Polyethylene Glycol Density and Length Affects Nanoparticle Uptake by Cancer Cells

Abstract

The prospective cancer therapy applications of inorganic nanoparticles (NPs) have been encouraged by surface modifications with polyethylene glycol (PEG). When grafted at high densities, PEG reduces NP surface interaction with its environment, hence minimizing its detection by the immune system. The drawback of high density PEG surfaces is its reduced uptake by cancer cells. This is disadvantageous for applications that favor intracellular localization of such NPs. On the other hand, reduced PEG density leads to nonspecific adsorption of proteins on NP surface. Adsorbed proteins may either facilitate cancer cell entry or mark inorganic NPs for clearance from the body. This trade-off between intracellular localization and in vivo residency time was observed in this study. Two grafting densities of 1 PEG/nm2 and 1 PEG/2 nm2 for two PEG chain lengths with molecular weights of 2kDa and 5kDa were used to coat gold NPs (GNPs). Spherical GNPs with a diameter of 50 nm were used as a model system to investigate the effect of PEG characteristics on NP nonspecific protein adsorption and uptake by cancer cells in vitro in HeLa, MDA-MB-231 and MCF-7 cells. Higher grafting densities resulted into less protein adsorption and lower NP uptake by all cell lines. Longer PEG chain lengths also resulted into less cancer cell entry in all cell lines. Quantitative results were confirmed qualitatively via hyperspectral imaging of NPs in cancer cells. Hence, lower PEG grafting densities and shorter chain lengths lead to higher cellular uptake at the cost of greater nonspecific protein adsorption. Higher density grafting of shorter PEG chain lengths was found most favorable. This combination resulted into reduced nonspecific protein adsorption and higher uptake when compared to its lower density and longer chain length counterparts, respectively. To maximize cancer therapy improvement via inorganic NP platforms, using such PEG grafting characteristics may be beneficial.