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Pharm Res. 2012 Dec;29(12):3312-24. doi: 10.1007/s11095-012-0823-4. Epub 2012 Jul 14.

Mechanisms of tumor vascular priming by a nanoparticulate doxorubicin formulation.

Author information

1
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 445 Kapoor Hall, Buffalo, New York 14214-8033, USA.

Abstract

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, k(trans) (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 nanoparticle-based agents for tumor vascular priming.

PMID:
22798260
PMCID:
PMC3631713
DOI:
10.1007/s11095-012-0823-4
[Indexed for MEDLINE]
Free PMC Article

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