Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation
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- Roy Chaudhuri, T., Arnold, R.D., Yang, J. et al. Pharm Res (2012) 29: 3312. doi:10.1007/s11095-012-0823-4
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.
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).
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.
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 nanoparticle-based agents for tumor vascular priming.
KEY WORDSbrain tumors nanoparticulate drug carriers sterically-stabilized liposomes tumor priming tumor vascular permeability
dynamic contrast-enhanced magnetic resonance imaging
enhanced green fluorescent protein
distereoylphosphatidylethanolamine derivatized with polyethylene glycol
quantitative reverse transcriptase—polymerase chain reaction
sterically stabilized liposomes
sterically stabilized liposomes containing doxorubicin