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Wei Xiong Siow,1,2 Yi-Ting Chang,1,2 Michal Babič,3 Yi-Ching Lu,2 Daniel Horák,3 Yunn-Hwa Ma1,2,4 1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Guishan, Taoyuan, Taiwan, Republic of China; 2Department of Physiology and Pharmacology and Healthy Aging Research Center, College of Medicine, Chang Gung University, Guishan, Taoyuan, Taiwan, Republic of China; 3Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic; 4Department of Neurology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan, Republic of China Background: Poly-L-lysine (PLL) enhances nanoparticle (NP) uptake, but the molecular mechanism remains unresolved. We asked whether PLL may interact with negatively charged glycoconjugates on the cell surface and facilitate uptake of magnetic NPs (MNPs) by tumor cells.Methods: PLL-coated MNPs (PLL-MNPs) with positive and negative ζ-potential were prepared and characterized. Confocal and transmission electron microscopy was used to analyze cellular internalization of MNPs. A colorimetric iron assay was used to quantitate cell-associated MNPs (MNPcell).Results: Coadministration of PLL and dextran-coated MNPs in culture enhanced cellular internalization of MNPs, with increased vesicle size and numbers/cell. MNPcell was increased by eight- to 12-fold in response to PLL in a concentration-dependent manner in human glioma and HeLa cells. However, the application of a magnetic field attenuated PLL-induced increase in MNPcell. PLL-coating increased MNPcell regardless of ζ-potential of PLL-MNPs, whereas magnetic force did not enhance MNPcell. In contrast, epigallocatechin gallate and magnetic force synergistically enhanced PLL-MNP uptake. In addition, heparin, but not sialic acid, greatly reduced the enhancement effects of PLL; however, removal of heparan sulfate from heparan sulfate proteoglycans of the cell surface by heparinase III significantly reduced MNPcell.Con