Cyclic Strain Mitigates Nanoparticle Internalization by Vascular Smooth Muscle Cells

Abstract

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 (MNP cell ) 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 MNP cell 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 MNP cell , 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.

Biomechanics-mediated endocytosis in atherosclerosis

“…Researchers have also found that physiological cyclic stretch promotes the internalization of silica nanoparticles, which is related to cell stress and exocytotic events ( 142 ). Moreover, the changes in plasma membrane morphology by cyclic stretch will affect the distribution of actin and reduce the internalization of nanoparticles in VSMCs ( 143 ). Thus, understanding the role of nanoscale materials in endocytosis is important for investigating intracellular delivery and providing more targeted points for nanomedicine.…”

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

“… Cyclic stretch with frequency of 1 Hz and cyclic strain (5%, 10%, and 15%) [ 214 ] Tensile forces Flexcell® tension system (Flexcell Int.) Cyclic stretch with frequency of 1 Hz and 10% equibiaxial strain [ 192 ] Tensile forces Flexcell® tension system (Flexcell Int.) Cyclic stretch with frequency of 1 Hz and 5% cyclic elongation [ 208 ] Interstitial fluid pressure Xenograft tumors in nude mice implanted via subcutaneous injection of 1 × 10 6 cells in 50% Matrigel ~ 10–20 mmHg [ 194 ] TCPS, standard tissue culture polystyrene; PDMS, polydimethylsiloxane …”

“…The analysis of effects of tensile forces on nanoparticle-cell interactions reveals that tensile forces (similarly with ECM stiffness of shear stress) may either promote or inhibit the uptake of nanoparticles by cells (Table 2 ). For example, the application of cyclic strain resulted in a significant reduction of nanoparticle uptake in vascular smooth muscle cells (VSMCs) [ 192 ]. This reduction was associated with the attenuation of microvilli and a decrease in vesicle size per cell, although not in the number of vesicles per cell [ 192 ].…”

“…For example, the application of cyclic strain resulted in a significant reduction of nanoparticle uptake in vascular smooth muscle cells (VSMCs) [ 192 ]. This reduction was associated with the attenuation of microvilli and a decrease in vesicle size per cell, although not in the number of vesicles per cell [ 192 ]. Interestingly, both cyclic strain and fibronectin coating of the culture plate led to a decrease in internalized nanoparticles, which were co-localized with vinculin [ 192 ].…”

“…This reduction was associated with the attenuation of microvilli and a decrease in vesicle size per cell, although not in the number of vesicles per cell [ 192 ]. Interestingly, both cyclic strain and fibronectin coating of the culture plate led to a decrease in internalized nanoparticles, which were co-localized with vinculin [ 192 ]. Additionally, it was found that nanoparticle uptake was dependent on actin polymerization but not on myosin II [ 192 ].…”