Electrostatic assembly can be used to engineer coatings that yield release of different drugs, DNA or protein, resulting in highly tunable multi -agent delivery nanolayered release systems for tissue engineering, biomedical devices, and wound healing applications. Most recently, we have developed a modular nanoparticle approach using liposomal core particles and layering them with an electrostatic layer-by-layer (LBL) process in a simple and elegant method of constructing highly tailored ultrathin polymer coatings. The resulting LbL nanoparticles (LbL NPs) have negatively charged outer layers that present polyelectrolytes such as dextran sulfate or hyaluronic acid in a hydrated brush arrangement that enables hydration, steric repulsion, colloidal and serum stability, and specific or non-specific targeting. We have demonstrated that these particles have long systemic plasma blood half-lives and good tumor accumulation over time, and demonstrate efficacy in advanced breast and lung cancer models in which siRNA targets have been delivered with chemotherapy drugs in the same nanoparticle system.

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 we are exploring ways to utilize these differences in affinity for more selective tumor cell binding and deliver within cells.

Ongoing work includes addressing barriers to transport of these nanoparticles relevant to tumor or other tissue penetration, and will be discussed, including new work involving the understanding of these trafficking patterns and a means to leverage them toward the delivery of cytokines for activation of the immune system against ovarian cancer, a cancer which has not previously benefitted from immunotherapeutic approaches. In vitro and in vivo results will be discussed, as well as release mechanisms, toxicity studies and clinical outlook for these targeted systems. Ongoing work includes examination of how these LbL NP systems might be adapted to enhance delivery across the blood-brain barrier for glioblastoma, or modified to enhance tumor accumulation and penetration. These and other uses of controlled polyelectrolytes and their complexes for delivery within tissues and across barriers will be addressed.