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Title: In vitro and in vivo evaluation of tumor targeting styrene-maleic acid copolymer-pirarubicin micelles: Survival improvement and inhibition of liver metastases.
Austin Authors: Daruwalla, Jurstine;Nikfarjam, Mehrdad ;Greish, Khaled;Malcontenti-Wilson, Caterina;Muralidharan, Vijayaragavan ;Christophi, Christopher ;Maeda, Hiroshi
Affiliation: Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 17-May-2010
Publication information: Cancer Science 2010; 101(8): 1866-74
Abstract: Pirarubicin is a derivative of doxorubicin with improved intracellular uptake and reduced cardiotoxicity. We have prepared a micellar formulation of pirarubicin using styrene-maleic acid copolymer (SMA) of mean molecular weight of 1.2 kDa, which exhibits a mean diameter of 248 nm in solution. Being a macromolecule, SMA-pirarubicin micelles exhibit excellent tumor targeting capacity due to the enhanced permeability and retention (EPR) effect. Here we report the antitumor activity of SMA-pirarubicin micelles on human colon and breast cancer cell lines in vitro, and a murine liver metastasis model in vivo. Metastatic tumor microvasculature, necrosis, apoptosis, proliferation, and survival were also investigated using immunohistochemistry for Ki-67, active caspase-3, and CD34, respectively. Drug cytotoxicity in vitro was assessed using MTT (3-[4,5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide) assay. In vivo, SMA-pirarubicin was administered at 100, 150, or 200 mg/kg (pirarubicin equivalent). Tumor microvasculature was also assessed using scanning electron microscopy. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles were toxic against human colorectal and breast cancer cells in vitro. IC(50) was at or below 1 muM, free pirarubicin equivalent. In vivo, SMA-pirarubicin at 100 mg/kg reduced tumor volume by 80% and achieved a survival rate of 93% at 40 days after tumor inoculation. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles demonstrated potent antitumor activity in this liver metastases model, contributing to prolonged survival. Histological examination of tumor nodules showed significant reduction and proliferation of tumor cells (>90%). The present results suggest that investigation of the effect of multiple dosing at later time points to further improve survival is warranted.
Gov't Doc #: 20579075
DOI: 10.1111/j.1349-7006.2010.01619.x
Type: Journal Article
Subjects: Animals
Apoptosis.drug effects
Caspase 3.physiology
Cell Line, Tumor
Cell Proliferation.drug effects
Doxorubicin.administration & dosage.analogs & derivatives
Liver Neoplasms, Experimental.prevention & control.secondary
Maleates.administration & dosage
Mice, Inbred CBA
Neoplasms, Experimental.blood supply.drug therapy.mortality.pathology
Polystyrenes.administration & dosage
Appears in Collections:Journal articles

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