Friedlander Founders Lecture: Paula Hammond

“Electrostatic assembly for nanoparticle targeting of cells and tissues”

Nanomaterials of many types have been applied to address biomedical challenges, particularly in the delivery of drug to targeted regions of the body. One of the most powerful interactions that can regulate tissue transport and nanomaterial trafficking is electrostatic charge. In our lab, we have used electrostatic assembly methods in conjunction with well-defined charged macromolecules to enable delivery of drug to specific tissues or organs based on a combination of multivalent charge interactions coupled with other secondary non-specific or specific binding interactions. These systems vary from highly designed synthetic vectors that can deliver mRNA and even gene editing systems to electrostatically assembled complexes that can be generated with a great deal of control. The generation of such systems requires, in each case, a tuning of the ratio of charged species, and an ability to direct responsive behavior that enables release in such systems. In one approach, a layer-by-layer (LbL) technique toward construction of nanostructured nanoparticles provides multiple advantages for chemotherapy. We have generated LbL outer layers that provide effective stealth properties, with long systemic plasma blood half lives and higher tumor accumulation over time. We have demonstrated efficacy in genetically induced non-small cell lung cancer mouse models in which key siRNA targets have been selected with chemotherapy drug in the same nanoparticle system, and are now examining new siRNA and drug combinations in ovarian cancer. By staging release of different drug components via the adaptation of the nanoparticle structure, we can achieve highly synergistic release behavior in these systems. We have found that certain LbL nanoparticle formulations traffic differently in cells based on the negatively charged polypeptide, and are exploring ways to utilize these differences in affinity for more selective tumor cell binding and deliver within cells. Ongoing work that includes new ovarian cancer and lymphoma efforts utilizing siRNA and combination drug therapies will be discussed, including new work involving the delivery of cytokines for activation of the immune system against cancer. Finally, we have also begun investigating the use of these LbL nanoparticle systems as a means of targeting nanoparticles across the blood-brain-barrier using conjugated peptides, followed by targeting of glioma cells based on affinity of the particle outer layer for tumor cells. Recent developments in this area will also be presented.

Paula Hommand Flyer(5-17-19)