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Nanoparticles (NPs) demonstrate promising properties as therapeutic carriers to efficiently deliver drug molecules into diseased cells. The surfaces of NPs are usually grafted with polyethylene glycol (PEG) polymers, during -so-called PEGylation, to improve water solubility, avoid aggregation, and prevent opsonization during blood circulation. The interplay between grafting density σp and grafted PEG polymerization degree N makes cellular uptake of PEGylated NPs distinct from that of bare NPs. To understand the role played by grafted PEG polymers, we study the endocytosis of 8-nm sized PEGylated NPs with different σp and N through large scale dissipative particle dynamics (DPD) simulations. The following results are obtained from our DPD simulations. First, for a given N, the internalization rate of PEGylated NPs monotonically increases with increasing σp, as the ligand–receptor interactions depend linearly on σp. Second, the free energy difference of grafted PEG polymers, before and after endocytosis, is found to have an effect which is comparable to, or even larger than, the bending energy of the membrane during endocytosis, based on our self-consistent field theory. By incorporating this free energy change, the critical ligand–receptor binding strength for PEGylated NPs to be internalized can be correctly predicted by a simple analytical equation. Without considering the free energy change of grafted PEG polymers, it is not possible to predict whether the PEGylated NPs will be delivered into the diseased cells. Third, an optimal σp ~ 0.8 chains/nm2, which can balance the ligand–receptor interactions with bending energy of the membrane and the free energy loss of grafted PEG polymers, is identified through our DPD simulations for N = 18. Finally, at fixed σp, the internalization rate of PEGylated NPs can be dramatically slowed by increasing N, due to the enlarged size of PEGylated NP and free energy change of the PEG polymers. These findings pave the way for designing efficient PEGylated NP-based therapeutic carriers with improved cellular targeting and uptake.

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Endocytosis of PEGylated nanoparticles: what is the role of grafted polyethylene glycol?

Nanoparticles (NPs) demonstrate promising properties as therapeutic carriers to efficiently deliver drug molecules into diseased cells. The surfaces of NPs are usually grafted with polyethylene glycol (PEG) polymers, during -so-called PEGylation, to improve water solubility, avoid aggregation, and prevent opsonization during blood circulation. The interplay between grafting density σp and grafted PEG polymerization degree N makes cellular uptake of PEGylated NPs distinct from that of bare NPs. To understand the role played by grafted PEG polymers, we study the endocytosis of 8-nm sized PEGylated NPs with different σp and N through large scale dissipative particle dynamics (DPD) simulations. The following results are obtained from our DPD simulations. First, for a given N, the internalization rate of PEGylated NPs monotonically increases with increasing σp, as the ligand–receptor interactions depend linearly on σp. Second, the free energy difference of grafted PEG polymers, before and after endocytosis, is found to have an effect which is comparable to, or even larger than, the bending energy of the membrane during endocytosis, based on our self-consistent field theory. By incorporating this free energy change, the critical ligand–receptor binding strength for PEGylated NPs to be internalized can be correctly predicted by a simple analytical equation. Without considering the free energy change of grafted PEG polymers, it is not possible to predict whether the PEGylated NPs will be delivered into the diseased cells. Third, an optimal σp ~ 0.8 chains/nm2, which can balance the ligand–receptor interactions with bending energy of the membrane and the free energy loss of grafted PEG polymers, is identified through our DPD simulations for N = 18. Finally, at fixed σp, the internalization rate of PEGylated NPs can be dramatically slowed by increasing N, due to the enlarged size of PEGylated NP and free energy change of the PEG polymers. These findings pave the way for designing efficient PEGylated NP-based therapeutic carriers with improved cellular targeting and uptake.