Mechanisms of tumor vascular priming by a nanoparticulate doxorubicin formulation.
OBJECTIVE
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.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 445 Kapoor Hall, Buffalo, New York 14214-8033, USA.
Tista
T
Roy Chaudhuri
Robert D
RD
Arnold
Jun
J
Yang
Steven G
SG
Turowski
Yang
Y
Qu
Joseph A
JA
Spernyak
Richard
R
Mazurchuk
Donald E
DE
Mager
Robert M
RM
Straubinger
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D008081:Liposomes; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin