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Glutathione responsive iNOS inhibiting polymeric prodrug for targeted Inhibition of angiogenesis

Alimoradi, Houman ; Fallah, Anita ; Jespers, Pascale ; Bolaky, Nargis ; Gregoire, Françoise ; Townley, Helen ; Törnroth-Horsefield, Susanna LU ; Shavandi, Armin ; Dewachter, Laurence and Delporte, Christine (2026) In Journal of Nanobiotechnology 24(1).
Abstract

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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Angiogenesis, Gluthatione-responsive prodrug, iNOS, Nitric oxide, Tumor microenvironment
in
Journal of Nanobiotechnology
volume
24
issue
1
article number
194
publisher
BioMed Central (BMC)
external identifiers
  • pmid:41618417
  • scopus:105031115302
ISSN
1477-3155
DOI
10.1186/s12951-026-04022-z
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2026.
id
67d81609-bd5d-43f6-8567-51e61e05da21
date added to LUP
2026-04-16 16:24:58
date last changed
2026-04-17 03:00:02
@article{67d81609-bd5d-43f6-8567-51e61e05da21,
  abstract     = {{<p>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 (NP<sub>BeS</sub>). These dual-function nanoparticles (NP<sub>BeS</sub>) 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, NP<sub>BeS</sub> inhibits iNOS, as evidenced by suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. NP<sub>BeS</sub> 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.</p>}},
  author       = {{Alimoradi, Houman and Fallah, Anita and Jespers, Pascale and Bolaky, Nargis and Gregoire, Françoise and Townley, Helen and Törnroth-Horsefield, Susanna and Shavandi, Armin and Dewachter, Laurence and Delporte, Christine}},
  issn         = {{1477-3155}},
  keywords     = {{Angiogenesis; Gluthatione-responsive prodrug; iNOS; Nitric oxide; Tumor microenvironment}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Nanobiotechnology}},
  title        = {{Glutathione responsive iNOS inhibiting polymeric prodrug for targeted Inhibition of angiogenesis}},
  url          = {{http://dx.doi.org/10.1186/s12951-026-04022-z}},
  doi          = {{10.1186/s12951-026-04022-z}},
  volume       = {{24}},
  year         = {{2026}},
}