Understanding the Effect of Surface-Grafted Polyethylene Glycol Chains on Scavenger Endothelial Cell Sequestration of Polymeric Nanoparticles via Quantitative Pharmacokinetic Analysis in Zebrafish Larvae

Scavenger endothelial cells (SECs) lining the liver sinusoids play a critical role in the rapid blood clearance of nanoparticle (NP)-based drug-delivery systems. However, how these cells recognize synthetic materials is largely unknown, which hampers the establishment of NP design criteria for prolonging their blood circulation time upon systemic administration. This study investigates how the surface-grafted chain conformation on the NPs affects their uptake by SECs. Polystyrene NPs are grafted with polyethylene glycol (PEG) polymers having different molecular weights (MWs = 2, 5, 10, and 20 kDa). The conformation of surface PEG chains depends on their MWs, with PEG chains being in the mushroom regime for the lowest MW and transforming into a brush configuration with an increase in the MW. The surface PEG chains with a brush conformation inhibit cellular uptake of the NPs by a SEC model cell line SK-Hep-1 significantly, while NPs with a mushroom conformation are readily taken up. Furthermore, quantitative pharmacokinetic analysis in zebrafish larvae by combining a single-particle tracking technique and computer-aided image analysis reveals that NPs with longer PEG chains, especially for 20 kDa, show significantly prolonged blood circulation time due to avoiding clearance by SECs.