Nitric Oxide-Releasing Polymers Containing the [N(O)NO]-Group
Abstract
Ions of structure X[N(O)NO]- display broad-spectrum pharmacological activity that correlates with the rate and extent of their spontaneous, first-order decomposition to nitric oxide when dissolved. We report incorporation of this functional group into polymeric matrices that can be used for altering the time course of nitric oxide release and/or targeting it to tissues with which the polymers are in physical contact. Structural types prepared include those in which the [N(O)NO]- group is attached to heteroatoms in low molecular weight species that are noncovalently distributed throughout the polymeric matrix, in groupings pendant to the polymer backbone, and in the polymer backbone itself. They range in physical form from films that can be coated onto other surfaces to microspheres, gels, powders, and moldable resins. Chemiluminescence measurements confirm that polymers to which the [N(O)NO]- group is attached can serve as localized sources of nitric oxide, with one prototype providing sustained NO release for 5 weeks in pH 7.4 buffer at 37 degrees C. The latter composition, a cross-linked poly-(ethylenimine) that had been exposed to NO, inhibited the in vitro proliferation of rat aorta smooth muscle cells when added as a powder to the culture medium and showed potent antiplatelet activity when coated on a normally thrombogenic vascular graft situated in an arteriovenous shunt in a baboon's circulatory system. The results suggest that polymers containing the [N(O)NO]- functional group may hold considerable promise for a variety of biomedical applications in which local delivery of NO is desired.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
Boussif, O., Lezoualc’h, F., Zanta, M. A., Djavaheri‐Mergny, M., Scherman, D., DEMENEIX, B. A., & Behr, J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.16.7297 · Cited by 6,256 · see citing works
Garg, U. C., & Hassid, A. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114081 · Cited by 2,154 · see citing works
DNA Deaminating Ability and Genotoxicity of Nitric Oxide and its Progenitors
Wink, D. A., Kasprzak, K. S., Maragos, C. M., Elespuru, R. K., Misra, M., Dunams, T. M., Cebula, T. A., Koch, W. H., Andrews, A. W., Allen, J. S., et al. (1991) · Science · doi:10.1126/science.1948068 · Cited by 1,235 · see citing works
Self-citationIgnarro, L. J., Fukuto, J. M., Griscavage, J. M., Rogers, N. E., & Byrns, R. E. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8103 · Cited by 856 · see citing works
von der Leyen, H. E., Gibbons, G. H., Morishita, R., Lewis, N. P., Zhang, L., Nakajima, M., Kaneda, Y., Cooke, J. P., & Dzau, V. J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.4.1137 · Cited by 763 · see citing works
Maragos, C. M., Morley, D., Wink, D. A., Dunams, T. M., Saavedra, J. E., Hoffman, A., Bove, A. A., Isaac, L., Hrabie, J. A., & Keefer, L. K. (1991) · Journal of Medicinal Chemistry · doi:10.1021/jm00115a013 · Cited by 722 · see citing works
Self-citationKeefer, L. K., Nims, R. W., Davies, K. M., & Wink, D. A. (1996) · Methods in Enzymology · doi:10.1016/s0076-6879(96)68030-6 · Cited by 670 · see citing works
Self-citationMellion, B. T., Ignarro, L. J., Ohlstein, E. H., Pontecorvo, E., Hyman, A. L., & Kadowitz, P. (1981) · Blood · doi:10.1182/blood.v57.5.946.946 · Cited by 639 · see citing works
New nitric oxide-releasing zwitterions derived from polyamines
Hrabie, J. A., Klose, J. R., Wink, D. A., & Keefer, L. K. (1993) · The Journal of Organic Chemistry · doi:10.1021/jo00058a030 · Cited by 593 · see citing works
Self-citationNakaki, T., Nakayama, M., & Kato, R. (1990) · European Journal of Pharmacology Molecular Pharmacology · doi:10.1016/0922-4106(90)90031-r · Cited by 238 · see citing works
Regulation of Vascular Homeostasis by Nitric Oxide
Radomski, M. W., & Moncada, S. (1993) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1646156 · Cited by 232 · see citing works
Diodati, J. G., Quyyumi, A. A., & Keefer, L. K. (1993) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199308000-00018 · Cited by 228 · see citing works
Self-citationHill-West, J. L., Chowdhury, S. M., Slepian, M. J., & Hubbell, J. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.13.5967 · Cited by 221 · see citing works
Nitric Oxide (NO) Donor Molecules
Mooradian, D. L., Hutsell, T. C., & Keefer, L. K. (1995) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199504000-00023 · Cited by 221 · see citing works
Self-citationThe Reaction of Nitrogen(II) Oxide with Diethylamine
Drago, R. S., & Paulik, F. E. (1960) · Journal of the American Chemical Society · doi:10.1021/ja01486a021 · Cited by 163 · see citing works
Kariya, K., Kawahara, Y., Araki, S.-I., Fukuzaki, H., & Takai, Y. (1989) · Atherosclerosis · doi:10.1016/0021-9150(89)90022-1 · Cited by 137 · see citing works
Maragos, C. M., Wang, J., Hrabie, J. A., Oppenheim, J. J., & Keefer, L. K. (1993) · PubMed · Cited by 135 · see citing works
Self-citationThe Reaction of Nitrogen(II) Oxide with Various Primary and Secondary Amines
Drago, R. S., & Karstetter, B. R. (1961) · Journal of the American Chemical Society · doi:10.1021/ja01469a012 · Cited by 127 · see citing works
Platelet interactions with Dacron vascular grafts. A model of acute thrombosis in baboons.
Hanson, S. R., Kotzé, H. F., Savage, B., et al. (1985) · Arteriosclerosis An Official Journal of the American Heart Association Inc · doi:10.1161/01.atv.5.6.595 · Cited by 120 · see citing works
Self-citationHubbell, J. A., & Langer, R. (1995) · Chemical & Engineering News · doi:10.1021/cen-v073n011.p042 · Cited by 100 · see citing works
DNA Sequence Changes Induced by Two Nitric Oxide Donor Drugs in the supF Assay
Routledge, M. N., Wink, D. A., Keefer, L. K., & Dipple, A. (1994) · Chemical Research in Toxicology · doi:10.1021/tx00041a007 · Cited by 85 · see citing works
Self-citationSecondary amine/nitric oxide complex ions, R2N[N(O)NO]-. O-Functionalization chemistry
Saavedra, J. E., Dunams, T. M., Flippen-Anderson, J. L., & Keefer, L. K. (1992) · The Journal of Organic Chemistry · doi:10.1021/jo00049a017 · Cited by 84 · see citing works
Self-citationGuo, J. P., Milhoan, K. A., Tuan, R. S., & Lefer, A. M. (1994) · Circulation Research · doi:10.1161/01.res.75.1.77 · Cited by 79 · see citing works
Morley, D. L., Maragos, C. M., Zhang, X., Boignon, M., Wink, D. A., & Keefer, L. K. (1993) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199304000-00023 · Cited by 78 · see citing works
Self-citationSavage, B., McFadden, P., Hanson, S., et al. (1986) · Blood · doi:10.1182/blood.v68.2.386.bloodjournal682386 · Cited by 67 · see citing works
Self-citationJackson, C. L. (1994) · Trends in Cardiovascular Medicine · doi:10.1016/1050-1738(94)90064-7 · Cited by 67 · see citing works
Infrainguinal vein graft stenosis
Varty, K., Allen, K. E., Bell, P. R. F., et al. (1993) · British journal of surgery · doi:10.1002/bjs.1800800706 · Cited by 66 · see citing works
Controlled Protein Release from Polyethyleneimine-Coated Poly(L-lactic Acid)/Pluronic Blend Matrices
Park, T. G., Cohen, S., & Langer, R. (1992) · Pharmaceutical Research · doi:10.1023/a:1018971525301 · Cited by 63 · see citing works
Diodati, J. G., Quyyumi, A. A., Hussain, N., & Keefer, L. K. (1993) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1649644 · Cited by 61 · see citing works
Self-citationPlatelet-Mediated Thrombosis in Microvascular Surgery
Johnson, P. C. (1990) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-199008000-00032 · Cited by 59 · see citing works
Stability of the Chloro-complexes of Iodine in Aqueous Solution1
Cason, D. L., & Neumann, H. M. (1961) · Journal of the American Chemical Society · doi:10.1021/ja01469a013 · Cited by 52 · see citing works
Reactions of Nitrogen(II) Oxide with Miscellaneous Lewis Bases
Longhi, R., Ragsdale, R. O., & Drago, R. S. (1962) · Inorganic Chemistry · doi:10.1021/ic50004a011 · Cited by 51 · see citing works
Savage, B., McFadden, P., Hanson, S., et al. (1986) · Blood · doi:10.1182/blood.v68.2.386.386 · Cited by 48 · see citing works
Self-citationNitric Oxide Donors: A Continuing Opportunity in Drug Design
Hanson, S. R., Hutsell, T. C., Keefer, L. K., Mooradian, D. L., & Smith, D. J. (1995) · Advances in Pharmacology · doi:10.1016/s1054-3589(08)61099-6 · Cited by 47 · see citing works
Self-citationChapter 15 Device thrombosis and thromboembolism
Hanson, S. R. (1993) · Cardiovascular Pathology · doi:10.1016/1054-8807(93)90056-8 · Cited by 35 · see citing works
Self-citationExogenous nitric oxide inhibits in vivo platelet adhesion following balloon angioplasty
Groves, P. H., Penny, W. J., Cheadle, H. A., et al. (1992) · Cardiovascular Research · doi:10.1093/cvr/26.6.615 · Cited by 34 · see citing works
Prediction of a Crystallization Pathway for Z-DNA Hexanucleotides
Ho, P. S., Kagawa, T. F., Tseng, K., et al. (1991) · Science · doi:10.1126/science.1948069 · Cited by 32 · see citing works
Reactions of Nitrogen(II) Oxide
Drago, R. S. (1962) · Advances in chemistry series · doi:10.1021/ba-1962-0036.ch015 · Cited by 29 · see citing works
Wolfe, J. L., VanderVelde, D. G., & Borchardt, R. T. (1992) · The Journal of Organic Chemistry · doi:10.1021/jo00049a018 · Cited by 29 · see citing works
Platelet Interactions With the Vessel Wall and Prosthetic Grafts
Rubin, B. G., Santoro, S. A., & Sicard, G. A. (1993) · Annals of Vascular Surgery · doi:10.1007/bf02001017 · Cited by 12 · see citing works
Metal-Containing Compounds of the Anion (C2H5)2NN2O2
Longhi, R., & Drago, R. S. (1963) · Inorganic Chemistry · doi:10.1021/ic50005a024 · Cited by 7 · see citing works
SCHULZ, W. (1995) · Chemical & Engineering News · doi:10.1021/cen-v073n046.p054 · Cited by 3 · see citing works
Prosthetic graft seeding: breathing new life into old grafts.
Pe, B., Cn, M., & Marston, A. (1994) · PubMed · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nitric oxide release: Part II. Therapeutic applications
Carpenter, A. W., & Schoenfisch, M. H. (2012) · Chemical Society Reviews · doi:10.1039/c2cs15273h · Cited by 964 · see citing works
Nitric oxide release: Part I. Macromolecular scaffolds
Riccio, D. A., & Schoenfisch, M. H. (2012) · Chemical Society Reviews · doi:10.1039/c2cs15272j · Cited by 475 · see citing works
Characterization of topographical effects on macrophage behavior in a foreign body response model
Chen, S., Jones, J. A., Xu, Y., Low, H.-Y., Anderson, J. M., & Leong, K. W. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.01.074 · Cited by 389 · see citing works
Frost, M. C., Reynolds, M. M., & Meyerhoff, M. E. (2005) · Biomaterials · doi:10.1016/j.biomaterials.2004.06.006 · Cited by 343 · see citing works
Wo, Y., Brisbois, E. J., Bartlett, R. H., & Meyerhoff, M. E. (2016) · Biomaterials Science · doi:10.1039/c6bm00271d · Cited by 251 · see citing works
Polymer‐Based Nitric Oxide Therapies: Recent Insights for Biomedical Applications
Jen, M. C., Serrano, M. C., van Lith, R., & Ameer, G. A. (2012) · Advanced Functional Materials · doi:10.1002/adfm.201101707 · Cited by 194 · see citing works
Nitric Oxide Donors for Cardiovascular Implant Applications
Naghavi, N., de Mel, A., Alavijeh, O. S., Cousins, B. G., & Seifalian, A. M. (2013) · Small · doi:10.1002/smll.201200458 · Cited by 188 · see citing works
Zhang, H., Annich, G. M., Miskulin, J., Stankiewicz, K., Osterholzer, K., Merz, S. I., Bartlett, R. H., & Meyerhoff, M. E. (2003) · Journal of the American Chemical Society · doi:10.1021/ja0291538 · Cited by 176 · see citing works
Novel thromboresistant materials
Jordan, S. W., & Chaikof, E. L. (2007) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2007.02.048 · Cited by 153 · see citing works
Taite, L. J., Yang, P., Jun, H., & West, J. L. (2008) · Journal of Biomedical Materials Research Part B: Applied Biomaterials · doi:10.1002/jbm.b.30850 · Cited by 136 · see citing works
Duong, H. T. T., Jung, K., Kutty, S. K., Agustina, S., Adnan, N. N. M., Basuki, J. S., Kumar, N., Davis, T. P., Barraud, N., & Boyer, C. (2014) · Biomacromolecules · doi:10.1021/bm500422v · Cited by 126 · see citing works
Reynolds, M. M., Frost, M. C., & Meyerhoff, M. E. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.06.019 · Cited by 116 · see citing works
Zhou, Z., & Meyerhoff, M. E. (2005) · Biomaterials · doi:10.1016/j.biomaterials.2005.04.046 · Cited by 115 · see citing works
Hwang, S., & Meyerhoff, M. E. (2008) · Biomaterials · doi:10.1016/j.biomaterials.2008.02.004 · Cited by 82 · see citing works
Wu, Y., & Meyerhoff, M. E. (2008) · Talanta · doi:10.1016/j.talanta.2007.06.022 · Cited by 65 · see citing works
Reynolds, M. M., & Annich, G. M. (2011) · Organogenesis · doi:10.4161/org.7.1.14029 · Cited by 60 · see citing works
Nitric Oxide Donors: A Continuing Opportunity in Drug Design
Hanson, S. R., Hutsell, T. C., Keefer, L. K., Mooradian, D. L., & Smith, D. J. (1995) · Advances in Pharmacology · doi:10.1016/s1054-3589(08)61099-6 · Cited by 47 · see citing works
Self-citationNitric Oxide: Implications for Vascular and Endovascular Surgery
Vural, K. M., & Bayazit, M. (2001) · European Journal of Vascular and Endovascular Surgery · doi:10.1053/ejvs.2001.1448 · Cited by 43 · see citing works
Sol–gel derived nitric oxide-releasing oxygen sensors
Marxer, S. M., Robbins, M. E., & Schoenfisch, M. H. (2005) · The Analyst · doi:10.1039/b412079e · Cited by 23 · see citing works
Preparation and characterization of diazeniumdiolate releasing ethylcellulose films
Wan, A., Gao, Q., & Li, H. (2009) · Journal of Materials Science: Materials in Medicine · doi:10.1007/s10856-008-3511-5 · Cited by 14 · see citing works
- Authors
- Smith, D. J., Chakravarthy, D., Pulfer, S., Simmons, M. L., Hrabie, J. A., Citro, M. L., Saavedra, J. E., Davies, K. M., Hutsell, T. C., Mooradian, D. L., Hanson, S. R., & Keefer, L. K.
- Affiliations
- University of Akron (US)
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1996-01-01
- Volume
- 39
- Issue
- 5
- Pages
- 1148-1156
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2022143873
- Cited by
- 208
- References
- 43
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 12 · 2018: 5 · 2017: 9 · 2016: 11 · 2015: 7 · 2014: 5 · 2013: 8 · 2012: 8
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1p01hl048667-01, 5r01hl031469-15)
- National Heart, Lung, and Blood Institute (HL 31469, HL-48667)
- National Cancer Institute (CA-26731, P01CA026731)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- polyethyleneimine, chemiluminescence, antiplatelet activity, arteriovenous shunt, thromboprophylaxis, local drug delivery
- MeSH terms
- Animals, Anions, Cell Division, Chemistry, Physical, Hydrogen-Ion Concentration, Kinetics, Luminescent Measurements, Male, Muscle, Smooth, Vascular, Nitric Oxide, Nitrogen, Oxygen, Papio, Platelet Aggregation Inhibitors, Polymers, Thrombosis, Molecular Structure, Chemical Phenomena
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
