Research Paper

Pharmaceutical Research

, Volume 29, Issue 12, pp 3312-3324

Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation

  • Tista Roy ChaudhuriAffiliated withDepartment of Pharmaceutical Sciences, University at Buffalo, State University of New YorkDepartment of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute
  • , Robert D. ArnoldAffiliated withDepartment of Pharmaceutical Sciences, University at Buffalo, State University of New YorkDepartment of Pharmacal, Harrison School of Pharmacy, Auburn University
  • , Jun YangAffiliated withDepartment of Pharmaceutical Sciences, University at Buffalo, State University of New York
  • , Steven G. TurowskiAffiliated withDepartment of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute
  • , Yang QuAffiliated withDepartment of Pharmaceutical Sciences, University at Buffalo, State University of New York
  • , Joseph A. SpernyakAffiliated withDepartment of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute
  • , Richard MazurchukAffiliated withDepartment of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer InstituteDivision of Cancer Prevention, National Cancer Institute
  • , Donald E. MagerAffiliated withDepartment of Pharmaceutical Sciences, University at Buffalo, State University of New York
  • , Robert M. StraubingerAffiliated withDepartment of Pharmaceutical Sciences, University at Buffalo, State University of New YorkDepartment of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer InstituteNew York State Center of Excellence in Bioinformatics and Life Sciences Email author 

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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 tumors nanoparticulate drug carriers sterically-stabilized liposomes tumor priming tumor vascular permeability