Pharmaceutical Research

, Volume 29, Issue 12, pp 3312–3324

Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation

Authors

  • Tista Roy Chaudhuri
    • Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New York
    • Department of Molecular and Cellular Biophysics and BiochemistryRoswell Park Cancer Institute
  • Robert D. Arnold
    • Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New York
    • Department of Pharmacal, Harrison School of PharmacyAuburn University
  • Jun Yang
    • Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New York
  • Steven G. Turowski
    • Department of Molecular and Cellular Biophysics and BiochemistryRoswell Park Cancer Institute
  • Yang Qu
    • Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New York
  • Joseph A. Spernyak
    • Department of Molecular and Cellular Biophysics and BiochemistryRoswell Park Cancer Institute
  • Richard Mazurchuk
    • Department of Molecular and Cellular Biophysics and BiochemistryRoswell Park Cancer Institute
    • Division of Cancer PreventionNational Cancer Institute
  • Donald E. Mager
    • Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New York
    • Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New York
    • Department of Molecular and Cellular Biophysics and BiochemistryRoswell Park Cancer Institute
    • New York State Center of Excellence in Bioinformatics and Life Sciences
Research Paper

DOI: 10.1007/s11095-012-0823-4

Cite this article as:
Roy Chaudhuri, T., Arnold, R.D., Yang, J. et al. Pharm Res (2012) 29: 3312. doi:10.1007/s11095-012-0823-4

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, 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 nanoparticle-based agents for tumor vascular priming.

KEY WORDS

brain tumorsnanoparticulate drug carrierssterically-stabilized liposomestumor primingtumor vascular permeability

ABBREVIATIONS

DCE-MRI

dynamic contrast-enhanced magnetic resonance imaging

dNTP

deoxynucleotide triphosphate

DSPC

distearoylphosphatidylcholine

DXR

doxorubicin

eGFP

enhanced green fluorescent protein

PEG-DSPE

distereoylphosphatidylethanolamine derivatized with polyethylene glycol

PK

pharmacokinetic

qRT-PCR

quantitative reverse transcriptase—polymerase chain reaction

SSL

sterically stabilized liposomes

SSL-DXR

sterically stabilized liposomes containing doxorubicin

Copyright information

© Springer Science+Business Media, LLC 2012