Nanoparticles Adapted For Gene Delivery, Immunotherapy
Gene therapies could revolutionize medicine, including many forms of cancer treatment. For their potential to be realized, however, researchers must develop ways to prevent unintended immune responses and cell mutations. To achieve the benefits of gene therapy without negative side effects, NIBIB grantee Dr. Jordan J. Green develops biodegradable nanoparticles that can be biochemically engineered to carry therapies that can seek out and kill cancer tumors.
Green is associate professor of biomedical engineering, ophthalmology, oncology, neurosurgery and materials science & engineering at Johns Hopkins University School of Medicine. Last May, upon nomination by the National Institute of Biomedical Imaging and Bioengineering, he was one of 105 recipients of the Presidential Early Career Awards for Scientists.
Green visited NIBIB recently to describe his work developing gene therapies for treating cancer using biomaterials and nano-biotechnology techniques. His team has explored targeting cancer cells from the inside out, as well as from the outside in.
From the inside-out angle, Green’s team seeks a biochemical route so that nanoparticles can selectively be taken up by cells. Libraries of biodegradable polymeric nanoparticles can be constructed for safe and effective intracellular delivery of nucleic acids, such as DNA, small-interfering RNA and micro RNA. In addition, these particles can be packaged with therapeutic biological molecules that can program immune cells. Green has found that small chemical changes cause big differences in the uptake of the nanoparticles. With chemical manipulation, his team is able to promote greater cytoplasmic delivery of the therapeutic particles into cells, which will hopefully result in more effective therapies.
“Sometimes polymers work a lot better in healthy cells and not the cancer cells, and sometimes we find they will work in both equally,” Green said.
In studies of mice with the brain cancer glioblastoma, Green’s team has shown that particular polymer structures increase the efficacy of therapeutic gene delivery. “We see this specificity when we [study] the brain cancer cells and the healthy neural cells,” Green said. “We get this specific knockdown and cell death when we deliver RNA to trigger cell death of the cancer cells without killing the healthy cells.”
Approaching the problem from the outside in—experimenting with the shapes of biomimetic microparticles and nanoparticles used in the therapies—Green’s group has compared the immune reaction generated by particles that mimic a type of cell called an antigen presenting cell. Those that are spherical don’t seem to be as effective as those with varied contours. “Overall, what we’re finding is that size and shape matter,” Green said.
According to Green, the advanced bioengineering approaches that his team is developing have the potential to impact not only cancer therapy, but also the fields of regenerative medicine, ophthalmology and immunology.—Raymond MacDougall