Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Abstract

Purpose Low molecular weight (LMW) chemotherapeutics are believed to reach tumors through diffusion across capillary beds as well as membrane transporters. Unexpectedly, the delivery of these agents appears to be augmented by reductions in tumor interstitial fluid pressure (TIFP), an effect typically associated with high molecular weight molecules which reach tumors principally through convection. We investigated the hypothesis that improved intratumoral convection can alter tumor metabolism and enhance the delivery of a LMW chemotherapeutic agent to solid tumors. Experimental Design For this purpose we applied 31P/19F MR spectroscopy and spectroscopic imaging to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown subcutaneously in mice. Results Collagenase effected a 34% reduction in TIFP with an attendant disintegration of intratumoral collagen. Neither mice administered collagenase nor controls receiving PBS demonstrated changes in 31PMRS-measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pie) was observed in tumors of collagenase-treated animals. 31PMRSI demonstrated that this increase underscored a more homogeneous distribution of Pie in tumors of experimental mice. 19FMRS showed that these changes were associated with a 50% increase in 5FU uptake in tumors of experimental versus control animals; however, this increase resulted in an increase in 5FU catabolites rather than fluoronucleotide intermediates that are required for subsequent cytotoxicity. Conclusions These data indicate that the modulation of convective flow within tumors can improve the delivery of (LMW) chemotherapeutics and demonstrate the potential role for non-invasive imaging of this process in vivo.

Interstitial Inorganic Phosphate as a Tumor Microenvironment Marker for Tumor Progression

“…The observed elevated Pi concentration in TME of breast tumors vs. normal mammary glands, and in highly metastatic tumor xenografts compared to non-metastatic tumors raises questions about the role of interstitial inorganic phosphate in tumor progression and metastasis. Among the other factors, alterations in interstitial fluid pressure and/or tumor blood flow could influence the amount of inorganic phosphate observed in the extracellular compartment20. We did not observe a difference in the degree of vascularization of the non-metastatic PC14 and metastatic PC14HM tumor xenografts which suggests that this factor may not contribute to the difference in [Pi] between two types of xenograft tumors (Fig.…”

Erbb2 DNA Vaccine Combined with Regulatory T Cell Deletion Enhances Antibody Response and Reveals Latent Low-Avidity T Cells: Potential and Limits of Its Therapeutic Efficacy

“…Survival, in fact, is no more than marginally extended if this combination is administered when they are nearly palpable in the mammary pad (20th wk of age), because it does no more than slow down the progress of a few lesions and reduce the number of tumors per mouse. This loss of efficacy is probably due to increased resistance acquired by the more advanced neoplastic lesions as they become more compact and refractory to the immune mechanisms thus activated (43,44). The growth of these lesions is fatal, even if the expansion of smaller lesions is still controlled by the immune response.…”

Stromal regulation of vessel stability by MMP14 and TGFβ

“…Previous studies have reported that ectopically applied collagenase, or a reduced accumulation of collagen fibrils in tissue, correlates with enhanced 'drug' delivery to tumors Brown et al, 2003;Loeffler et al, 2006;Gade et al, 2009), thus indicating that the organization and structure of perivascular collagen fibrils regulate vascular leakage. To directly assess whether inhibition of collagenolytic MMP activity impacted vascular leakage, we used the Miles assay (Miles and Miles, 1952), which is an in vivo assay of vascular leakage, to analyze the acute cutaneous vascular response to mustard oil (MO) in mice that were pretreated systemically with the broad-spectrum metalloproteinase (MP) inhibitor GM6001.…”

“…Reduced type I collagen accumulation enhances drug penetration and drug responses Brown et al, 2003;Loeffler et al, 2006;McKee et al, 2006), as does ectopic delivery of interstitial collagenases (Gade et al, 2009). Thus, transient blockade of TGFb would be expected to not only reduce matrix synthesis, but also to reduce perivascular and stromal cell contractility, leading to reduced interstitial fluid pressure, and improved tissue perfusion and drug delivery.…”