In vitro and in vivo evaluation of tumor targeting styrene-maleic acid copolymer-pirarubicin micelles: Survival improvement and inhibition of liver metastases.

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.

• Authors: Jurstine Daruwalla, Mehrdad Nikfarjam, Khaled Greish, Cathy Malcontenti-Wilson, Vijayaragavan Muralidharan, Chris Christophi, Hiroshi Maeda
• Journal: Cancer science (Cancer Sci) Vol. 101 Issue 8 Pg. 1866-74 (Aug 2010) ISSN: 1349-7006 [Electronic] England
• PMID: 20579075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Maleates
• Micelles
• Polystyrenes
• styrene-maleic acid polymer
• Doxorubicin
• pirarubicin
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (physiology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Doxorubicin (administration & dosage, analogs & derivatives)
• Humans
• Liver Neoplasms, Experimental (prevention & control, secondary)
• Male
• Maleates (administration & dosage)
• Mice
• Mice, Inbred CBA
• Micelles
• Necrosis
• Neoplasms, Experimental (blood supply, drug therapy, mortality, pathology)
• Polystyrenes (administration & dosage)