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Aggregation of Polyethylene glycol Polymers Suppresses Receptor-mediated Endocytosis of PEGylated Liposomes

Abstract

PEGylated liposome, composed of an aqueous core and a fluid state lipid bilayer shell, is one of the few Food and Drug Administration (FDA) approved drug delivery platforms. To prevent absorption of serum proteins, the surface of a liposome is decorated by hydrophilic and bio-compatible polyethylene glycol (PEG) polymers, which can significantly extend the blood circulation time of liposomes. In this work, with the help of dissipative particle dynamics (DPD) simulations, we explore how the tethered PEG polymers will affect the membrane wrapping process of PEGylated liposomes during endocytosis. Specifically, we compare the membrane wrapping process of a PEGylated rigid nanoparticle (NP) with a PEGylated liposome under identical conditions. Due to the mobility of grafted PEG polymers on the liposome's surface, the complete wrapping of a PEGylated liposome can be dramatically delayed and blocked, in comparison with a PEGylated rigid NP. For the first time, we observe aggregation of PEG polymers in the contact region between a PEGylated liposome and the membrane, which in turn leads to a ligand-free region on the surface of the liposome during endocytosis. Subsequently, the partially wrapped PEGylated liposome can be bounced back to a less wrapped state. Through free energy analysis, we find that the aggregation of PEG polymers during the membrane wrapping process of a PEGylated liposome introduces a dramatic free energy penalty about $\sim 800\,\kT$, which is almost twice that of the PEGylated rigid NP. Here $\kB$ and $T$ are the Boltzmann constant and temperature, respectively. Such a large energy barrier and existence of ligand-free region on the surface of PEGlylated liposomes prevents their membrane wrapping, thereby reducing the chance of internalization by tumor cells. Therefore, our DPD simulation results provide a possible explanation for the inefficient cellular uptake of PEGylated liposomes. In addition, we suggest that by increasing the repulsive interactions between grafted PEG polymers it might be possible to limit their aggregation, and in turn, facilitate the internalization of PEGylated liposome. The current study provides fundamental insights into the endocytosis of PEGylated liposomes, which could help to design this platform with high efficacy for drug delivery.

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Publication details

The article was received on 04 Dec 2017, accepted on 25 Jan 2018 and first published on 26 Jan 2018


Article type: Paper
DOI: 10.1039/C7NR09011K
Citation: Nanoscale, 2018, Accepted Manuscript
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    Aggregation of Polyethylene glycol Polymers Suppresses Receptor-mediated Endocytosis of PEGylated Liposomes

    Z. shen, H. Ye, M. Kroger and Y. Li, Nanoscale, 2018, Accepted Manuscript , DOI: 10.1039/C7NR09011K

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