Abstract 3909: Assessing the role of tumor vascularity in nanotherapeutics delivery.
Authors: Van de Ven-Moloney Anne L. , Landis Melissa D. , Burey Lacey A. , Ferrari Mauro , Chang Jenny C. 
Published: August 2014

Chemotherapeutic delivery is generally poor in tumors characterized by rapid perfusion and low blood volume fraction. Nanoparticles can be engineered to overcome abnormal flow conditions to act as intravascular drug depots for the localized delivery of high concentrations of chemotherapeutics. We hypothesized that the ability of multi-stage nanotherapeutics to accumulate in tumors is highly dependent on tumor perfusion and that matching particle parameters to tumor-specific flow parameters can improve the delivery of nanotherapeutics. To test this hypothesis, we measured first-pass perfusion of an intra-arterial bolus of FITC-dextran using intravital microscopy (IVM) in 4 patient-derived breast tumor xenograft (PDX) lines: BCM-2665, BCM-4195, BCM-2147, and BCM-3887. These PDX lines were established directly from patient samples and maintain the triple negative biomarker status of the original patient tumors. Selected for their differing vascular morphologies, these 4 tumor lines yielded distinct, reproducible transport features unique to each tissue. BCM-2665 tumors (n=6) were characterized by regions of dense vascularization interspersed with regions of little to no blood flow. BCM-2147 tumors (n=6) were dominated by large tortuous vessels like those observed in BCM-2665 tumors, but also had a well-developed capillary network interconnecting the large vessels. BCM-3887 tumors (n=6) were characterized by an extensive network of poorly defined, dilated, leaky microvessels. BCM-4195 tumors were uniformly covered with a well-defined, widely spaced microvessel network. The arteriovenous transit time (AVTT) was measured by tracking a bolus of 40kDa FITC-dextran through the tumor vasculature in real-time. Both 2665 and 2147 tumors were rapidly perfused (∼10 - 25 seconds), whereas a majority of 3887 and 4195 tumors required ∼45 seconds or more. The blood volume fraction (BVF) varied by nearly an order of magnitude, with 2665 and 2147 tumors exhibiting the lowest BVF (∼0.11 - 0.12). The tracer elimination constant (Kel), which was measured as a surrogate for tumor permeability using time-lapse IVM images, was an order of magnitude lower for 3887 and 4195 tumors (∼0.11/hr vs. ∼1.17/hr) indicating that these tumors are much more permeable than 2665 and 2147 tumors. Interestingly, flow parameters that adversely impact drug accumulation appear to favor particle accumulation. In clinical studies, tumors characterized by rapid perfusion and low blood volume fraction generally respond poorly to chemotherapy and radiation therapy. We have observed this phenomenon in our cancer models: BCM-2665 and BCM-2147 tumors fail to show growth inhibition at clinically relevant doses of docetaxel, whereas BCM-4195 and BCM-3887 tumors show complete growth inhibition. As such, we believe these tumors will provide an excellent model for studying the relative importance of tumor-specific transport features for improving drug delivery.

Citation Format: Anne L. Van de Ven-Moloney, Melissa D. Landis, Lacey A. Burey, Mauro Ferrari, Jenny C. Chang. Assessing the role of tumor vascularity in nanotherapeutics delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3909. doi:10.1158/1538-7445.AM2013-3909