Dataset Information

Effect of partial PEGylation on particle uptake by macrophages.

ABSTRACT: Controlling the internalization of synthetic particles by immune cells remains a grand challenge for developing successful drug carrier systems. Polyethylene glycol (PEG) is frequently used as a protective coating on particles to evade immune clearance, but it also hinders the interactions of particles with their intended target cells. In this study, we investigate a spatial decoupling strategy, in which PEGs are coated on only one hemisphere of particles, so that the other hemisphere is available for functionalization of cell-targeting ligands without the hindrance effect from the PEGs. The partial coating of PEGs is realized by creating two-faced Janus particles with different surface chemistries on opposite sides. We show that a half-coating of PEGs reduces the macrophage uptake of particles as effectively as a complete coating. Owing to the surface asymmetry, Janus particles that are internalized enter macrophage cells via a combination of ligand-guided phagocytosis and macropinocytosis. By spatially segregating PEGs and ligands for targeting T cells on Janus particles, we demonstrate that the Janus particles bind T cells uni-directionally from the ligand-coated side, bypassing the hindrance from the PEGs on the other hemisphere. The results reveal a new mechanistic understanding on how a spatial coating of PEGs on particles changes the phagocytosis of particles. This study also suggests a new design principle for therapeutic particles - the spatial decoupling of PEGs and cell-targeting moieties reduces the interference between the two functions while attaining the protective effect of PEGs for macrophage evasion.

SUBMITTER: Sanchez L

PROVIDER: S-EPMC6397647 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of partial PEGylation on particle uptake by macrophages.

Sanchez Lucero L Yi Yi Y Yu Yan Y

Nanoscale 20161202 1

Controlling the internalization of synthetic particles by immune cells remains a grand challenge for developing successful drug carrier systems. Polyethylene glycol (PEG) is frequently used as a protective coating on particles to evade immune clearance, but it also hinders the interactions of particles with their intended target cells. In this study, we investigate a spatial decoupling strategy, in which PEGs are coated on only one hemisphere of particles, so that the other hemisphere is availab ...[more]

PMID: 27909711

Similar Datasets

Project description:UnlabelledRadiotracers based on the peptide A20FMDV2 selectively target the cell surface receptor integrin αvβ6. This integrin has been identified as a prognostic indicator correlating with the severity of disease for several challenging malignancies. In previous studies of A20FMDV2 peptides labeled with 4-(18)F-fluorobenzoic acid ((18)F-FBA), we have shown that the introduction of poly(ethylene glycol) (PEG) improves pharmacokinetics, including increased uptake in αvβ6-expressing tumors. The present study evaluated the effect of site-specific C-terminal or dual (N- and C-terminal) PEGylation, yielding (18)F-FBA-A20FMDV2-PEG28 (4) and (18)F-FBA-PEG28-A20FMDV2-PEG28 (5), on αvβ6-targeted tumor uptake and pharmacokinetics. The results are compared with (18)F-FBA -labeled A20FMDV2 radiotracers (1- 3) bearing either no PEG or different PEG units at the N terminus.MethodsThe radiotracers were prepared and radiolabeled on solid phase. Using 3 cell lines, DX3puroβ6 (αvβ6+), DX3puro (αvβ6-), and BxPC-3 (αvβ6+), we evaluated the radiotracers in vitro (serum stability; cell binding and internalization) and in vivo in mouse models bearing paired DX3puroβ6-DX3puro and, for 5, BxPC-3 xenografts.ResultsThe size and location of the PEG units significantly affected αvβ6 targeting and pharmacokinetics. Although the C-terminally PEGylated 4 showed some improvements over the un-PEGylated (18)F-FBA-A20FMDV2 (1), it was the bi-terminally PEGylated 5 that displayed the more favorable combination of high αvβ6 affinity, selectivity, and pharmacokinetic profile. In vitro, 5 bound to αvβ6-expressing DX3puroβ6 and BxPC-3 cells with 60.5% ± 3.3% and 48.8% ± 8.3%, respectively, with a significant fraction of internalization (37.2% ± 4.0% and 37.6% ± 4.1% of total radioactivity, respectively). By comparison, in the DX3puro control 5: showed only 3.0% ± 0.5% binding and 0.9% ± 0.2% internalization. In vivo, 5: maintained high, αvβ6-directed binding in the paired DX3puroβ6-DX3puro model (1 h: DX3puroβ6, 2.3 ± 0.2 percentage injected dose per gram [%ID/g]; DX3puroβ6/DX3puro ratio, 6.5:1; 4 h: 10.7:1). In the pancreatic BxPC-3 model, uptake was 4.7 ± 0.9 %ID/g (1 h) despite small tumor sizes (20-80 mg).ConclusionThe bi-PEGylated radiotracer 5 showed a greatly improved pharmacokinetic profile, beyond what was predicted from individual N- or C-terminal PEGylation. It appears that the 2 PEG units acted synergistically to result in an improved metabolic profile including high αvβ6+ tumor uptake and retention.

Dataset Information

Effect of partial PEGylation on particle uptake by macrophages.

Publications

Effect of partial PEGylation on particle uptake by macrophages.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets