CD44-targeting hydrophobic phosphorylated gemcitabine prodrug nanotherapeutics augment lung cancer therapy

Gemcitabine (GEM) is among the most used chemotherapies for advanced malignancies including non- small cell lung cancer. The clinical efficacy of GEM is, however, downplayed by its poor bioavailabil- ity, short half-life, drug resistance, and dose-limiting toxicities (e.g. myelosuppression). In spite of many approaches exploited to improve the efficacy and safety of GEM, limited success was achieved. The short A6 peptide (sequence: Ac-KPSSPPEE-NH 2 ) is clinically validated for specific binding to CD44 on metastatic tumors. Here, we designed a robust and CD44-specific GEM nanotherapeutics by encapsulat- ing hydrophobic phosphorylated gemcitabine prodrug (HPG) into the core of A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG), which exhibited reduction-triggered HPG release and specific targetability to CD44 overexpressing tumor cells. Interestingly, A6 greatly enhanced the internalization and inhibitory activity of micellar HPG (mHPG) in CD44 positive A549 cells, and increased its accumula- tion in A549 cancerous lung, leading to potent repression of orthotopic tumor growth, depleted toxicity, and marked survival benefits compared to free HPG and mHPG (median survival time: 59 days versus 30 and 45 days, respectively). The targeted delivery of gemcitabine prodrug with disulfide-crosslinked biodegradable micelles appears to be a highly appealing strategy to boost gemcitabine therapy for ad- vance tumors.

B.B. Guo, J.J. Wei, J.Y. Wang, Y.P. Sun, J.D. Yuan, andZ.Y. Zhong*,F.H. Meng*,CD44-targeting hydrophobic phosphorylated gemcitabine prodrug nanotherapeutics augment lung cancer therapy,Acta Biomaterialia2022, 145, 200-209.