Over the last decade, the benefits of drug vectors to treat cancer have been well recognized. However, drug delivery and vector distribution differences in tumor-associated capillary bed at different stages of disease progression are not well understood. To obtain further insights into drug vector distribution changes in vasculature during tumor progression, we combined intra-vital imaging of metastatic tumors in mice, microfluidics-based artificial tumor capillary models, and Computational Fluid Dynamics (CFD) modeling. Microfluidic and CFD circulation models were designed to mimic tumor progression by escalating flow complexity and chaoticity. We examined flow of 0.5 and 2 μm spherical particles, and tested the effects of hematocrit on particle local accessibility to flow area of capillary beds by co-circulating red blood cells (RBC). Results showed that tumor progression modulated drug vector distribution in tumor-associated capillaries. Both particles shared 80–90% common flow area, while 0.5 and 2 μm particles had 2–9% and 1–2% specific flow area, respectively. Interestingly, the effects of hematocrit on specific circulation area was opposite for 0.5 and 2 μm particles. Dysfunctional capillaries with no flow, a result of tumor progression, limited access to all particles, while diffusion was shown to be the only prevailing transport mechanism. In view of drug vector distribution in tumors, independent of formulation and other pharmacokinetic aspects, our results suggest that the evolution of tumor vasculature during progression may influence drug delivery efficiency. Therefore, optimized drug vectors will need to consider primary vs metastatic tumor setting, or early vs late stage metastatic disease, when undergoing vector design.