(681c) Modeling Effects of Nanoparticle Size and Ligand Display On Targeted Cell-Surface Binding

The specific targeting of therapeutic nanoparticles (NP's) to tumor cells greatly expedites the detection and eradication of cancer from the body. For example, the tagging of circulating tumor cells (CTC's) from a blood sample with these NP's is a much less invasive way to evaluate a cancer's metastatic potential than through a biopsy. Normal cells outnumber CTC's by a factor of millions in the bloodstream, so any NP-CTC interaction must have a very large affinity relative to the NP-normal cell interaction. Therefore, the design of the NP is vital to the success of the treatment. At the heart of this challenge is optimization of the particle size and the density of surface ligands, which bind to receptors on cancer cell surfaces. Elevated densities of certain surface receptors have been known to characterize and distinguish many cancer cells from normal cells, so the ligands on the NP's should be designed to favorably interact with these unique receptor displays. These interactions can eventually induce cell uptake through receptor-mediated endocytosis (RME), which is a potential way to deliver therapeutics packaged inside the NP's that can induce apoptosis or halt metastasis. Understanding the self-assembly of clathrin proteins that guide membrane curvature during RME is also necessary to accurately model the membrane-NP binding and uptake process. A dynamic model is presented that couples the motion of the membrane, surface receptors and NP's to simulate the binding and initial stages of membrane wrapping. Discrete ligand-receptor binding events and the thermal fluctuations of the membrane and NP are not represented in similar existing studies, and we incorporate them into our simulation. Thermal fluctuations enable the dynamic binding of ligands and receptors by probing varied conformations; however, fluctuations also contribute an entropic cost of wrapping a membrane around a NP instead of letting it freely fluctuate. These systems are also subject to forces from elastic deformation of the membrane and local tethering at receptor-ligand complexes. The balance between forces due to membrane deformation and those due to ligand-receptor affinity, along with entropic contributions, dictate the dynamics and equilibrium conformations of the NP-membrane complex. We also model the self-assembly of clathrin on the elastic membrane to show the stabilizing effects of these proteins on the deformed membrane structures. Our study combines the effects of these different components to identify the key characteristics of NP's for binding to varying types of afflicted cells, enabling the systematic design of NP's with improved abilities to target a diverse range of cancer.