title: Cellular signal transduction can be induced by TRAIL conjugated to microcapsules.
abstract: The extracellular agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in tumor cells but spare normal cells. Ligation of TRAIL to a nanoparticle would serve to facilitate targeting to an extravascular site. Polymeric ultrasound contrast agents (UCA) (microencapsulated gas bubbles) can be tracked by ultrasound imaging, and fragmented into nanoparticles by focused ultrasound. This tumor-targeted delivery system has been shown to deliver more efficiently than solid nanoparticles. Additionally, small molecule inhibitors such as bortezomib, shown to sensitize TRAIL-resistant cells, could be co-administered within these UCA. In this pilot study, TRAIL was conjugated to UCA while preserving the agent's sensitivity to ultrasound. Human cancer cell lines, OVCAR-3 and A2058, were bathed with the TRAIL-UCA with and without the addition of bortezomib. Apoptosis was quantified using flow cytometry. OVCAR-3 treated with TRAIL-UCA exhibit significant (p < 0.05) apoptotosis compared to unmodified UCA, equal to positive controls, but no synergistic effect when combined with bortezomib. A2058 cells treated with TRAIL-UCA also exhibited significant apoptosis (p < 0.01) compared to unmodified UCA, similar to positive controls and bortezomib significantly increased apoptosis in combination with TRAIL-UCA. We conclude that TRAIL-ligated UCA show exciting potential as a new therapy.
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, USA. wheatley@coe.drexel.edu
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Wheatley
authors.forename: Michael C
authors.initials: MC
authors.lastname: Cochran
authors.forename: John R
authors.initials: JR
authors.lastname: Eisenbrey
authors.forename: Kelleny L
authors.initials: KL
authors.lastname: Oum
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002214:Capsules / Q000737:chemistry*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008545:Melanoma / Q000473:pathology; D008567:Membranes, Artificial; D010316:Particle Size; D011091:Polyesters; D011108:Polymers / Q000737:chemistry; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013194:Staining and Labeling; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014465:Ultrasonics
chemical_list: D017304:Annexin A5; D001897:Boronic Acids; D002214:Capsules; D003287:Contrast Media; D008567:Membranes, Artificial; D011091:Polyesters; D011108:Polymers; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D019344:Lactic Acid; C033616:poly(lactide); D000069286:Bortezomib; D004317:Doxorubicin