Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor's Name

Anthony J. McGoron

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Wei - Chiang Lin

Second Advisor's Committee Title

committee member

Third Advisor's Name

Chenzhong Li

Third Advisor's Committee Title

committee member

Fourth Advisor's Name

Bruce McCord

Fourth Advisor's Committee Title

committee member

Fifth Advisor's Name

Sakhrat Khizroev

Fifth Advisor's Committee Title

committee member

Date of Defense

7-16-2015

Abstract

Multifunctional agents for the management of highly heterogeneous diseases, like cancer, are gaining increased interest with the intent of improving the diagnostics and therapy of cancer patients. These agents are also important because more than one treatment modality is typically used for cancer therapy in the clinic. Further, nanotechnology offers a platform where more than one agent can be combined to help provide improved cancer diagnosis and therapy. Near-infrared light-activatable phototherapeutic agents have great potential in vivo. Body tissues have minimum absorption in the near- infrared range. They also have been shown to enhance the cytotoxic effect of chemotherapeutic drugs when used in combination with them. We have, hence, investigated the potential of two multifunctional targeted nanoparticles for combined chemo-phototherapy (employing near- infrared light activable agent) and for understanding their underlying cellular responses. The first is employing polymeric Poly-lactic acid-co-glycolic acid (PLGA) nanoparticles with simultaneous incorporation of Indocyanine Green (ICG) (a near-infrared light-activatable photothermal agent) and Doxorubicin (DOX) and surface conjugated with anti-Human Epithelial Receptor-2 (HER-2). The PLGA nanoparticles were subjected to two modes of hyperthermia, incubator and laser hyperthermia, to mimic whole-body and localized hyperthermia used clinically. These nanoparticles upon laser exposure showed a rapid heat shock protein 70 (HSP70) response in comparison to the cellular HSP70 response upon incubator hyperthermia exposure. However, 12h post-treatment, downregulation of HSP70, was observed, thus, causing cellular apoptosis or necrosis based on the degree of thermal insult. These targeted nanoparticles, simultaneously incorporating agents, suffer from the limitation of release of both the agents from the nanoparticles and the need to control their release for bringing in effective therapy. Therefore, the second multifunctional nanoparticle employing silver nanoparticles (AgNPs) conjugated with Doxorubicin was formulated. AgNP serve as a near-infrared activatable agent itself, other than serving as a drug delivery vehicle. Thus, these nanoparticles only require the need to control the release of DOX alone. We further studied their mechanism of action, which included enhanced reactive oxygen species (ROS) production and reduction of intracellular thiol levels.

Identifier

FIDC000130

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