BACKGROUND: Intravascular delivery of nanoparticles for theranostic application permits direct interaction of nanoparticles and vascular cells. Since vascular smooth muscle cells (VSMCs), the major components of the vascular wall, are constantly subjected to mechanical stimulation from hemodynamic influence, we asked whether cyclic strain may modulate internalization of magnetic nanoparticles (MNPs) by cultured VSMCs. METHODS: Cyclic strain (1 Hz and 10%) was applied with Flexcell system in cultured VSMCs from rats, with cell-associated MNPs (MNPcell) determined by a colorimetric iron assay. Transmission and scanning electron microscopy were used for morphology studies. Confocal microscopy was used to demonstrate distribution of actin assembly in VSMCs. RESULTS: Incubation of poly(acrylic acid) (PAA)-coated MNPs with VSMCs for 4 h induced microvilli formation and MNP internalization. Application of cyclic strain for 4-12 h significantly reduced MNPcell by up to 65% (p < 0.05), which was associated with blunted microvilli and reduced vesicle size/cell, but not vesicle numbers/cell. Confocal microscopy demonstrated that both cyclic strain and fibronectin coating of the culture plate reduced internalized MNPs, which were co-localized with vinculin. Furthermore, cytochalasin D reduced MNPcell, suggesting a role of actin polymerization in MNP uptake by VSMCs; however, a myosin II ATPase inhibitor, blebbistatin, exhibited no effect. Cyclic strain also attenuated uptake of PAA-MNPs by LN-229 cells and uptake of poly-L-lysine-coated MNPs by VSMCs. CONCLUSION: In such a dynamic milieu, cyclic strain may impede cellular internalization of nanocarriers, which spares the nanocarriers and augments their delivery to the target site in the lumen of vessels or outside of the circulatory system.

Department of Biochemistry and Molecular Biology College of Medicine Chang Gung University Taoyuan 33302 Taiwan Republic of China

Department of Medical Imaging and Intervention Chang Gung Memorial Hospital Taoyuan 33305 Taiwan Republic of China

Department of Physiology and Pharmacology Chang Gung University Taoyuan 33302 Taiwan Republic of China

Institute of Biomedical Sciences Chang Gung University Taoyuan 33302 Taiwan Republic of China

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Prague 6 162 06 Czech Republic

Liver Research Center Chang Gung Memorial Hospital Taoyuan 33305 Taiwan Republic of China

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Panyam J, Labhasetwar V. Dynamics of endocytosis and exocytosis of poly(D,L-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells. Pharm Res. 2003;20(2):212–220. doi:10.1023/A:1022219003551 PubMed DOI

Freese C, Schreiner D, Anspach L, et al. In vitro investigation of silica nanoparticle uptake into human endothelial cells under physiological cyclic stretch. Part Fibre Toxicol. 2014;11:68. doi:10.1186/s12989-014-0068-y PubMed DOI PMC

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. doi:10.1039/C4NR00617H PubMed DOI

Kakisis JD, Liapis CD, Sumpio BE. Effects of cyclic strain on vascular cells. Endothelium. 2004;11(1):17–28. doi:10.1080/10623320490432452 PubMed DOI

Su BY, Shontz KM, Flavahan NA, Nowicki PT. The effect of phenotype on mechanical stretch-induced vascular smooth muscle cell apoptosis. J Vasc Res. 2006;43(3):229–237. doi:10.1159/000091102 PubMed DOI

Ando J, Yamamoto K. Effects of shear stress and stretch on endothelial function. Antioxid Redox Signal. 2011;15(5):1389–1403. doi:10.1089/ars.2010.3361 PubMed DOI

Fang Y, Wu D, Birukov KG. Mechanosensing and mechanoregulation of endothelial cell functions. Compr Physiol. 2019;9(2):873–904. PubMed PMC

van Engeland NCA, Pollet A, den Toonder JMJ, Bouten CVC, Stassen O, Sahlgren CM. A biomimetic microfluidic model to study signalling between endothelial and vascular smooth muscle cells under hemodynamic conditions. Lab Chip. 2018;18(11):1607–1620. doi:10.1039/C8LC00286J PubMed DOI PMC

Jufri NF, Mohamedali A, Avolio A, Baker MS. Mechanical stretch: physiological and pathological implications for human vascular endothelial cells. Vasc Cell. 2015;7:8. doi:10.1186/s13221-015-0033-z PubMed DOI PMC

Lim CG, Jang J, Kim C. Cellular machinery for sensing mechanical force. BMB Rep. 2018;51(12):623–629. doi:10.5483/BMBRep.2018.51.12.237 PubMed DOI PMC

Rensen SS, Doevendans PA, van Eys GJ. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J. 2007;15(3):100–108. doi:10.1007/BF03085963 PubMed DOI PMC

Chen J, Zhou Y, Liu S, Li C. Biomechanical signal communication in vascular smooth muscle cells. J Cell Commun Signal. 2020;14(4):357–376. doi:10.1007/s12079-020-00576-1 PubMed DOI PMC

Hu X, Zhao P, Lu Y, Liu Y. ROS-based nanoparticles for atherosclerosis treatment. Materials (Basel). 2021;14(22):6921. doi:10.3390/ma14226921 PubMed DOI PMC

Behzadi S, Serpooshan V, Tao W, et al. Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev. 2017;46(14):4218–4244. doi:10.1039/C6CS00636A PubMed DOI PMC

Oh N, Park JH. Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomedicine. 2014;9(Suppl1):51–63. PubMed PMC

Zhang S, Gao H, Bao G. Physical principles of nanoparticle cellular endocytosis. ACS Nano. 2015;9(9):8655–8671. doi:10.1021/acsnano.5b03184 PubMed DOI PMC

Yameen B, Choi WI, Vilos C, Swami A, Shi J, Farokhzad OC. Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release. 2014;190:485–499. doi:10.1016/j.jconrel.2014.06.038 PubMed DOI PMC

Swanson JA. Shaping cups into phagosomes and macropinosomes. Nat Rev Mol Cell Biol. 2008;9(8):639–649. doi:10.1038/nrm2447 PubMed DOI PMC

Mooren OL, Galletta BJ, Cooper JA. Roles for actin assembly in endocytosis. Annu Rev Biochem. 2012;81:661–686. doi:10.1146/annurev-biochem-060910-094416 PubMed DOI

Gauthier NC, Masters TA, Sheetz MP. Mechanical feedback between membrane tension and dynamics. Trends Cell Biol. 2012;22(10):527–535. doi:10.1016/j.tcb.2012.07.005 PubMed DOI

Carlsson AE. Membrane bending by actin polymerization. Curr Opin Cell Biol. 2018;50:1–7. doi:10.1016/j.ceb.2017.11.007 PubMed DOI PMC

Blanchoin L, Boujemaa-Paterski R, Sykes C, Plastino J. Actin dynamics, architecture, and mechanics in cell motility. Physiol Rev. 2014;94(1):235–263. doi:10.1152/physrev.00018.2013 PubMed DOI

Gallop JL. Filopodia and their links with membrane traffic and cell adhesion. Semin Cell Dev Biol. 2020;102:81–89. doi:10.1016/j.semcdb.2019.11.017 PubMed DOI

Mogilner A. On the edge: modeling protrusion. Curr Opin Cell Biol. 2006;18(1):32–39. doi:10.1016/j.ceb.2005.11.001 PubMed DOI

Ohashi K, Fujiwara S, Mizuno K. Roles of the cytoskeleton, cell adhesion and rho signalling in mechanosensing and mechanotransduction. J Biochem. 2017;161(3):245–254. PubMed

Bauer MS, Baumann F, Daday C, et al. Structural and mechanistic insights into mechanoactivation of focal adhesion kinase. Proc Natl Acad Sci U S A. 2019;116(14):6766–6774. doi:10.1073/pnas.1820567116 PubMed DOI PMC

Wrighton KH. Cell adhesion: the ‘ins’ and ‘outs’ of integrin signalling. Nat Rev Mol Cell Biol. 2013;14(12):752. PubMed

Xiao Y, Du J. Superparamagnetic nanoparticles for biomedical applications. J Mater Chem B. 2020;8(3):354–367. doi:10.1039/C9TB01955C PubMed DOI

Revia RA, Zhang M. Magnetite nanoparticles for cancer diagnosis, treatment, and treatment monitoring: recent advances. Mater Today (Kidlington). 2016;19(3):157–168. doi:10.1016/j.mattod.2015.08.022 PubMed DOI PMC

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

Siow WX, Chang YT, Babič M, Lu YC, Horák D, Ma YH. Interaction of poly-l-lysine coating and heparan sulfate proteoglycan on magnetic nanoparticle uptake by tumor cells. Int J Nanomedicine. 2018;13:1693–1706. doi:10.2147/IJN.S156029 PubMed DOI PMC

Dabaghi M, Hilger I. Magnetic nanoparticles behavior in biological solutions; the impact of clustering tendency on sedimentation velocity and cell uptake. Materials (Basel). 2020;13(7):1644. doi:10.3390/ma13071644 PubMed DOI PMC

Rouse JG, Haslauer CM, Loboa EG, Monteiro-Riviere NA. Cyclic tensile strain increases interactions between human epidermal keratinocytes and quantum dot nanoparticles. Toxicol in Vitro. 2008;22(2):491–497. doi:10.1016/j.tiv.2007.10.010 PubMed DOI

Ma YH, Wei HW, Su KH, Ives HE, Morris RC. Chloride-dependent calcium transients induced by angiotensin II in vascular smooth muscle cells. Am J Physiol Cell Physiol. 2004;286(1):C112–118. doi:10.1152/ajpcell.00605.2002 PubMed DOI

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. doi:10.1016/j.jmmm.2016.11.010 DOI

Casella JF, Flanagan MD, Lin S. Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change. Nature. 1981;293(5830):302–305. doi:10.1038/293302a0 PubMed DOI

Kovács M, Tóth J, Hetényi C, Málnási-Csizmadia A, Sellers JR. Mechanism of blebbistatin inhibition of myosin II. J Biol Chem. 2004;279(34):35557–35563. doi:10.1074/jbc.M405319200 PubMed DOI

Sakulkhu U, Mahmoudi M, Maurizi L, Salaklang J, Hofmann H. Protein Corona composition of superparamagnetic iron oxide nanoparticles with various physico-chemical properties and coatings. Sci Rep. 2014;4:5020. doi:10.1038/srep05020 PubMed DOI PMC

Kokkinopoulou M, Simon J, Landfester K, Mailänder V, Lieberwirth I. Visualization of the protein Corona: towards a biomolecular understanding of nanoparticle-cell-interactions. Nanoscale. 2017;9(25):8858–8870. doi:10.1039/C7NR02977B PubMed DOI

Chiu CY, Chung TW, Chen SY, Ma YH. Effects of PEGylation on capture of dextran-coated magnetic nanoparticles in microcirculation. Int J Nanomedicine. 2019;14:4767–4780. PubMed PMC

Raucher D, Sheetz MP. Cell spreading and lamellipodial extension rate is regulated by membrane tension. J Cell Biol. 2000;148(1):127–136. doi:10.1083/jcb.148.1.127 PubMed DOI PMC

Batchelder EL, Hollopeter G, Campillo C, et al. Membrane tension regulates motility by controlling lamellipodium organization. Proc Natl Acad Sci U S A. 2011;108(28):11429–11434. doi:10.1073/pnas.1010481108 PubMed DOI PMC

Hu J, Liu Y. Cyclic strain enhances cellular uptake of nanoparticles. J Nanomater. 2015;2015:1–8.

Freese C, Anspach L, Deller RC, et al. Gold nanoparticle interactions with endothelial cells cultured under physiological conditions. Biomater Sci. 2017;5(4):707–717. doi:10.1039/C6BM00853D PubMed DOI

Nozumi M, Nakatsu F, Katoh K, Igarashi M. Coordinated movement of vesicles and actin bundles during nerve growth revealed by superresolution microscopy. Cell Rep. 2017;18(9):2203–2216. doi:10.1016/j.celrep.2017.02.008 PubMed DOI

Onishi K, Shafer B, Lo C, Tissir F, Goffinet AM, Zou Y. Antagonistic functions of Dishevelleds regulate Frizzled3 endocytosis via filopodia tips in Wnt-mediated growth cone guidance. J Neurosci. 2013;33(49):19071–19085. doi:10.1523/JNEUROSCI.2800-13.2013 PubMed DOI PMC

Bu W, Chou AM, Lim KB, Sudhaharan T, Ahmed S. The Toca-1-N-WASP complex links filopodial formation to endocytosis. J Biol Chem. 2009;284(17):11622–11636. doi:10.1074/jbc.M805940200 PubMed DOI PMC

Dent EW, Kwiatkowski AV, Mebane LM, et al. Filopodia are required for cortical neurite initiation. Nat Cell Biol. 2007;9(12):1347–1359. doi:10.1038/ncb1654 PubMed DOI

Young LE, Heimsath EG, Higgs HN. Cell type-dependent mechanisms for formin-mediated assembly of filopodia. Mol Biol Cell. 2015;26(25):4646–4659. doi:10.1091/mbc.E15-09-0626 PubMed DOI PMC

Le Roux AL, Quiroga X, Walani N, Arroyo M, Roca-Cusachs P. The plasma membrane as a mechanochemical transducer. Philos Trans R Soc Lond B Biol Sci. 2019;374(1779):20180221. doi:10.1098/rstb.2018.0221 PubMed DOI PMC

Qi YX, Han Y, Jiang ZL. Mechanobiology and vascular remodeling: from membrane to nucleus. Adv Exp Med Biol. 2018;1097:69–82. PubMed

Li W, Sancho A, Chung WL, et al. Differential cellular responses to adhesive interactions with galectin-8- and fibronectin-coated substrates. J Cell Sci. 2021;134(8):jcs252221. doi:10.1242/jcs.252221 PubMed DOI PMC

Chazotte B. Labeling membrane glycoproteins or glycolipids with fluorescent wheat germ agglutinin. Cold Spring Harb Protoc. 2011;5:pdb.prot5623. doi:10.1101/pdb.prot5623 PubMed DOI

Dhein S, Schreiber A, Steinbach S, et al. Mechanical control of cell biology. Effects of cyclic mechanical stretch on cardiomyocyte cellular organization. Prog Biophys Mol Biol. 2014;115(2–3):93–102. doi:10.1016/j.pbiomolbio.2014.06.006 PubMed DOI

Impact of mechanical cues on key cell functions and cell-nanoparticle interactions