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Glutathione responsive iNOS inhibiting polymeric prodrug for targeted Inhibition of angiogenesis
Houman Alimoradi1,2, Anita Fallah3, Pascale Jespers4,5
1Laboratory of Pathophysiological and Nutritional Biochemistry (LPNB), Faculty of Medicine, Université Libre de Bruxelles, 808 Route de Lennik, Blg G/E CP 611, Brussels, 1070, Belgium. houman.alimoradi@ulb.be.
Background:
Inducible nitric oxide synthase (iNOS) is a key driver of aberrant angiogenesis in inflammatory conditions and cancer, making it an attractive therapeutic target. Nevertheless, its function can be affected by the complex immune responses and tumor microenvironment (TME). Hence, combinatorial treatment approaches that simultaneously target iNOS and immune-modulatory signaling are strongly recommended for cancer therapy. Moreover, the current iNOS inhibitors are limited by poor pharmacokinetics and a lack of selectivity.
Results:
To address these challenges, we developed a glutathione (GSH)-responsive iNOS-inhibiting polymeric prodrug (GRIP) decorated with betamethasone succinate (NPBeS). These dual-function nanoparticles (NPBeS) remain stable under physiological conditions but selectively release their payload in response to elevated GSH levels, a hallmark of the TME. Only upon activation by GSH, NPBeS inhibits iNOS, as evidenced by suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. NPBeS also normalized vascular endothelial growth factor (VEGF)-mediated tube formation in HUVECs and 3T3-L1 fibroblast cell migration, and angiogenesis in the CAM assay, demonstrating its anti-angiogenic activity. Importantly, GRIP did not impair acetylcholine (ACh)-induced vasodilation in rat aorta, even at elevated concentrations, indicating preservation of eNOS function.
Conclusions:
This is the first report of a GSH-responsive polymeric prodrug system that leverages intracellular GSH for both controlled release of anionic therapeutic agents and in situ synthesis of an iNOS antagonist. Through these two complementary pathways, the system enables targeted, sustained anti-angiogenic effects and promotes vascular normalization. This dual-function platform holds strong potential for the treatment of cancer-associated angiogenesis.
Insights
We developed a novel nanoparticle that releases an inducible nitric oxide synthase (iNOS) inhibitor in response to tumor microenvironment conditions. This targeted approach shows promise for treating cancer-associated angiogenesis by normalizing blood vessels.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Inducible nitric oxide synthase (iNOS) drives aberrant angiogenesis in cancer and inflammatory conditions.
- Current iNOS inhibitors face challenges with pharmacokinetics and selectivity.
- Combinatorial approaches targeting iNOS and immune signaling are crucial for cancer therapy.
Purpose of the Study:
- To develop a glutathione (GSH)-responsive polymeric prodrug system for targeted iNOS inhibition.
- To create dual-function nanoparticles (NPBeS) for controlled drug release and iNOS antagonism.
- To evaluate the anti-angiogenic and vascular normalization effects of the developed system.
Main Methods:
- Development of a GSH-responsive iNOS-inhibiting polymeric prodrug (GRIP) decorated with betamethasone succinate (NPBeS).
- Assessment of NPBeS payload release in response to elevated GSH levels.
- Evaluation of iNOS inhibition via suppressed nitric oxide (NO) production in macrophages.
- Analysis of anti-angiogenic activity through VEGF-mediated tube formation, fibroblast migration, and CAM assay.
- Testing for preservation of endothelial nitric oxide synthase (eNOS) function in rat aorta vasodilation.
Main Results:
- NPBeS demonstrated selective payload release in response to high GSH levels characteristic of the tumor microenvironment (TME).
- Activated NPBeS effectively inhibited iNOS, reducing NO production and normalizing VEGF-driven angiogenesis.
- The nanoparticles exhibited anti-angiogenic activity in vitro and in vivo (CAM assay).
- Crucially, NPBeS preserved acetylcholine (ACh)-induced vasodilation, indicating no impairment of normal eNOS function.
Conclusions:
- This study introduces the first GSH-responsive prodrug system for controlled release and in situ iNOS antagonist synthesis.
- The dual-action platform achieves targeted, sustained anti-angiogenic effects and promotes vascular normalization.
- This novel dual-function nanoparticle system holds significant potential for treating cancer-associated angiogenesis.
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