Combining two strategies to improve perfusion and drug delivery in solid tumors
Year: 2013
Type: article
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.
Authors: Triantafyllos Stylianopoulos, Rakesh K. Jain
Language: English
Subfield: Modeling and Simulation
Field: Mathematics
Domain: Physical Sciences
Open Access status: green
Funder: National Cancer Institute
Awards: Role of BMDCs in Solid Tumor Growth and Relapse, Training Program in Integrative Pathophysiology of Solid Tumors, Integrative Biology of Tumor Metastasis, Nitric Oxide in Tumor Angiogenesis, Microcirculation and Radiation Therapy, Integrative Pathophysiology of Solid Tumors, Probing Tumor Microenvironment Using Nanotechnology, Transport of Large Molecules and Viral Vectors in Tumors: Effects of Cytotoxic an
OpenAlex ID: W1964128680