Induction of Apoptosis by Targeted Ultrasound Contrast Agents in Cancer Therapy

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Lauren J. Jablonowski, Averie M. Palovcak, and Margaret A. Wheatley, PhD, Drexel University, School of Biomedical Engineering, Science & Health Systems, Philadelphia, PA

Abstract

Studies have shown polymer-stabilized gas microbubbles to be effective in enhancing an ultrasound image, especially those involving cancerous tumors. These contrast agents can serve a dual purpose when designed to include a specific ligand conjugated to the surface for targeting or a drug encapsulated in the shell. Research is underway to harness these techniques in the fight against cancer. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a protein that not only binds to cell death receptors (DR4 and DR5) on cancerous cells for targeting, but this binding also promotes apoptosis in the targeted cell. Healthy cells have decoy receptors that compete for binding. Our hypothesis is that intravenously injected TRAIL-conjugated microbubbles, when exposed to ultrasound (US), will burst to form nanoshards (n-Sh) which will transport the TRAIL to cancer cell receptors, where binding initiates apoptosis.

The main objective of this study is to conjugate TRAIL to the surface of Poly (lactic-acid) (PLA) microbubbles for targeted cancer therapy. Eight batches of PLA microbubbles were made and characterized, evaluating the acoustic enhancement and stability in the ultrasound beam, as well as surface morphology before and after conjugation. Finally, the apoptotic activity of the conjugated TRAIL was tested against TRAIL-sensitive human breast cancer cells and TRAIL-resistant fibroblast controls, comparing the TRAIL-ligated microbubbles, TRAIL-ligated ultrasound generated n-Sh, free TRAIL, and unmodified microbubbles.

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