Sunitinib lipid nanoparticles remodel tumor vasculature to synergize with two-stage radiotherapy for enhanced radiosensitivity in breast Cancer
Abstract
Radiotherapy (RT) is a standard treatment for breast cancer, the most common malignancy in women. However, its efficacy is limited in 20-30 % of patients due to acquired resistance, primarily caused by tumor hypoxia resulting from abnormal vasculature in the tumor microenvironment (TME). Vascular normalization strategies aim to stabilize tumor vasculature and alleviate hypoxia. Although preclinical studies indicate survival benefits from vascular normalization，their clinical translation remains limited by spatiotemporal constraints and a narrow therapeutic window where excessive modulation can induce detrimental effects. Here, we engineered microenvironment-responsive PEGylated lipid nanoparticles (PL) that encapsulate varying doses of sunitinib (Sun@PL) to achieve sustained release, selecting the optimal dose for dose-controlled vascular normalization within tumor tissue. When synergized with "two-stage RT", this strategy effectively enhanced tumor oxygenation and radiosensitization. Initial RT softened the extracellular matrix (ECM), alleviated vascular compression, and amplified Sun@PL-driven normalization, significantly improving tumor oxygenation. The subsequent RT, conducted in the improved oxygenated microenvironment, effectively enhanced anti-tumor efficacy. Our findings emphasize the critical role of dosage and controlled-release strategies in vascular normalization and highlight the potential of synergizing Sun@PL with RT as a strategy to overcome radioresistance in breast cancer and enhance therapeutic efficacy.
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Such systems frequently incorporated catalytic and microenvironment-responsive components designed to address tumor hypoxia, redox imbalance, and metabolic vulnerabilities.
“Such systems frequently incorporated catalytic and microenvironment-responsive components designed to address tumor hypoxia, redox imbalance, and metabolic vulnerabilities within the tumor microenvironment [17,19,21,43,47,53].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [47]
Additional strategies included depletion of intracellular glutathione and modulation of redox balance, as well as metabolic interventions targeting glycolysis or cellular energetics.
“Additional strategies included depletion of intracellular glutathione (GSH) and modulation of redox balance [17,19,45,47,68], as well as metabolic interventions targeting glycolysis or cellular energetics [49,69,75,76].”
From Nanoparticle-Mediated Radiosensitization in Breast Cancer: A Systematic Review of Preclinical Evidence and Translational Challenges (2026) · cites this paper as [47]
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- Authors
- Li, P., Dong, Z., Jiang, Q., Yu, C., Liu, Y., Yuan, R., Qiu, Y., Meng, T., Hu, F., & Yuan, H.
- Affiliations
- Zhejiang University (CN)
- Westlake University (CN)
- Corresponding author
- Yuan, Hong
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2026-01
- Volume
- 389
- Pages
- 114406
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W4416438814
- Cited by
- 6
- References
- 71
- Citations by year
- 2026: 6
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Zhejiang Province Natural Science Foundation (LZ22H060001)
- Zhejiang University
- National Natural Science Foundation of China (82473857)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- sunitinib, lipid nanoparticles, vascular normalization, breast cancer, radiosensitization, tumor hypoxia, tumor microenvironment, extracellular matrix, sustained drug release, radioresistance (biology), tumor oxygenation
- MeSH terms
- Sunitinib, Animals, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Lipids, Liposomes, Mice, Inbred BALB C, Mice, Nude, Radiation Tolerance, Radiation-Sensitizing Agents, Cell Line, Tumor, Mice, Nanoparticles, Tumor Microenvironment
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