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Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation

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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.

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Notes

  1. Yang J, Roy Chaudhuri T, Mager DE, Spernyak JA, Straubinger RM. Application of nonlinear mixed effects analysis to dynamic contrast enhanced magnetic resonance imaging in a rat brain tumor model. Unpublished 2011.

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

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank Dr. D. Brazeau (present address: University of New England) for advice and assistance in analyzing the qRT-PCR data, and Dr. Stelios Andreadis (University at Buffalo/SUNY) for the retroviral vector that was used to generate the 9L-eGFP cell line.

Support was provided by grant R01-CA107570 from the National Cancer Inst., National Institutes of Health, to RMS and the Comprehensive Cancer Center support grant (P30-CA016056) at Roswell Park. JY was supported by an unrestricted postdoctoral fellowship from the UB-Pfizer Strategic Alliance.

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Correspondence to Robert M. Straubinger.

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Roy Chaudhuri, T., Arnold, R.D., Yang, J. et al. Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation. Pharm Res 29, 3312–3324 (2012). https://doi.org/10.1007/s11095-012-0823-4

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  • DOI: https://doi.org/10.1007/s11095-012-0823-4

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