Access Type

Open Access Dissertation

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemical Engineering and Materials Science

First Advisor

Sandro R. da Rocha

Abstract

Lung cancers are leading cause of cancer death for both men and women in the world. Lungs are also one of the primary organs to which almost all cancer can spread. Chemothepray plays a crucial role in the fight against both primary lung cancers and lung metastases. Doxorubicin (DOX) is a potent anticancer drug that has been approved for treating many cancers including lung cancers. However, only a few percent of systemically administered DOX can be found in the lungs. The issue is further complicated by dose-limiting toxicity of DOX. Another major challenge in the use of DOX is its cardiac toxicity. Free DOX in bloodstream can accumulate in cardiac tissues, thus leading to fatal heart damages. On the other hand, the lungs are considered as a portal to external environment and suitable for local delivery. Additionally, oral inhalation (OI) has long been accepted as the preferred mode of administration of therapeutics to the lungs. To address these discussed challenges, we used a strategy — polymeric nanocarriers (PNCs) to achieve the spatial and temporal drug release and local delivery of drug to the lungs. In this work, we desgined polyamidoamine dendrimer (PAMAM) conjugates which can only release DOX intracellularly, while being stable in physiological environment. We observed the PAMAM-DOX conjugates upon local delivery to the lungs can significantly inhibit tumor growth both in vitro and in vivo. We also successfully prepared the PAMAP-DOX conjugates into propellant-based aerosol formulations which is conducive to deep lung areas. To our knowledge, it is for the first time that polymeric nanocarrier-based drug delivery system has been formulated into propellant-based aerosol formulations.

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