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<p>Hypoxia-driven angiogenesis, mediated by the HIF-1α–VEGF–VEGFR-2 signaling axis, plays a central role in breast cancer progression, therapeutic resistance, and metastasis. Betulinic acid (BA), a plant-derived pentacyclic triterpenoid with anticancer activity, is limited by poor solubility and low bioavailability.&#xa0;Betulinic acid–loaded chitosan nanoparticles (BA-CS NPs) were prepared using ionic gelation and characterized for size, surface charge, encapsulation efficiency, and pH-responsive drug release. Their anticancer and anti-angiogenic effects were evaluated in breast cancer cells and endothelial cells under normoxic and hypoxic conditions using cell viability, clonogenic, tube formation, migration, and VEGF ELISA assays. Mechanistic studies assessed modulation of HIF-1α, VEGF/VEGFR-2, and Akt/ERK signaling. In vivo efficacy was examined in an orthotopic breast cancer mouse model.&#xa0;BA-CS NPs exhibited a mean size of 148.6 ± 6.3&#xa0;nm, low polydispersity (0.21), positive surface charge (+ 32.4 mV), and high encapsulation efficiency (86.7%), with enhanced drug release under acidic conditions (~ 68% at pH 6.5). Compared with free BA, BA-CS NPs significantly reduced cell viability (IC₅₀ = 8.9–13.4 µM), clonogenic survival (~ 72–78%), endothelial tube formation (~ 65–72%), migration (~ 70%), and VEGF secretion (63–75%) under hypoxia. Mechanistically, BA-CS NPs suppressed HIF-1α stabilization (~ 65%), downregulated VEGF/VEGFR-2 (55–70%), and inhibited Akt/ERK phosphorylation (50–68%). In vivo, BA-CS NPs significantly inhibited tumor growth (~ 66%), reduced microvessel density (~ 62%), and showed no detectable systemic toxicity.&#xa0;BA-CS nanoparticles effectively inhibit hypoxia-driven angiogenesis and tumor progression by targeting the HIF-1α–VEGF–VEGFR-2 axis, representing a promising nanotherapeutic strategy for aggressive breast cancer.</p> Graphical Abstract <p></p>

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Betulinic Acid–Loaded Chitosan Nanoparticles Suppress Angiogenesis and Tumor Progression Via VEGF/VEGFR and HIF-1α Blockade in Hypoxic Breast Cancer Models

  • 期刊论文

  • 发表日期：

    2026年7月28日

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  • Cletus Anes Ukwubile,
  • Maryam Bukar Bababe,
  • Troy Salvia Malgwi,
  • Babagana Modu,
  • Chidi Kaosi Clement

摘要

Hypoxia-driven angiogenesis, mediated by the HIF-1α–VEGF–VEGFR-2 signaling axis, plays a central role in breast cancer progression, therapeutic resistance, and metastasis. Betulinic acid (BA), a plant-derived pentacyclic triterpenoid with anticancer activity, is limited by poor solubility and low bioavailability. Betulinic acid–loaded chitosan nanoparticles (BA-CS NPs) were prepared using ionic gelation and characterized for size, surface charge, encapsulation efficiency, and pH-responsive drug release. Their anticancer and anti-angiogenic effects were evaluated in breast cancer cells and endothelial cells under normoxic and hypoxic conditions using cell viability, clonogenic, tube formation, migration, and VEGF ELISA assays. Mechanistic studies assessed modulation of HIF-1α, VEGF/VEGFR-2, and Akt/ERK signaling. In vivo efficacy was examined in an orthotopic breast cancer mouse model. BA-CS NPs exhibited a mean size of 148.6 ± 6.3 nm, low polydispersity (0.21), positive surface charge (+ 32.4 mV), and high encapsulation efficiency (86.7%), with enhanced drug release under acidic conditions (~ 68% at pH 6.5). Compared with free BA, BA-CS NPs significantly reduced cell viability (IC₅₀ = 8.9–13.4 µM), clonogenic survival (~ 72–78%), endothelial tube formation (~ 65–72%), migration (~ 70%), and VEGF secretion (63–75%) under hypoxia. Mechanistically, BA-CS NPs suppressed HIF-1α stabilization (~ 65%), downregulated VEGF/VEGFR-2 (55–70%), and inhibited Akt/ERK phosphorylation (50–68%). In vivo, BA-CS NPs significantly inhibited tumor growth (~ 66%), reduced microvessel density (~ 62%), and showed no detectable systemic toxicity. BA-CS nanoparticles effectively inhibit hypoxia-driven angiogenesis and tumor progression by targeting the HIF-1α–VEGF–VEGFR-2 axis, representing a promising nanotherapeutic strategy for aggressive breast cancer.

Graphical Abstract