The mechanical properties of submicron particles offer a unique design space for advanced drug-delivery particle engineering. However, the recognition of this potential is limited by a poor consensus about both the specificity and sensitivity of mechanosensitive endocytosis over a broad particle stiffness range. In this report, our model series of polystyrene-co-poly(N-isopropylacrylamide) (pS-co-NIPAM) microgels have been prepared with a nominally constant monomer composition (50 mol % styrene and 50 mol % NIPAM) with varied bis-acrylamide cross-linking densities to introduce a tuned spectrum of particle mechanics without significant variation in particle size and surface charge. While previous mechanosensitive studies use particles with moduli ranging from 15 kPa to 20 MPa, the pS-co-NIPAM particles have Young's moduli (E) ranging from 300 to 700 MPa, which is drastically stiffer than these previous studies as well as pure pNIPAM. Despite this elevated stiffness, particle uptake in RAW264.7 murine macrophages displays a clear stiffness dependence, with a significant increase in particle uptake for our softest microgels after a 4 h incubation. Preferential uptake of the softest microgel, pS-co-NIPAM-1 (E = 310 kPa), was similarly observed with nonphagocytic HepG2 hepatoma cells; however, the uptake kinetics were distinct relative to that observed for RAW264.7 cells. Pharmacological inhibitors, used to probe for specific routes of particle internalization, identify actin- A nd microtubule-dependent pathways in RAW264.7 cells as sensitive particle mechanics. For our pS-co-NIPAM particles at nominally 300-400 nm in size, this microtubule-dependent pathway was interpreted as a phagocytic route. For our high-stiffness microgel series, this study provides evidence of cell-specific, mechanosensitive endocytosis in a distinctly new stiffness regime that will further broaden the functional landscape of mechanics as a design space for particle engineering.
|Number of pages||12|
|Journal||ACS Applied Bio Materials|
|State||Published - Nov 19 2018|
Bibliographical noteFunding Information:
Research reported in this publication was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under award no. R21EB021035. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Furthermore, this work utilized the Zeiss LSM710 confocal microscope in the University of Iowa Central Microscopy Research Facilities that was purchased with funding from the NIH SIG grant no. S10RR022498.
Copyright © 2018 American Chemical Society.
- drug delivery
- mechanical properties
ASJC Scopus subject areas
- Chemistry (all)
- Biomedical Engineering
- Biochemistry, medical