Mechanisms of tumor vascular priming by a nanoparticulate doxorubicin formulation

Purpose: Tumor vascular normalization by antiangiogenic agents may increase tumor perfusion but reestablish vascular barrier properties in CNS tumors. Vascular priming via nanoparticulate carriers represents a mechanistically distinct alternative. This study investigated mechanisms by which sterically-stabilized liposomal doxorubicin (SSL-DXR) modulates tumor vascular properties. Methods: Functional vascular responses to SSL-DXR were investigated in orthotopic rat brain tumors using deposition of fluorescent permeability probes and dynamic contrast-enhanced magnetic resonance imaging. Microvessel density and tumor burden were quantified by immunohistochemistry (CD-31) and quantitative RT-PCR (VE-cadherin). Results: Administration of SSL-DXR (5.7 mg/kg iv) initially (3-4 days post-treatment) decreased tumor vascular permeability, ktrans (vascular exchange constant), vascular endothelial cell content, microvessel density, and deposition of nanoparticulates. Tumor vasculature became less chaotic. Permeability and perfusion returned to control values 6-7 days post-treatment, but intratumor SSL-DXR depot continued to effect tumor vascular endothelial compartment 7-10 days post-treatment, mediating enhanced permeability. Conclusions: SSL-DXR ultimately increased tumor vascular permeability, but initially normalized tumor vasculature and decreased tumor perfusion, permeability, and nanoparticulate deposition. These temporal changes in vascular integrity resulting from a single SSL-DXR dose have important implications for the design of combination therapies incorporating nanoparticlebased agents for tumor vascular priming.