Hypoxia-activated glutamine antagonist prodrug combined with combretastatin A4 nanoparticles for tumor-selective metabolic blockade

6-Diazo-5-oxo-L-norleucine (DON) is a potent glutamine antagonist with toxic side effects; in order to reduce these effects, multiple prodrugs have been designed. However, there are currently no reports of a DON prodrug with a defined mechanism to achieve high tumor selectivity. To improve the selective toxicity of DON to tumor cells while reducing systemic toxicity, a hypoxia-activated prodrug, termed HDON, was designed. HDON achieved remarkable tumor suppression of 76.4 ± 5.2% without leading to weight loss in an H22 murine liver cancer model with high hypoxia. Moreover, to augment the therapeutic efficacy of HDON, combretastatin A4 nanoparticles were used to aggravate tumor hypoxia of MC38 murine colon cancer and 4T1 murine breast cancer, activate HDON to DON, and stimulate a robust anti-tumor immune response while selectively killing in tumor cells in vivo, achieving significantly elevated tumor suppression rates of 98.3 ± 3.4% and 98.1 ± 3.1%, with cure rates of 80.0% and 20.0%, respectively.

 

Comments:

That's a comprehensive and detailed study on the development of a prodrug, HDON, derived from 6-Diazo-5-oxo-L-norleucine (DON), aiming to enhance its selectivity and efficacy against tumors while minimizing systemic toxicity. The use of hypoxia-activated prodrugs is a fascinating approach since many solid tumors often have regions of low oxygen levels (hypoxia), making them an ideal target.

The combination of HDON with combretastatin A4 nanoparticles seems particularly promising. These nanoparticles could exacerbate tumor hypoxia, triggering the activation of HDON into DON, thereby inducing a robust anti-tumor immune response while selectively targeting tumor cells. Achieving such high tumor suppression rates, especially with elevated cure rates in murine liver, colon, and breast cancer models, is quite impressive.

This research appears to address several critical aspects in cancer therapy: specificity in targeting tumor cells, utilizing the tumor microenvironment to activate the prodrug, and triggering an immune response against the tumor. It seems like a significant step towards developing more effective and selective cancer treatments.

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