Design and development of PEGylated liposomal formulation of HER2 blocker Lapatinib for enhanced anticancer activity and diminished cardiotoxicity.

ABSTRACT

Breast cancer is most frequently diagnosed cancer and fifth leading cause of death in women. About 20-30% of all breast cancers overexpress HER2/neu receptors. Lapatinib is a dual tyrosin kinase inhibitor of EGFR and HER2. It exhibits its anticancer effect via blocking intracellular domain of HER2 receptor in breast cancer. Lapatinib belongs to class II of BSC classification due to its poor solubility restricting its clinical application. Due to presence of HER2 receptor on cardiomyocytes, it is associated with generation of cardiotoxicity. The present study was aimed to design a PEGylated liposomal formulation of Lapatinib and evaluate its anticancer potential. Lapatinib liposomes were prepared using lipid layer hydration method and its characterization was done by determining its particle size, zeta potential, entrapment efficiency and in vitro release profiling. The anti-tumor activity of PEGylated liposomal formulation was evaluated in xenografted tumor induced by MDA-MB-453 breast cancer cells in chick embryos. The anti-tumor effect of lapatinib was enhanced by its PEGylated liposomal preparation as it led to the reduction in tumor size to a greater extent compared to the embryos treated with free lapatinib. Flowcytometric analysis and immunoflurescence study using cleaved PARP antibody demonstrated the enhanced apoptotic potential of PEGylated liposomes of lapatinib. SGOT levels, marker for cardiotoxicity and hepatotoxicity, significantly decreased in serum of embryos treated with PEGylated liposomes of lapatinib compared to free drug treated embryos. Hence, the PEGylated liposomal formulation of lapatinib can be used as a therapeutic strategy against HER2 positive breast cancer either alone or in combination with conventional anticancer agents and hormonal therapies.