title: Substrate stiffness regulates cellular uptake of nanoparticles.
abstract: Nanoparticle (NP)-bioconjugates hold great promise for more sensitive disease diagnosis and more effective anticancer drug delivery compared with existing approaches. A critical aspect in both applications is cellular internalization of NPs, which is influenced by NP properties and cell surface mechanics. Despite considerable progress in optimization of the NP-bioconjugates for improved targeting, the role of substrate stiffness on cellular uptake has not been investigated. Using polyacrylamide (PA) hydrogels as model substrates with tunable stiffness, we quantified the relationship between substrate stiffness and cellular uptake of fluorescent NPs by bovine aortic endothelial cells (BAECs). We found that a stiffer substrate results in a higher total cellular uptake on a per cell basis, but a lower uptake per unit membrane area. To obtain a mechanistic understanding of the cellular uptake behavior, we developed a thermodynamic model that predicts that membrane spreading area and cell membrane tension are two key factors controlling cellular uptake of NPs, both of which are modulated by substrate stiffness. Our experimental and modeling results not only open up new avenues for engineering NP-based cancer cell targets for more effective in vivo delivery but also contribute an example of how the physical environment dictates cellular behavior and function.
authors.affiliation: Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Changjin
authors.initials: C
authors.lastname: Huang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Butler
authors.forename: Sheng
authors.initials: S
authors.lastname: Tong
authors.forename: Hari S
authors.initials: HS
authors.lastname: Muddana
authors.forename: Gang
authors.initials: G
authors.lastname: Bao
authors.forename: Sulin
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D013379:Substrate Specificity; D013499:Surface Properties; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D000099166:Polyacrylamides