The effect of interstitial pressure on therapeutic agent transport

coupling with the tumor blood and lymphatic vascular systems

Min Wu, Hermann B. Frieboes, Mark A. J. Chaplain, Steven R. McDougall, Vittorio Cristini, John S. Lowengrub (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    47 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)194-207
    Number of pages14
    JournalJournal of Theoretical Biology
    Volume355
    DOIs
    Publication statusPublished - 21 Aug 2014

    Fingerprint

    Lymphatic System
    Blood Vessels
    Blood
    Tumors
    Tumor
    Pressure
    therapeutics
    blood vessels
    neoplasms
    blood
    Extracellular Fluid
    extracellular fluids
    Neoplasms
    Area Under Curve
    Hydraulic Conductivity
    hydraulic conductivity
    Hydraulic conductivity
    Therapeutics
    Chemotherapy
    drug therapy

    Keywords

    • Chemotherapy
    • Cancer simulation
    • Tumor vasculature
    • Tumor lymphatics
    • Interstitial fluid pressure

    Cite this

    Wu, Min ; Frieboes, Hermann B. ; Chaplain, Mark A. J. ; McDougall, Steven R. ; Cristini, Vittorio ; Lowengrub, John S. / The effect of interstitial pressure on therapeutic agent transport : coupling with the tumor blood and lymphatic vascular systems. In: Journal of Theoretical Biology. 2014 ; Vol. 355. pp. 194-207.
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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.",
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    The effect of interstitial pressure on therapeutic agent transport : coupling with the tumor blood and lymphatic vascular systems. / Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A. J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John S. (Lead / Corresponding author).

    In: Journal of Theoretical Biology, Vol. 355, 21.08.2014, p. 194-207.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The effect of interstitial pressure on therapeutic agent transport

    T2 - coupling with the tumor blood and lymphatic vascular systems

    AU - Wu, Min

    AU - Frieboes, Hermann B.

    AU - Chaplain, Mark A. J.

    AU - McDougall, Steven R.

    AU - Cristini, Vittorio

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    AB - 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.

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    KW - Cancer simulation

    KW - Tumor vasculature

    KW - Tumor lymphatics

    KW - Interstitial fluid pressure

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