Cited by 508Mathematical Biology Tumor GrowthAngiogenesis and VEGF in CancerCancer Cells and Metastasis

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Combining two strategies to improve perfusion and drug delivery in solid tumors

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Stylianopoulos, Triantafyllos, Jain, Rakesh K.·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1318415110PMC PMC3832007

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Abstract

Blood perfusion in tumors can be significantly lower than that in the surrounding normal tissue owing to the leakiness and/or compression of tumor blood vessels. Impaired perfusion reduces oxygen supply and results in a hypoxic microenvironment. Hypoxia promotes tumor progression and immunosuppression, and enhances the invasive and metastatic potential of cancer cells. Furthermore, poor perfusion lowers the delivery of systemically administered drugs. Therapeutic strategies to improve perfusion include reduction in vascular permeability by vascular normalization and vascular decompression by alleviating physical forces (solid stress) inside tumors. Both strategies have shown promise, but guidelines on how to use these strategies optimally are lacking. To this end, we developed a mathematical model to guide the optimal use of these strategies. The model accounts for vascular, transvascular, and interstitial fluid and drug transport as well as the diameter and permeability of tumor vessels. Model simulations reveal an optimal perfusion region when vessels are uncompressed, but not very leaky. Within this region, intratumoral distribution of drugs is optimized, particularly for drugs 10 nm in diameter or smaller and of low binding affinity. Therefore, treatments should modify vessel diameter and/or permeability such that perfusion is optimal. Vascular normalization is more effective for hyperpermeable but largely uncompressed vessels (e.g., glioblastomas), whereas solid stress alleviation is more beneficial for compressed but less-permeable vessels (e.g., pancreatic ductal adenocarcinomas). In the case of tumors with hyperpermeable and compressed vessels (e.g., subset of mammary carcinomas), the two strategies need to be combined for improved treatment outcomes.

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Authors: Stylianopoulos, T., & Jain, R. K.
Affiliations: University of Cyprus (CY)
Harvard University (US)
ORCID: Stylianopoulos, Triantafyllos
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-10-28
Volume: 110
Issue: 46
Pages: 18632-18637
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1318415110
PMC: PMC3832007
OpenAlex: W1964128680
Cited by: 508
References: 67
Citations by year: 2026: 49 · 2025: 46 · 2024: 45 · 2023: 47 · 2022: 29 · 2021: 35 · 2020: 53 · 2019: 29 · 2018: 39 · 2017: 35 · 2016: 34 · 2015: 47 · 2014: 19 · 2013: 1
FWCI: 34.83
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: other-oa
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA115767, T32CA073479, R01CA085140, R01CA096915, P01CA080124, R01CA126642, R01CA098706)
Topics: Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords: tumor perfusion, drug delivery, solid tumors, vascular normalization, solid stress, tumor hypoxia, vascular permeability, interstitial fluid flow, mathematical model, drug distribution, glioblastoma, pancreatic ductal adenocarcinoma, breast cancer
MeSH terms: Biomechanical Phenomena, Capillary Permeability, Computer Simulation, Humans, Models, Biological, Neoplasms, Regional Blood Flow, Drug Delivery Systems

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Combining two strategies to improve perfusion and drug delivery in solid tumors

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