CBTE Kewaunee Lecture: Designer Nanocarriers for Cancer Therapy
One of the challenges of nanomedicine is determining sets of design rules that dictate where nanoparticles localize in the body, and the targeting of specific organs or cell types. Electrostatic assembly provides a route to nanomaterials that enable a broad range of surface chemistries that can be designed for targeting disease, while incorporating a range of core nanoparticle systems whose properties can be independently tuned. We have developed a modular nanoparticle approach using 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. Ultimately, it is also important to introduce other kinds of interactions, particularly when targeting specific cells such as immune or cancer cells; often these interactions include receptor-specific interactions, but non-specific interactions can also have a very significant role in directing particles to cancer or other disease-associated cell types. Ultimately, we seek to explore and exploit these interactions to target layer-by-layer and layered complex nanoparticles to a range of different cell types. Efforts on the use of high throughput sampling of nanoparticle-cell interactions on understanding nanoparticle-cell interactions and targeted uptake will also be discussed. Recent work includes addressing barriers to transport of these nanoparticles within tumors, and will be discussed, including 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. Ongoing work also includes examination of the role of mechanical properties of the core nanoparticle in tumor targeting, and how these LbL NP systems might be adapted to enhance delivery across the blood-brain barrier and designed to target glioblastoma.