ROLE OF ICAM-1-MEDIATED ENDOCYTOSIS IN ENDOTHELIAL FUNCTION AND IMPLICATIONS FOR CARRIER-ASSISTED DRUG DELIVERY

Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein found on the surface of vascular endothelial cells (ECs). Its expression is upregulated at inflammatory sites, allowing for targeted delivery of therapeutics using ICAM-1-binding drug carriers. Engagement of multiple copies of ICAM-1 by these drug carriers induces cell adhesion molecule (CAM)-mediated endocytosis, which results in trafficking of carriers to lysosomes and across ECs. Knowledge about the regulation behind CAM-mediated endocytosis can help improve drug delivery, but questions remain about these regulatory mechanisms. Furthermore, little is known about the natural function of this endocytic pathway. To address these gaps in knowledge, we focused on two natural binding partners of ICAM-1 that potentially elicit CAM-mediated endocytosis: leukocytes (which bind ICAM-1 via β₂ integrins) and fibrin polymers (a main component of blood clots which binds ICAM-1 via the γ3 sequence). First, inspired by properties of these natural binding partners, we varied the size and targeting moiety of model drug carriers to determine how these parameters affect CAM-mediated endocytosis. Increasing ICAM-1-targeted carrier size slowed carrier uptake kinetics, reduced carrier trafficking to lysosomes, and increased carrier transport across ECs. Changing targeting moieties from antibodies to peptides decreased particle binding and uptake, lowered trafficking to lysosomes, and increased transport across ECs. Second, using cell culture models of leukocyte/EC interactions, inhibiting regulatory elements of the CAM-mediated pathway disrupted leukocyte sampling, a process crucial to leukocyte crossing of endothelial layers (transmigration). This inhibition also decreased leukocyte transmigration across ECs, specifically through the transcellular route, which occurs through a single EC without disassembly of cell-cell junctions. Third, fibrin meshes, which mimic blood clot fragments/remnants, bound to ECs at ICAM-1-enriched sites and were internalized by the endothelium. Inhibiting the CAM-mediated pathway disrupted this uptake. Following endocytosis, fibrin meshes trafficked to lysosomes where they were degraded. In mouse models, CAM-mediated endocytosis of fibrin meshes appeared to remove fibrin remnants at the endothelial surface, preventing re-initiation of the coagulation cascade. Overall, these results support a link between CAM-mediated endocytosis and leukocyte transmigration as well as uptake of fibrin materials by ECs. Furthermore, these results will guide the future design of ICAM-1-targeted carrier-assisted therapies.

Improving Photovoltaics with High Luminescence Efficiency Quantum Dot Layers

A solar cell relies on its ability to turn photons into current. Because short wavelength photons are typically absorbed near the top surface of a cell, the generated charge carriers recombine before being collected. But when a layer of quantum dots (nanoscale semiconductor particles) is placed on top of the cell, it absorbs short wavelength photons and emits them into the cell at longer wavelengths, which enables more efficient carrier collection. However, the resulting power conversion efficiency of the system depends critically on the quantum dot luminescence efficiency – the nature of this relationship was previously unknown. Our calculations suggest that a quantum dot layer must have high luminescence efficiency (at least 80%) to improve the current output of existing photovoltaic (PV) cells; otherwise, it may worsen the cell’s efficiency. Our quantum dot layer (using quantum dots with over 85% quantum yield) slightly reduced the efficiency of our PV cells. We observed a decrease in short circuit current of a commercial-grade cell from 0.1977 A to 0.1826 A, a 7.6% drop, suggesting that improved optical coupling from the quantum dot emission into the solar cell is needed. With better optical coupling, we predict current enhancements between ~6% and ~8% for a solar cell that already has an antireflection coating. Such improvements could have important commercial impacts if the coating could be deployed in a scalable fashion.