Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice
Open accessAbstract
Barriers presented by the tumor microenvironment including the abnormal tumor vasculature and interstitial matrix invariably lead to heterogeneous distribution of nanotherapeutics. Inspired by the close association between cyclooxygenase-2 (COX-2) and tumor-associated angiogenesis, as well as tumor matrix formation, we proposed that tumor microenvironment normalization by COX-2 inhibitors might improve the distribution and efficacy of nanotherapeutics for solid tumors. The present study represents the first time that celecoxib, a special COX-2 inhibitor widely used in clinics, was explored to normalize the tumor microenvironment and to improve tumor nanotherapeutics delivery using a human-derived A549 tumor xenograft as the solid tumor model. Immunofluorescence staining of tumor slices demonstrated that oral celecoxib treatment at a dose of 200 mg/kg for two weeks successfully normalized the tumor microenvironment, including tumor-associated fibroblast reduction, fibronectin bundle disruption, tumor vessel normalization, and tumor perfusion improvement. Furthermore, it also significantly enhanced the in vivo accumulation and deep penetration of 22-nm micelles rather than 100-nm nanoparticles in tumor tissues by in vivo imaging and distribution experiments and improved the therapeutic efficacy of paclitaxel-loaded micelles in tumor xenograft-bearing mouse models in the pharmacodynamics experiment. As celecoxib is widely and safely used in clinics, our findings may have great potential in clinics to improve solid tumor treatment.
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Celecoxib, a COX-2 inhibitor, acts as an angiogenesis inhibitor and results in vascular normalization and improved EPR effect in the tumor site.
“In addition, celecoxib a cyclooxygenase-2 (COX-2) inhibitors also act as an angiogenesis inhibitor and result in vascular normalization and improved EPR effect in the tumor site [30].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [30]
The Results and Discussion (page not provided) report reduced tumor microvessel density and normalized vessels after celecoxib treatment, consistent with inhibition of angiogenesis. The Abstract and Results and Discussion report improved tumor accumulation and penetration of 22-nm micelles, but not 100-nm nanoparticles, in A549 tumor-bearing mice. Thus, the unqualified claim of an improved EPR effect is broader than the delivery finding shown. (LLM, conf=0.84)
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- Authors
- Zhang, B., Jin, K., Jiang, T., Wang, L., Shen, S., Luo, Z., Tuo, Y., Liu, X., Hu, Y., & Pang, Z.
- Affiliations
- Wuhan Union Hospital (CN)
- Fudan University (CN)
- Corresponding author
- Hu, Yu
- Pang, Zhiqing
- Venue
- Scientific Reports
- Published
- 2017-08-30
- Volume
- 7
- Issue
- 1
- Pages
- 10071-10071
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5577220
- OpenAlex
- W2748209289
- Cited by
- 49
- References
- 58
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 6 · 2017: 1
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81361140344, 81370622, 81600175, 81301974, 81472757)
- Ministry of Education of the People's Republic of China (20100071120050)
- Fudan University
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- celecoxib, COX-2 inhibitors, tumor microenvironment normalization, cancer-associated fibroblasts, tumor vasculature normalization, tumor perfusion, micelle size, tumor angiogenesis
- MeSH terms
- Celecoxib, A549 Cells, Animals, Antineoplastic Agents, Phytogenic, Adenocarcinoma, Bronchiolo-Alveolar, Drug Administration Schedule, Drug Synergism, Drug Therapy, Combination, Humans, Lung Neoplasms, Male, Mice, Nude, Micelles, Neovascularization, Pathologic, Polyesters, Polyethylene Glycols, Gene Expression, Drug Delivery Systems, Paclitaxel, Xenograft Model Antitumor Assays, Tumor Burden, Mice, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Nanoparticles, Tumor Microenvironment
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