降低脱靶毒性方面具有独特优势，已被广泛用于抗肿瘤药物递送。然而，前药激活仍然是发挥治疗作用的限速步骤，这需要快速达到游离药物的最低有效浓度。幸运的是，我们发现一种天然化合物（BL - 193）在无效剂量浓度下能选择性提高乳腺癌细胞对鬼臼毒素（PPT）的化疗敏感性。基于此，我们建议将前药纳米组装与化疗增敏相结合，以充分释放PPT的化疗潜力。具体而言，通过将9 - 芴甲醇（Fmoc - OH）与通过二硫键连接的PPT偶联，合成了PPT的氧化还原敏感前药（PSSF）。有趣的是，具有π共轭结构的PSSF很容易与BL - 193共同组装成稳定的纳米组装体。值得注意的是，BL - 193作为一种出色的化疗增敏剂，为PPT创造了超低剂量的化疗窗口。此外，前药设计和精确的混合纳米组装很好地控制了脱靶毒性。正如预期的那样，这种由BL - 193赋能的前药纳米组装体引发了强大的抗肿瘤反应。这项研究提供了一种放大化疗疗效 - 毒性益处的新范例。
