Cell surface receptors facilitate cell signalling and nutrient uptake. These processes are dynamic, requiring receptors to be recycled and replenished on the cell surface frequently. Due to their abundant expression, receptors are often the target of drug-delivery vehicles, which are adorned with ligands that bind specifically to receptors. These vehicles are taken into the cell by multiple routes of internalization, where the best characterized pathway is clathrin-mediated endocytosis. It is well documented that these carriers can target the clathrin pathway; however, most experiments have utilized bulk assays of uptake, rather than observing individual endocytic events. As a result, the detailed mechanisms of drug carrier uptake remain obscure. To address this gap, we have employed a live-cell imaging approach to study the uptake of individual drug carriers as they interact with clathrin-coated structures. By tracking individual drug carriers during internalization, we find that carriers tend stabilize nascent endocytic structures, while also slowing their departure from the cell surface. Interestingly, our studies show that the size of drug carriers, rather than the density of the ligands on their surfaces, determines their probability of uptake. Specifically, our studies reveal only a modest impact of ligand density on uptake. Nonetheless, having a higher ligand density appears to drive uptake of larger particles, illustrating a potential role for targeting. Our ongoing work is probing how physical parameters, such as size and rigidity, along with biochemical parameters, such as ligand density and receptor affinity, collectively impact carrier uptake, with the goal of determining a set of criteria for the optimal design of drug carriers.

Tracking the uptake of individual drug carriers via clathrin-mediated endocytosis

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