INHALABLE NANOCOMPOSITES AND ANTICANCER AGENTS FOR CANCER THERAPY

Cancer is designated as the leading cause of mortality worldwide and lung cancer is responsible for nearly 30% of all cancer related deaths. Over the last few decades mortality rates have only marginally increased and rates of recurrence remain high. These factors, among others, suggest the need for more innovative treatment modalities in lung cancer therapy. Targeted pulmonary delivery is well established for treating pulmonary diseases such as asthma and provides a promising platform for lung cancer therapy. Increasing local deposition of anticancer agents (ACAs) and reducing systemic exposure of these toxic moieties could lead to better therapeutic outcomes and higher quality of life for lung cancer patients receiving such harsh chemotherapy regimens. In this work, a novel lung cancer treatment modality is presented wherein ACAs are incorporated into inhalable dry powder composites for targeted delivery to the pulmonary tract. Additionally, nanoparticles were added to inhalable composites to increase the therapeutic potential of these unique materials. A variety of dry powder composites were formulated via spray drying and the physicochemical properties of the resulting systems were characterized. Additionally, the performance of the cargo incorporated into these composites was evaluated in order to insure the activity of the components after release from the inhalable dry powders. The aerodynamic performance of the dry powder systems was evaluated with the Next Generation Impactor® to determine if these materials were suitable for inhalation purposes. Iron oxide (Fe3O4) magnetic nanoparticles were synthesized and incorporated into dry powders to examine the feasibility of administering these materials to the lungs for remotely actuated hyperthermia. Remote heating studies were performed on the nanoparticles released from these composites using a custom Taylor Winfield® alternating magnetic field source, and in vitro hyperthermia studies were performed using advanced multicellular spheroid cell culture models. These studies elicited the effectiveness of these systems on physiologically relevant models. In addition to the iron oxide composites, dry powders were formulated with two common ACAs, cisplatin and erlotinib, for inhalable chemotherapy. The activity of the drugs released from these composites was evaluated on the human pulmonary lung cancer cell lines A549 and H358 and compared with the free form of the drugs in order to evaluate the effectiveness of these therapies. Finally, responsive hydrogel nanoparticles (HNPs) that contain the ability to respond to environmental changes in pH were synthesized and evaluated as responsive drug carriers. The response of these particles to pH was evaluated and their stability was examined before and after inclusion into dry powder composites. Overall, inhalable dry powder nanocomposites are promising materials for innovative lung cancer treatment modalities and have the potential to provide a safer and more effective option for addressing this devastating disease

Toxicity Evaluation of Magnetic Hyperthermia Induced by Remote Actuation of Magnetic Nanoparticles in 3D Micrometastasic Tumor Tissue Analogs for Triple Negative Breast Cancer

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/ mL) caused significant increase in cellular death/ damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies