Transmembrane Cell Signaling by Targeted Ultrasound Contrast Agents in Cancer Therapy

Wednesday, May 25, 2016

10:00 AM-12:00 PM

BIOMED PhD Thesis Defense

Title:
Transmembrane Cell Signaling by Targeted Ultrasound Contrast Agents in Cancer Therapy

Speaker:
Lauren Jablonowski, PhD Candidate, School of Biomedical Engineering, Science and Health Systems

Advisor:
Margaret Wheatley, PhD, John M. Reid Professor of Biomedical Engineering, School of Biomedical Engineering, Science and Health Systems

Abstract:
According to the American Cancer Society, over 1.68 million people in the United States are expected to be diagnosed with cancer in 2016. Approximately 85% of cancer cases involve solid tumors, 50% of which result in metastasis and death. Traditional drug delivery methods rely on systemic administration, exposing both diseased and healthy tissues to toxic treatment. Success in cancer therapy presents numerous other challenges, including multiple drug resistance (MDR), reduced cellular uptake of therapeutics in solid tumors, and collateral damage to susceptible organs and tissues. In an effort to overcome these challenges, the goal of this research is to develop an injectable polymer-based microbubble platform to enable ultrasound-triggered, non-invasive delivery of bioactive molecules directly to solid cancerous tumors. The platform consists of biodegradable non-immunogenic, targeted microbubbles decorated with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) that initiates apoptosis through transmembrane cell signaling. This platform also encapsulates a chemotherapeutic drug within the polymer shell to allow for targeted, localized delivery in doses that are more potent to the target tissue while shielding healthy and susceptible tissue from systemic exposure. Most importantly, we have redesigned these microbubbles to present a surface decorated with a brush of polyethylene glycol (PEG) chains in a successful effort to increase the in vivo half-life by preventing opsonization and uptake by the immune system.

These functionalized microbubbles are designed such that their resonant frequency is within the diagnostic imaging range, making them susceptible to inertial cavitation, which will burst the microbubble into so called nanoshards (n-Sh). The central hypothesis is that ultrasound-facilitated in situ inertial cavitation of TRAIL- and PEG-decorated microbubbles generates TRAIL-ligated PEGylated n-Sh housing encapsulated bioactives. While radiation forces move the microbubbles toward the vessel walls, the explosive force of inertial cavitation propels the n-Sh that are created toward and through the tumor vessel wall. These cavitating microbubbles, together with the ultrasound (US) waves, open up the already leaky pores in the angiogenic vessels to facilitate transmembrane transit for effective therapeutic delivery to solid cancer tumors.

We have found that PEGylation, and subsequent functionalization with ligation of TRAIL and co-encapsulation of bioactive molecules, does not significantly affect n-Sh production upon exposure to ultrasound. When exposed to these functionalized agents, we observed that MDA-MB-231 and MCF7 human breast adenocarcinoma cells exhibited significant degrees of apoptosis and cell death, compared to healthy MCF-12A breath epithelial cells. Based on our results, these agents represent a great potential for targeted drug delivery and cancer therapy.

Contact Information

Ken Barbee
215-895-1335
barbee@drexel.edu