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. CONCLUSION: Our results suggest that PLL-heparan sulfate proteoglycan interaction may be the first step mediating PLL-MNP internalization by tumor cells. Given these results, PLL may facilitate NP interaction with tumor cells via a molecular mechanism shared by infection machinery of certain viruses.

Department of Neurology Chang Gung Memorial Hospital Guishan Taoyuan Taiwan Republic of China

Department of Physiology and Pharmacology and Healthy Aging Research Center College of Medicine Chang Gung University Guishan Taoyuan Taiwan Republic of China

Graduate Institute of Biomedical Sciences College of Medicine Chang Gung University Guishan Taoyuan Taiwan Republic of China

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

Hoshyar N, Gray S, Han H, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine (Lond) 2016;11(6):673–692. PubMed PMC

Zhang S, Gao H, Bao G. Physical principles of nanoparticle cellular endocytosis. ACS Nano. 2015;9(9):8655–8671. PubMed PMC

Zhu L, Zhou Z, Mao H, Yang L. Magnetic nanoparticles for precision oncology: theranostic magnetic iron oxide nanoparticles for image-guided and targeted cancer therapy. Nanomedicine (Lond) 2016;12(1):73–87. PubMed PMC

Singh D, McMillan JM, Kabanov AV, Sokolsky-Papkov M, Gendelman HE. Bench-to-bedside translation of magnetic nanoparticles. Nanomedicine (Lond) 2014;9(4):501–516. PubMed PMC

Estelrich J, Escribano E, Queralt J, Busquets MA. Iron oxide nanoparticles for magnetically-guided and magnetically-responsive drug delivery. Int J Mol Sci. 2015;16(4):8070–8101. PubMed PMC

Lu YC, Chang FY, Tu SJ, Chen JP, Ma YH. Cellular uptake of magnetite nanoparticles enhanced by NdFeB magnets in staggered arrangement. J Magn Magn Mater. 2017;427:71–80.

Ulbrich K, Holá K, Šubr V, Bakandritsos A, Tuček J, Zbořil R. Targeted drug delivery with polymers and magnetic nanoparticles: covalent and noncovalent approaches, release control, and clinical studies. Chem Rev. 2016;116(9):5338–5431. PubMed

Khan MA, Wu VM, Ghosh S, Uskoković V. Gene delivery using calcium phosphate nanoparticles: optimization of the transfection process and the effects of citrate and poly(l-lysine) as additives. J Colloid Interf Sci. 2016;471:48–58. PubMed PMC

Jin H, Yu Y, Chrisler WB, Xiong Y, Hu D, Lei C. Delivery of microRNA-10b with polylysine nanoparticles for inhibition of breast cancer cell wound healing. Breast Cancer (Auckl) 2012;6:9–19. PubMed PMC

Askarian S, Abnous K, Taghavi S, Oskuee RK, Ramezani M. Cellular delivery of shRNA using aptamer-conjugated PLL-alkyl-PEI nanoparticles. Colloids Surf B Biointerfaces. 2015;136:355–364. PubMed

Wang X, Zhang H, Jing H, Cui L. Highly efficient labeling of human lung cancer cells using cationic poly-l-lysine -assisted magnetic iron oxide nanoparticles. Nano Micro Lett. 2015;7(4):374–384. PubMed PMC

Wang X, Wei F, Liu A, et al. Cancer stem cell labeling using poly(l-lysine)-modified iron oxide nanoparticles. Biomaterials. 2012;33(14):3719–3732. PubMed

Babič M, Horák D, Trchová M, et al. Poly(l-lysine)-modified iron oxide nanoparticles for stem cell labeling. Bioconjug Chem. 2008;19(3):740–750. PubMed

Babič M, Schmiedtová M, Poledne R, Herynek V, Horák D. In vivo monitoring of rat macrophages labeled with poly(l-lysine)-iron oxide nanoparticles. J Biomed Mater Res B Appl Biomater. 2015;103(6):1141–1148. PubMed

Mishra SK, Khushu S, Gangenahalli G. Potential stem cell labeling ability of poly-l-lysine complexed to ultrasmall iron oxide contrast agent: an optimization and relaxometry study. Exp Cell Res. 2015;339(2):427–436. PubMed

Frank JA, Miller BR, Arbab AS, et al. Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology. 2003;228(2):480–487. PubMed

Arbab AS, Bashaw LA, Miller BR, et al. Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology. 2003;229(3):838–846. PubMed

Han G, Wu S, Wang J, Geng X, Liu G. poly-l-lysine mediated synthesis of gold nanoparticles and biological effects. J Nanosci Nanotechnol. 2015;15(9):6503–6508. PubMed

Albukhaty S, Naderi-Manesh H, Tiraihi T. In vitro labeling of neural stem cells with poly-l-lysine coated super paramagnetic nanoparticles for green fluorescent protein transfection. Iran Biomed J. 2013;17(2):71–76. PubMed PMC

Pongrac IM, Dobrivojević M, Ahmed LB, et al. Improved biocompatibility and efficient labeling of neural stem cells with poly(l-lysine)-coated maghemite nanoparticles. Beilstein J Nanotechnol. 2016;7:926–936. PubMed PMC

Riggio C, Calatayud MP, Hoskins C, et al. poly-l-lysine -coated magnetic nanoparticles as intracellular actuators for neural guidance. Int J Nanomedicine. 2012;7:3155–3166. PubMed PMC

Heng BC, Cowan CM, Davalian D, et al. Electrostatic binding of nanoparticles to mesenchymal stem cells via high molecular weight polyelectrolyte chains. J Tissue Eng Regen Med. 2009;3(4):243–254. PubMed

Bush CA, Martin-Pastor M, Imberty A. Structure and conformation of complex carbohydrates of glycoproteins, glycolipids, and bacterial polysaccharides. Annu Rev Biophys Biomol Struct. 1999;28:269–293. PubMed

Dreyfuss JL, Regatieri CV, Jarrouge TR, Cavalheiro RP, Sampaio LO, Nader HB. Heparan sulfate proteoglycans: structure, protein interactions and cell signaling. An Acad Bras Cienc. 2009;81(3):409–429. PubMed

Mythreye K, Blobe GC. Proteoglycan signaling co-receptors: roles in cell adhesion, migration and invasion. Cell Signal. 2009;21(11):1548–1558. PubMed PMC

Lin X. Functions of heparan sulfate proteoglycans in cell signaling during development. Development. 2004;131(24):6009–6021. PubMed

Christianson HC, Belting M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol. 2014;35:51–55. PubMed

Zarska M, Novotny F, Havel F, et al. Two-step mechanism of cellular uptake of cationic gold nanoparticles modified by (16-mercaptohexadecyl)trimethylammonium bromide. Bioconjug Chem. 2016;27(10):2558–2574. PubMed

Belting M. Heparan sulfate proteoglycan as a plasma membrane carrier. Trends Biochem Sci. 2003;28(3):145–151. PubMed

Cheng MJ, Kumar R, Sridhar S, Webster TJ, Ebong EE. Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting. Int J Nanomedicine. 2016;11:3305–3315. PubMed PMC

Nasimuzzaman M, Persons DA. Cell membrane-associated heparan sulfate is a receptor for prototype foamy virus in human, monkey, and rodent cells. Mol Ther. 2012;20(6):1158–1166. PubMed PMC

Jones KS, Petrow-Sadowski C, Bertolette DC, Huang Y, Ruscetti FW. Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells. J Virol. 2005;79(20):12692–12702. PubMed PMC

Urbinati C, Nicoli S, Giacca M, et al. HIV-1 Tat and heparan sulfate proteoglycan interaction: a novel mechanism of lymphocyte adhesion and migration across the endothelium. Blood. 2009;114(15):3335–3342. PubMed

Tyagi M, Rusnati M, Presta M, Giacca M. Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. J Biol Chem. 2001;276(5):3254–3261. PubMed

Connell BJ, Lortat-Jacob H. Human immunodeficiency virus and heparan sulfate: from attachment to entry inhibition. Front Immunol. 2013;4:385. PubMed PMC

Wang H, Ma J, Yang Y, Zeng F, Liu C. Highly efficient delivery of functional cargoes by a novel cell-penetrating peptide derived from SP140-like protein. Bioconjug Chem. 2016;27(5):1373–1381. PubMed

Somiya M, Liu Q, Yoshimoto N, et al. Cellular uptake of hepatitis B virus envelope L particles is independent of sodium taurocholate cotransporting polypeptide, but dependent on heparan sulfate proteoglycan. Virology. 2016;497:23–32. PubMed

Lu YC, Luo PC, Huang CW, et al. Augmented cellular uptake of nanoparticles using tea catechins: effect of surface modification on nanoparticle-cell interaction. Nanoscale. 2014;6(17):10297–10306. PubMed

Kim HS, Quon MJ, Kim JA. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox Biol. 2014;2:187–195. PubMed PMC

Afzal M, Safer AM, Menon M. Green tea polyphenols and their potential role in health and disease. Inflammopharmacology. 2015;23(4):151–161. PubMed

Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011;82(12):1807–1821. PubMed PMC

Fujimura Y, Sumida M, Sugihara K, Tsukamoto S, Yamada K, Tachibana H. Green tea polyphenol EGCG sensing motif on the 67-kDa laminin receptor. PLoS One. 2012;7(5):e37942. PubMed PMC

Tachibana H, Koga K, Fujimura Y, Yamada K. A receptor for green tea polyphenol EGCG. Nat Struct Mol Biol. 2004;11(4):380–381. PubMed

Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A. 2013;110(43):17380–17385. PubMed PMC

Kou L, Sun J, Zhai Y, He Z. The endocytosis and intracellular fate of nanomedicines: implication for rational design. Asian J Pharmacol. 2013;8:1–10.

Sigismund S, Confalonieri S, Ciliberto A, Polo S, Scita G, Di Fiore PP. Endocytosis and signaling: cell logistics shape the eukaryotic cell plan. Physiol Rev. 2012;92(1):273–366. PubMed PMC

Hu Q, Kang T, Feng J, et al. Tumor microenvironment and angiogenic blood vessels dual-targeting for enhanced anti-glioma therapy. ACS Appl Mater Interfaces. 2016;8(36):23568–23579. PubMed

Li Z, Shuai C, Li X, Li X, Xiang J, Li G. Mechanism of poly-l-lysine -modified iron oxide nanoparticles uptake into cells. J Biomed Mater Res A. 2013;101(10):2846–2850. PubMed

Katebi S, Esmaeili A, Ghaedi K. Static magnetic field reduced exogenous oligonucleotide uptake by spermatozoa using magnetic nanoparticle gene delivery system. J Magn Magn Mater. 2016;402:184–189.

Shanehsazzadeh S, Lahooti A, Hajipour MJ, Ghavami M, Azhdarzadeh M. External magnetic fields affect the biological impacts of superparamagnetic iron nanoparticles. Colloids Surf B Biointerfaces. 2015;136:1107–1112. PubMed

Wang QM, Wang H, Li YF, et al. Inhibition of EMMPRIN and MMP-9 expression by epigallocatechin-3-gallate through 67-kDa laminin receptor in PMA-induced macrophages. Cell Physiol Biochem. 2016;39(6):2308–2319. PubMed

Pyrgiotakis G, Blattmann CO, Demokritou P. Real-time nanoparticle-cell interactions in physiological media by atomic force microscopy. ACS Sustain Chem Eng. 2014;2(7):1681–1690. PubMed PMC

Furlani EP, Xue X. Field, force and transport analysis for magnetic particle-based gene delivery. Microfluid Nanofluidics. 2012;13(4):589–602.

Nicolson GL. The fluid-mosaic model of membrane structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years. Biochim Biophys Acta. 2014;1838(6):1451–1466. PubMed

Cyclic Strain Mitigates Nanoparticle Internalization by Vascular Smooth Muscle Cells

Scavenging of reactive oxygen species by phenolic compound-modified maghemite nanoparticles

A Rapid Method for the Detection of Sarcosine Using SPIONs/Au/CS/SOX/NPs for Prostate Cancer Sensing