Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation
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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.
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- Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation
Volume 29, Issue 12 , pp 3312-3324
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- brain tumors
- nanoparticulate drug carriers
- sterically-stabilized liposomes
- tumor priming
- tumor vascular permeability
- Industry Sectors
- Author Affiliations
- 1. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 445 Kapoor Hall, Buffalo, New York, 14214-8033, USA
- 2. Department of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute, Elm/Carlton Streets, Buffalo, New York, 14263, USA
- 4. Department of Pharmacal, Harrison School of Pharmacy, Auburn University, Auburn, A, 36849-5504, USA
- 5. Division of Cancer Prevention, National Cancer Institute, Executive Plaza North, Ste. 3100, 6130 Executive Blvd., MSC 7362, Bethesda, Maryland, 20892-7362, USA
- 3. New York State Center of Excellence in Bioinformatics and Life Sciences, 701 Ellicott St., Buffalo, New York, 14203-1101, USA