title: Water-Stable Metal-Organic Framework/Polymer Composites Compatible with Human Hepatocytes.
abstract: Metal-organic frameworks (MOFs) have demonstrated promise in biomedical applications as vehicles for drug delivery, as well as for the ability of copper-based MOFs to generate nitric oxide (NO) from endogenous S-nitrosothiols (RSNOs). Because NO is a participant in biological processes where it exhibits anti-inflammatory, antibacterial, and antiplatelet activation properties, it has received significant attention for therapeutic purposes. Previous work has shown that the water-stable MOF H3[(Cu4Cl)3-(BTTri)8] (H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene), or CuBTTri, produces NO from RSNOs and can be included within a polymeric matrix to form NO-generating materials. While such materials demonstrate potential, the possibility of MOF degradation leading to copper-related toxicity is a concern that must be addressed prior to adapting these materials for biomedical applications. Herein, we present the first cytotoxicity evaluation of an NO-generating CuBTTri/polymer composite material using 3T3-J2 murine embryonic fibroblasts and primary human hepatocytes (PHHs). CuBTTri/polymer films were prepared from plasticized poly(vinyl chloride) (PVC) and characterized via PXRD, ATR-FTIR, and SEM-EDX. Additionally, the ability of the CuBTTri/polymer films to enhance NO generation from S-nitroso-N-acetylpenicillamine (SNAP) was evaluated. Enhanced NO generation in the presence of the CuBTTri/polymer films was observed, with an average NO flux (0.90 ± 0.13 nmol cm(-2) min(-1)) within the range associated with antithrombogenic surfaces. The CuBTTri/polymer films were analyzed for stability in phosphate buffered saline (PBS) and cell culture media under physiological conditions for a 4 week duration. Cumulative copper release in both cell media (0.84 ± 0.21%) and PBS (0.18 ± 0.01%) accounted for less than 1% of theoretical copper present in the films. In vitro cell studies performed with 3T3-J2 fibroblasts and PHHs did not indicate significant toxicity, providing further support for the potential implementation of CuBTTri-based materials in biomedical applications.
authors.affiliation: Department of Chemistry, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Neufeld
authors.affiliation: School of Biomedical Engineering, Colorado State University , Fort Collins, Colorado 80523, United States.|Department of Bioengineering, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Brenton R
authors.initials: BR
authors.lastname: Ware
authors.affiliation: Department of Chemistry, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Alec
authors.initials: A
authors.lastname: Lutzke
authors.affiliation: School of Biomedical Engineering, Colorado State University , Fort Collins, Colorado 80523, United States.|Department of Mechanical Engineering, Colorado State University , Fort Collins, Colorado 80523, United States.|Department of Bioengineering, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Salman R
authors.initials: SR
authors.lastname: Khetani
authors.affiliation: Department of Chemistry, Colorado State University , Fort Collins, Colorado 80523, United States.|School of Biomedical Engineering, Colorado State University , Fort Collins, Colorado 80523, United States.|Chemical and Biological Engineering, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Reynolds
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D000073396:Metal-Organic Frameworks / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D011108:Polymers / Q000737:chemistry*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D000073396:Metal-Organic Frameworks; D011108:Polymers; D014867:Water; D026423:S-Nitroso-N-Acetylpenicillamine
keywords: copper toxicity; cytocompatibility; metal−organic frameworks; nitric oxide; primary human hepatocytes