title: Amphiphilic Macromolecule Self-Assembled Monolayers Suppress Smooth Muscle Cell Proliferation.
abstract: A significant limitation of cardiovascular stents is restenosis, where excessive smooth muscle cell (SMC) proliferation following stent implantation causes blood vessel reocclusion. While drug-eluting stents minimize SMC proliferation through releasing cytotoxic or immunosuppressive drugs from polymer carriers, significant issues remain with delayed healing, inflammation, and hypersensitivity reactions associated with drug and polymer coatings. Amphiphilic macromolecules (AMs) comprising a sugar-based hydrophobic domain and a hydrophilic poly(ethylene glycol) tail are noncytotoxic and recently demonstrated a concentration-dependent ability to suppress SMC proliferation. In this study, we designed a series of AMs and studied their coating properties (chemical composition, thickness, grafting density, and coating uniformity) to determine the effect of headgroup chemistry on bioactive AM grafting and release properties from stainless steel substrates. One carboxyl-terminated AM (1cM) and two phosphonate- (Me-1pM and Pr-1pM) terminated AMs, with varying linker lengths preceding the hydrophobic domain, were grafted to stainless steel substrates using the tethering by aggregation and growth (T-BAG) approach. The AMs formed headgroup-dependent, yet uniform, biocompatible adlayers. Pr-1pM and 1cM demonstrated higher grafting density and an extended release from the substrate over 21 days compared to Me-1pM, which exhibited lower grafting density and complete release within 7 days. Coinciding with their release profiles, Me-1pM and 1cM coatings initially suppressed SMC proliferation in vitro, but their efficacy decreased within 7 and 14 days, respectively, while Pr-1pM coatings suppressed SMC proliferation over 21 days. Thus, AMs with phosphonate headgroups and propyl linkers are capable of sustained release from the substrate and have the ability to suppress SMC proliferation during the restenosis that occurs in the 3-4 weeks after stent implantation, demonstrating the potential for AM coatings to provide sustained delivery via desorption from coated coronary stents and other metal-based implants.
authors.affiliation: †Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, New Jersey 08854, United States.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Chan
authors.affiliation: ‡Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United States.
authors.forename: Yingyue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, New Jersey 08854, United States.|‡Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Uhrich
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D054855:Drug-Eluting Stents; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020099:Coated Materials, Biocompatible; D013501:Surface-Active Agents