Despite the time and expense that is involved in developing new cancer drugs, these compounds often fail to work during human clinical trials even after success in animal trials. With aerosol anticancer drugs in particular, this is usually due to a lack of cell assays available in the lab to effectively test such drugs prior to moving further in the drug development process. Therefore, there is a need for better methods to evaluate the effectiveness of aerosol anticancer drugs before starting clinical trials. This project aims to develop a novel cell culture assay involving the growth of mini-tumors in air to mimic lung cancer that will allow the investigators to evaluate aerosol anticancer therapeutics more effectively. The successful completion of this project will lead to significant savings in time, money, and animal subjects in addition to enabling the screening aerosol drug candidates that might not otherwise be considered for treatment.
Three-dimensional (3D) multicellular spheroid (MCS) models have been developed over the past several decades due to the improvement they provide in the physiological mimicking of in vivo tumors. Less than 5% of in vitro MCS models have been based on lung cancer models despite the fact that more patients die of lung cancer than any other type. However, current lung cancer MCS models involve the growth of spheroids in liquid media, which is not representative of tumors present in the airways of the lung. Thus, there is a need for the development of air-grown lung cancer MCS models to better represent lung tumors, as there are currently no authentic methods to evaluate aerosol anticancer therapeutics in vitro. The objective of this project is to develop air-grown lung MCS models and to validate these models using dry powder aerosol therapeutics. This objective will be accomplished by pursuing the following specific aims: 1) to cultivate air-grown lung MCS models and evaluate their cellular properties with respect to formation, viability, and proliferation, 2) to develop a new tissue culture-based platform for the production of lung cancer air-grown MCS models to allow for the evaluation of deeply penetrating dry powder aerosols, and 3) to evaluate the efficacy of dry powder aerosol anticancer formulations for the validation of the newly developed tissue culture platform and high-throughput lung cancer air-grown models. These aims will work synergistically to provide novel methods to better evaluate aerosol lung cancer products to potentially reduce drug failures and increase lung cancer treatment efficacy. In particular, air-grown spheroids will be cultivated on alginate gels in well plates. These spheroids will be comprised of one of four lung cancer cell types, which will vary in tumor origin and genetic mutations. The spheroid characteristics will be assessed and then the efficacy of dry powder aerosol particles will be evaluated using the newly developed MCS models. Two types of MCS platforms will be developed: a high throughput system in 96 well plates and a multi-spheroid system to be used in a twin-stage impinger. The rationale for the use of the air-grown in vitro tumor spheroid models is that they will allow for more physiologically relevant methods for evaluating aerosol chemotherapeutics, which will result in increased knowledge in drug resistance and efficacy. Improvement in the drug development process is a vital step to ensuring that lung cancer patients will have faster access to a multitude of therapeutics so that this disease can eventually be treated as a chronic condition. Undergraduate engineering students will be exposed to the project through independent research projects and lectures given in pharmaceutical science courses. The proposed research will be incorporated into an outreach program currently run by the PI serving underrepresented, underprivileged high school students, where the PI's students working on the project will act as mentors. This proposal is co-funded by the Biomedical Engineering Program in the Chemical, Bioengineering, Environmental and Transport Systems Division, and by the Biomaterials Program in the Division of Materials Research.