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<p>To overcome the inherent limitations of conventional nanocarriers such as therapeutic inefficacy and suboptimal drug loading capacity, a novel “polymeric nanodrug” strategy was developed. This approach redefines nanodrug design by employing glycyrrhetinic acid (GA) simultaneously as a bioactive agent and a polymerizable targeting monomer to synthesize poly-glycyrrhetinic acid (PGA), achieving near-theoretical drug loading approaching 100%. Subsequent PEGylation yielded hepatocellular carcinoma (HCC)-targeting PGA-PEG-GA nanodrugs, which exhibited a 1.89-fold enhancement in antitumor efficacy compared to free GA. The exceptionally low critical micelle concentration (CMC) of PGA-PEG-GA enables efficient encapsulation of additional therapeutics. Using doxorubicin (DOX) as a model drug, HCC-targeting nanodrugs (denoted as DOX@PGA-PEG-GA NDs) were fabricated. In vitro studies demonstrated that the nanodrugs induced 2.5-fold higher toxicity in tumor cells than normal cells, enhanced cellular uptake by 3.0-fold, and reduced DOX-induced cardiomyocyte apoptosis by 54%. In vivo evaluations revealed a tumor inhibition rate of 89.7 ± 5.2% for DOX@PGA-PEG-GA NDs and 40.09 ± 11.94% for blank PGA-PEG-GA NDs, together with 18.3-fold higher intra-tumoral accumulation compared to free DOX and complete mitigation of DOX-related cardiotoxicity. This integrated “structure-function-safety” strategy effectively overcomes critical challenges in drug-loading efficiency and functional synergy, offering a robust and novel platform for targeted nanodrug applications. </p> Graphical Abstract <p></p>

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Reengineering glycyrrhetinic acid into a therapeutic oligomer for targeted tumor therapy with cardioprotection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月12日

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  • Zixin Wang,
  • Bo Su,
  • Alu Ouyang,
  • ZiXuan Liang,
  • Pingyun Yuan,
  • Xin Qin,
  • Yu Li,
  • Xuejing Huang,
  • Ling Fan,
  • Hongwei Guo,
  • Ronghua Jin

摘要

To overcome the inherent limitations of conventional nanocarriers such as therapeutic inefficacy and suboptimal drug loading capacity, a novel “polymeric nanodrug” strategy was developed. This approach redefines nanodrug design by employing glycyrrhetinic acid (GA) simultaneously as a bioactive agent and a polymerizable targeting monomer to synthesize poly-glycyrrhetinic acid (PGA), achieving near-theoretical drug loading approaching 100%. Subsequent PEGylation yielded hepatocellular carcinoma (HCC)-targeting PGA-PEG-GA nanodrugs, which exhibited a 1.89-fold enhancement in antitumor efficacy compared to free GA. The exceptionally low critical micelle concentration (CMC) of PGA-PEG-GA enables efficient encapsulation of additional therapeutics. Using doxorubicin (DOX) as a model drug, HCC-targeting nanodrugs (denoted as DOX@PGA-PEG-GA NDs) were fabricated. In vitro studies demonstrated that the nanodrugs induced 2.5-fold higher toxicity in tumor cells than normal cells, enhanced cellular uptake by 3.0-fold, and reduced DOX-induced cardiomyocyte apoptosis by 54%. In vivo evaluations revealed a tumor inhibition rate of 89.7 ± 5.2% for DOX@PGA-PEG-GA NDs and 40.09 ± 11.94% for blank PGA-PEG-GA NDs, together with 18.3-fold higher intra-tumoral accumulation compared to free DOX and complete mitigation of DOX-related cardiotoxicity. This integrated “structure-function-safety” strategy effectively overcomes critical challenges in drug-loading efficiency and functional synergy, offering a robust and novel platform for targeted nanodrug applications.

Graphical Abstract