Quantitative Study of the Interaction of Multivalent Ligand-Modified Nanoparticles with Breast Cancer Cells with Tunable Receptor Density.

Multivalent nanoparticles that target a cell surface receptor that is overexpressed by cancer cells are a promising delivery system for cancer therapy. However, the impact of the receptor density and nanoparticle ligand valency on the cell uptake has not been studied in a system where both variables can be systematically tuned over a wide range. To address this lacuna, we report cell-uptake studies on a genetically engineered breast cancer cell line with tunable ErbB2 expression by a polypeptide micelle with tunable ligand valency. We examined the uptake of ErbB2-targeting micelles at 5 ligand densities and 11 receptor densities. We identified a matching pattern between receptors and ligands in which a receptor-to-ligand density ratio of 0.7-4.5 and a minimum of ∼1.6 bonds are required to initiate receptor-mediated endocytosis. Lower and upper limits of receptor density in the cell-uptake profile suggested a standard by which to categorize breast cancer patients as ErbB2-low, ErbB2-medium, and ErbB2-high, with each group expected to respond differently to multivalent therapeutic nanoparticles. At ErbB2-medium and ErbB2-high levels, increasing the ligand valency to 40-valent ErbB2-targeting peptides for a 20 nm radius nanoparticle accelerated the cell uptake, suggesting that the use of nanoparticles with high ligand valency for drug delivery will greatly benefit patients in these two groups. This study advances our understanding of how to rationally optimize nanotechnology for targeted drug delivery.