Access Type

Open Access Embargo

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemical Engineering and Materials Science

First Advisor

Sandro R. da Rocha

Abstract

Lung cancer remains the leading cause of cancer-related deaths in the United States. Secondary lung tumors metastasized from other cancer sites also remains highly prevalent, in which most metastatic tumors cannot be cured with existing therapies. Chemoresistance (multi drug resistance – MDR) that develops intrinsically or acquired is one of the key factors leading to fatality in these patients. MDR develops form a variety of resistance mechanisms that can occur consecutively or concurrently, therefore, making most current treatments unsuccessful. Current therapies have known to slow tumor growth, but rarely provide a cure. Immunotherapy has seen some promise, including the use of checkpoint inhibitors, when other therapies have not proven beneficial. However, only a small fraction of tumor types and patients have benefited from this type of treatment, and some toxicity has been stated. Therefore, establishing new types of treatments, as a single therapy or combination therapy, that can i) increase the rate of survival in patients suffering at early or late stages (when MDR and metastasis have developed) of lung cancer, and ii) reduce toxicity and adverse side effects of treatments is of great importance in pulmonary oncology.

In this work we describe alternative treatment modalities that suggest their potential to address MDR and prolong the rate of survival in patients suffering from primary and secondary lung tumors. A combination of local lung targeting (high payload to target side and reduced systemic toxicity), nanocarriers (to modulate interactions with physiological environment) intracellular organelle targeting (to repurpose cytoreductive therapies), siRNA as therapeutic agent (to target apoptotic pathways), and macrophage repolarization immunotherapy (to modulate the tumor microenvironment) are reported. We describe the development mitochondrial-targeted dendrimer nanocarriers (DNCs) as a platform for the repurposing of chemotherapeutics, the development of siRNA/TPP-DNC complexes (TPP-dendriplexes) as a platform for pulmonary delivery of siRNAs, the development of asymmetric dendrimers with a chemotherapeutic and varying surface functionalities to enhance tumor targeting and penetration, and address the impact of local pulmonary administration of tumor associated macrophage (TAM)-targeting immunotherapy. Overall, we conclude that all these strategies described above have the potential capability to address issues resulting from MDR and for the treatment of primary and secondary lung tumors.

Available for download on Wednesday, December 11, 2019

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