Lapatinib and Ketoconazole Combination Therapy using Novel Lipid Micellar Nanoparticles for Treatment of Lung Cancer

According to American Cancer Society, lung cancer was accountable for over 142,000 deaths in the USA in 2019. About 20% of all NSCLC patients are expected to harbor an EGFR activating mutation. EGFR inhibitors have been shown to provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Lapatinib is a small molecule tyrosine kinase inhibitor which acts reversibly on both Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2). Drug resistance forms in the majority of patients and hampers the effectiveness of these therapies. A recently submitted work showed that cholesterol synthesis enzyme, CYP51A1, along with total cellular cholesterol was upregulated in lapatinib resistant cells. Ketoconazole, a potent inhibitor of CYP51A1, is an FDA approved broad-spectrum systemic antifungal agent and also used in the treatment of the hormone dependent prostate cancer, due to its ability to block steroidogenesis. In that study ketoconazole and EGFR TKIs were shown to act synergistically to induce apoptosis and overcome the development of EGFR resistance. Both lapatinib and ketoconazole are poorly water soluble which is responsible for their variable oral absorption. Large daily dose of lapatinib limits its clinical usage significantly due to occurrence of various side effects. Nanoparticle based formulations offer remarkable promise in delivering hydrophobic drugs and enhancing their permeability and retention (EPR) inside tumors. In this project, we developed a lipid based micellar preparation (LMN) to deliver the combination of lapatinib and ketoconazole intranasally and enhance its efficacy as a treatment.