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The effect of interstitial pressure on therapeutic agent transport : coupling with the tumor blood and lymphatic vascular systems

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Date
21/08/2014
Author
Wu, Min
Frieboes, Hermann B.
Chaplain, Mark A. J.
McDougall, Steven R.
Cristini, Vittorio
Lowengrub, John S.
Keywords
Chemotherapy
Cancer simulation
Tumor vasculature
Tumor lymphatics
Interstitial fluid pressure
RM Therapeutics. Pharmacology
QH301 Biology
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Abstract
Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response slows down as the tumor shrinks due to the heterogeneity and low concentration of agents in the tumor interior compared with the cases where other pathological effects may combine to flatten the IFP and thus reduce the heterogeneity. We conclude that dual normalizations of the micronevironment ? both the vasculature and the interstitium ? are needed to maximize the effects of chemotherapy, while normalization of only one of these may be insufficient to overcome the physical resistance and may thus lead to sub-optimal outcomes.
Citation
Wu , M , Frieboes , H B , Chaplain , M A J , McDougall , S R , Cristini , V & Lowengrub , J S 2014 , ' The effect of interstitial pressure on therapeutic agent transport : coupling with the tumor blood and lymphatic vascular systems ' , Journal of Theoretical Biology , vol. 355 , pp. 194-207 . https://doi.org/10.1016/j.jtbi.2014.04.012
Publication
Journal of Theoretical Biology
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.jtbi.2014.04.012
ISSN
0022-5193
Type
Journal article
Rights
Copyright © 2014 Elsevier Ltd. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://dx.doi.org/10.1016/j.jtbi.2014.04.012
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  • University of St Andrews Research
URL
http://www.sciencedirect.com/science/article/pii/S002251931400232X
URI
http://hdl.handle.net/10023/8648

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