Leukocytes are implicated in inflammatory diseases, blood cancers, and leukocyte-tropic viral infections. However, systemic delivery to leukocytes is complicated by their resistance to conventional transfection methods and to their dispersal throughout the body. Dan Peer, Ph.D., head, laboratory of nanomedicine, Tel Aviv University, and colleagues created a novel approach that exclusively targets integrins of leukocytes using nanoparticles armed with specific monoclonal antibodies and entrap siRNAs.
“Often cationic-based nanoparticles have been utilized for delivery of siRNAs. But these can also produce a set of adverse effects such as cytokine storm that causes serious flu-like symptoms. It’s not just about delivery, it’s also about safety. We, instead, developed neutral lipid-based nanoparticles (~80 nanometers) surface functionalized with a polysugar called hyaluronan, a naturally occurring glycosaminoglycan. These biopolymers are safer and stealth-like to the immune system. They also create a scaffold for the attachment of antibodies or antibody fragments. Because this is a platform technology, one can change the targeting antigen, much like a GPS system, by changing the homing antibody.”
Dr. Peer cites the example of inflammatory bowel disease (IBD). In this case, particles are loaded with a monoclonal antibody against a gut-specific integrin called β7 integrin. “Using our I-tsNP (integrin-targeted stabilized nanoparticles) we identified cyclin D1 (CD1) as a potential novel target for IBD. CD1, a cell-cycle regulator, becomes upregulated during IBD in both epithelial and inflammatory cells. We utilized a mouse model and found that leukocyte-directed CD1 siRNA inhibits the intestinal inflammatory response.”
According to Dr. Peer, other applications include viral diseases that affect lymphocytes such as HIV. “In this case I-tsNP surface modified with LFA-1 integrin monoclonal antibodies were employed to deliver CCR5-siRNAs to human lymphocytes and monocytes. This system was shown to protect mice from HIV infection and did not induce an interferon response or secretion of TNF-alpha (an inflammatory cytokine).”
For the future, Dr. Peer plans to study gene-expression patterns to help identify novel targets. “We want to better understand the mechanisms and gene-expression patterns between patient and normal samples. We are already learning a lot from such studies.”