Combining two strategies to improve perfusion and drug delivery in solid tumors
| Autor: | Stylianopoulos, T., Jain, R. K. |
|---|---|
| Přispěvatelé: | Stylianopoulos, T. [0000-0002-3093-1696] |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Pathology
4 [2'] losartan sunitinib taxane derivative vasculotropin antibody Vascular permeability protein tyrosine phosphatase 0302 clinical medicine Drug Delivery Systems Models drug binding Neoplasms diphtheria toxin drug delivery system cediranib breast carcinoma cancer survival procollagen proline 2 oxoglutarate 4 dioxygenase Vessel permeability 0303 health sciences Multidisciplinary article neutralizing antibody tissue perfusion Biological Sciences 3. Good health Biomechanical Phenomena semaxanib priority journal Tumor microenvironment 030220 oncology & carcinogenesis Drug delivery saridegib medicine.symptom Vessel decompression Perfusion medicine.medical_specialty drug transport regulatory mechanism extracellular matrix bevacizumab Models Biological doxorubicin surgical technique nelfinavir monoclonal antibody DC101 Capillary Permeability 03 medical and health sciences blood vessel permeability Interstitial fluid medicine Humans Computer Simulation controlled study human vascular normalization 030304 developmental biology business.industry human cell glioblastoma 2 d]pyrimidine Hypoxia (medical) Biological pancreas adenocarcinoma 2 (4 hydroxyphenyl) 4 morpholinopyrido[3' 5]furo[3 Tumor progression Regional Blood Flow blood vessel diameter Cancer cell treatment outcome ovary carcinoma protein farnesyltransferase inhibitor solid tumor Mathematical modeling Mechanical forces business upregulation hydraulic conductivity |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | 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. 110 18632 18637 18632-18637 |
| Databáze: | OpenAIRE |
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