In Vitro Study of Inhalable Cisplatin and Erlotinib for the Treatment of Lung Cancer

                                         In vitro study of inhalable cisplatin and erlotinib for the treatment of lung cancer

Shuo Tang¹, Nathanael A. Stocke ^1,2, J. Zach Hilt¹

 

¹Department of Chemical and Materials Engineering,

University of Kentucky

Lung cancer has the highest mortality rate of all cancers and has shown minimal advances over the last few decades so new treatment strategies need to be explored.  Current methods of treating lung cancer include surgery, radiation, and chemotherapy, with the latter being administered orally or through intravenous infusion.  Most anticancer agents (ACAs) lead to undesired side effects so localizing these toxic agents could be a key factor in improving cancer treatment.  Pulmonary delivery offers an interesting alternative to systemic delivery of ACAs as it directly targets these agents to the tissue wherein the tumor lies, and thus, pulmonary delivery of chemotherapeutic drugs are expected to decrease the drug exposure area and the risk of side effects.  Cisplatin is a platinum-based anticancer drug which has been successfully applied to fight against cancer for over 30 years; it works through binding the DNA and causing DNA damage, which ultimately results in cell death.  Cisplatin kills proliferating cells non-specifically leading to high risk of side effects.  More recently, targeted agents (e.g., erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor) have been approved by the FDA for the treatment of patients with non-small cell lung cancer (NSCLC).  Erlotinib is used to treat patients with mutations in the genes that encode EGFR because of its specificity to cancer cells overexpressing EGRF.  Here, we are interested in the synergistic effect of combining erltinib with iron oxide (Fe₃O₄) magnetic nanoparticles (MNPs) for magnetically mediated hyperthermia, which is the heating of tissue to 41-45C.  Fe₃O₄ MNPs generate heat when exposed to an alternating magnetic field and this heat can be used for a variety of applications including hyperthermia, which has shown synergism when combined with chemotherapy.  In this study, organic solution advanced spray drying (SD) in closed-mode was used to formulate inhalable antitumor nanocomposite microparticles consisting of two commonly used ACAs, cisplatin and erlotinib.  These drugs were combined with D-mannitol and spray dried with and without iron oxide magnetic nanoparticles.  The systems were formulated, and the drug loading concentrations were determined with UV is spectroscopy.  Two human lung cell lines A549 and H358 were cultured, and the activity of erlotinib and cisplatin was examined before and after spray drying.  The synergism of using cisplatin and erlotinib has been previously reported so we confirmed this by carrying out combinational studies with these two drugs.  Additionally, we examined the ability to use the MNPs for magnetically mediated hyperthermia and showed minimal toxicity from the MNPs.  These data suggest that novel composites for targeted inhalation therapy can be formulated with spray drying while retaining the biological activity of the ACAs incorporated.  Additionally, the potential of combined hyperthermia with these materials have great potential for an innovative treatment modality that could improve on current clinical applications.