Enhancement in the therapeutic potential of lapatinib ditosylate against breast cancer by the use of β-cyclodextrin based ternary nanosponge system

Abstract

The present investigation was performed to demonstrate the therapeutic potential of lapatinib ditosylate (LD) loaded nanosponge for the treatment of breast cancer. The study reports the fabrication of nanosponge by reaction of β-cyclodextrin with a cross-linking agent, diphenyl carbonate, at several molar ratios using the ultrasound-assisted synthesis method. The drug was loaded into the rightest nanosponge by lyophilization with and without 0.25% w/w polyvinylpyrrolidone. The significantly reduced crystallinity of developed formulations was established by differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Morphological changes of LD, and formulations were compared by scanning electron microscopic (SEM) technique. Fourier transform infrared (FT-IR), and nuclear magnetic resonance (NMR) spectroscopic analysis were performed to establish the interacting groups of the host and guest molecules. It revealed interaction of the quinazoline ring, furan ring, and chlorobenzene functionality of LD with the hydroxyl group of β-cyclodextrin based nanosponge. Similar predictions were also obtained during their in-silico analysis. Saturation solubility and in vitro drug release studies revealed a 4.03-fold, and 2.43-fold rise in aqueous solubility, and dissolution of LD in the optimized formula (F2). The MCF-7 cell line study, too, revealed the higher efficiency of nanosponge formulations. The in vivo pharmacokinetic studies of optimized formulation illustrated 2.76-times, and 3.34-times enhancements in Cmax and oral bioavailability, respectively. Concomitant results were obtained during the in vivo studies performed using DMBA-induced breast cancer models in female Sprague Dawley rats. The tumor burden was found to be reduced to approximately 60% by the use of F2. The hematological parameters of animals treated with F2 were also improved. Histopathology of breast tissue excised from an F2-treated rat showed a reduced size of ductal epithelial cells associated with shrunken cribriform structures and cross-bridges. The in vivo toxicity studies also showcased reduced hepatotoxicity of the formulation. Altogether, it can be concluded that encapsulation of lapatinib ditosylate in β-cyclodextrin nanosponge has improved aqueous solubility, bioavailability and, in turn, therapeutic efficacy.