Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Vivek Gupta

Second Advisor

Sandra Reznik

Third Advisor

Abu Serajuddin

Abstract

Inhalation of therapeutics has been gaining importance owing to immense advantages offered by pulmonary route and have attracted significant advancements in the pharmaceutical field. However, pulmonary drug delivery has been challenging because of the complexity of the respiratory tract and the existing defense mechanism. The pulmonary drug delivery has experienced advances in approaches and strategies to combat the existing challenges by tailoring the physicochemical properties of the delivery carriers and enabling both localized as well as systemic delivery. Pulmonary drug delivery is governed by several biophysical parameters of the delivery carriers such as particle size, shape, density, charge, and surface modifications. Although much attention has been garnered for other parameters particle shape effects have been less likely explored. In this exploration we studied the impact of particle shape on the aerodynamic properties, ability to escape macrophage uptake and therapeutic effectiveness of particles against lung cancer. Interestingly, the results of in-vitro lung deposition demonstrated improved aerodynamic properties of the rod-shaped with high aspect ratio as compared to spherical particles. Results of macrophage uptake demonstrate that high aspect ratio particles were internalized less when compared to spherical particles. On the contrary, results of cellular uptake by small cell lung cancer cells revealed preferential uptake of rod-shaped particles than spherical particles. The results were further validated by in-vitro tumor simulation studies wherein rod-shaped particles displayed enhanced anti-tumorigenic activity against spheres. Moreover, the high aspect ratio particles also demonstrated diminished cardiotoxicity activity; adverse effect of DOX limiting its therapeutic use. These results provide valuable insights about influence of particle shape for designing inhalable therapeutics.

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