Paula T. Hammond
Massachusetts Institute of Technology
Charge Is on Our Side—Using Electrostatic Interplay with Cells and Tissues to Deliver Drugs
Nanomaterials of many types have been applied to address biomedical challenges, particularly in the delivery of drugs 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 laboratory, we have used electrostatic assembly methods in conjunction with well-defined charged macromolecules to enable delivery of drugs 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 a chemotherapy drug in the same nanoparticle system, and are now examining new siRNA and drug combinations in ovarian cancer. By staging the 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 delivery within cells. Ongoing work that includes new ovarian cancer and lymphoma efforts utilizing siRNA and a combination drug therapies will be discussed, including new work involving the delivery of cytokines for activation of the immune system against cancer.
Using a separate approach involving polyelectrolyte co-assembly to form nanoplexes, we found that a unique series of cationic polypeptides with variable charged side chain structures can enhance encapsulation of mRNA with the partnering translational protein, EIF4E, with optimal systems yielding 70 to 80 times that of the mRNA alone. A key to these polymers is their ability to cooperatively bind RNA with the associated protein machinery needed for translation together to enhance translation. More recently, we have found similar kinds of enhancements for the delivery of siRNA via co-complexation with the Ago-2 protein to create a pre-assembled version of RISC complex.
Finally, the manipulation of charge to target other tissues, in particular cartilage, is an important means of targeting the joint for osteoarthritis. We have generated unimolecular charged systems that can be precisely tuned to achieve deep penetration into avascular tissues such as cartilage to enable extended release treatments for cartilage regeneration. These and other uses of controlled polyelectrolytes and their complexes for delivery within tissues and across barriers will be addressed.