A natural compound-empowered podophyllotoxin prodrug nanoassembly magnifies efficacy-toxicity benefits in cancer chemotherapy

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences Pub Date : 2024-08-01 DOI:10.1016/j.ajps.2024.100892

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Abstract

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.

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一种由天然化合物赋能的荚叶毒素原药纳米组合可放大癌症化疗的疗效和毒性优势

小分子原药纳米组装技术在减少脱靶毒性方面具有独特优势，已被广泛应用于抗肿瘤给药。然而，原药活化仍然是发挥治疗作用的一个限制性步骤，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）能在无效剂量浓度下选择性地提高乳腺癌细胞对豆荚毒素（PPT）的化疗敏感性。在此基础上，我们提出将原药纳米组装与化疗增敏相结合，以充分释放 PPT 的化疗潜力。具体来说，我们将 9-芴基甲醇（Fmoc-OH）与通过二硫键连接的 PPT 结合在一起，合成了 PPT 的氧化还原敏感原药（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件。值得注意的是，BL-193 是一种出色的化疗增敏剂，为 PPT 创造了一个超低剂量化疗窗口。此外，原药设计和精确的混合纳米组装可以很好地控制脱靶毒性。正如预期的那样，这种由 BL-193 赋能的原药纳米组合能激发有效的抗肿瘤反应。这项研究为放大化疗疗效-毒性效益提供了一种新的范例。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

CiteScore

18.30

自引率

2.90%

发文量

审稿时长

14 days

期刊介绍： The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.

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