Drug-resistant Triple-negative Breast Cancer Research Articles

Abstract Chemotherapeutics delivery is generally poor in tumors characterized by rapid perfusion and low blood volume fraction. Systemically administered nanoparticles can be engineered to overcome abnormal flow conditions to act as intravascular drug depots for the localized delivery of high concentrations of chemotherapeutics. The feasibility of this approach was first demonstrated using melanoma, and is now being further investigated using well-characterized human triple-negative breast cancer biopsies implanted into mice. Intravital microscopy studies of human cancer-in-mice selected for differing vascular morphologies have yielded intriguing preliminary data regarding the role of tumor vascularity in drug and particle delivery. The first-pass perfusion of a 40kDa dextran tracer revealed that BCM-2665 tumors are perfused ∼6x more rapidly than BCM-4195 tumors (11.3 ± 2.3s vs. 67.6 ± 11.0) and contain ∼30% lower volume fraction of blood (0.046 ± 0.011 vs. 0.062 ± 0.015). Interestingly, flow parameters that adversely impact drug accumulation appear to favor plateloid particle accumulation. BCM-2665 xenografts receiving an i.v. injection of 1000×400 nm particles show ∼10x more particle accumulation than BCM-4195 tumors (24.8 ± 3.2 × 103/mm3 vs. 3.5 ± 0.4 × 103/mm3). The ability of these therapeutic particles to reach tumors appears to be primarily driven by flow-related parameters, which we characterize using a combination of intravital microscopy, computed tomography, and mathematical modeling. The total number of particles accumulated within a given tumor appears to be largely driven by the number of particles entering the tumor, since ∼65–70% of entering plateloid particles are retained by the tumor vasculature. This suggests that cytotoxic intravascular drug depots may be a promising strategy for increasing the efficiency of chemotherapeutics delivery to drug-resistant tumors and is the premise of ongoing therapeutic response studies. Clearly if more drugs can be delivered to the tumors, better outcomes can be expected for the patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-12.

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