Nitric oxide and nanotechnology: A novel approach to inhibit neointimal hyperplasia

Muneera R. Kapadia, Lesley W. Chow, Nick D. Tsihlis, Sadaf S. Ahanchi, Jason W. Eng, Jozef Murar, Janet Martinez, Daniel A. Popowich, Qun Jiang, Joseph A. Hrabie, Joseph E. Saavedra, Larry K. Keefer, James F. Hulvat, Samuel I Stupp, Melina R. Kibbe

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Objective: Nitric oxide (NO) has been shown to inhibit neointimal hyperplasia after arterial interventions in several animal models. To date, however, NO-based therapies have not been used in the clinical arena. Our objective was to combine nanofiber delivery vehicles with NO chemistry to create a novel, more potent NO-releasing therapy that can be used clinically. Thus, the aim of this study was to evaluate the perivascular application of spontaneously self-assembling NO-releasing nanofiber gels. Our hypothesis was that this application would prevent neointimal hyperplasia. Methods: Gels consisted of a peptide amphiphile, heparin, and a diazeniumdiolate NO donor (1-[N-(3-Aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate [DPTA/NO] or disodium 1-[(2-Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate [PROLI/NO]). Nitric oxide release from the gels was evaluated by the Griess reaction, and scanning electron microscopy confirmed nanofiber formation. Vascular smooth muscle cell (VSMC) proliferation and cell death were assessed in vitro by 3H-thymidine incorporation and Personal Cell Analysis (PCA) system (Guava Technologies, Hayward, Calif). For the in vivo work, gels were modified by reducing the free-water content. Neointimal hyperplasia after periadventitial gel application was evaluated using the rat carotid artery injury model at 14 days (n = 6 per group). Inflammation and proliferation were examined in vivo with immunofluorescent staining against CD45, ED1, and Ki67 at 3 days (n = 2 per group), and graded by blinded observers. Endothelialization was assessed by Evans blue injection at 7 days (n = 3 per group). Results: Both DPTA/NO and PROLI/NO, combined with the peptide amphiphile and heparin, formed nanofiber gels and released NO for 4 days. In vitro, DPTA/NO inhibited VSMC proliferation and induced cell death to a greater extent than PROLI/NO. However, the DPTA/NO nanofiber gel only reduced neointimal hyperplasia by 45% (intima/media [I/M] area ratio, 0.45 ± 0.07), whereas the PROLI/NO nanofiber gel reduced neointimal hyperplasia by 77% (I/M area ratio, 0.19 ± 0.03, P <.05) vs control (injury alone I/M area ratio, 0.83 ± 0.07; P <.05). Both DPTA/NO and PROLI/NO nanofiber gels significantly inhibited proliferation in vivo (1.06 ± 0.30 and 0.19 ± 0.11 vs injury alone, 2.02 ± 0.20, P <.05), yet had minimal effect on apoptosis. Only the PROLI/NO nanofiber gel inhibited inflammation (monocytes and leukocytes). Both NO-releasing nanofiber gels stimulated re-endothelialization. Conclusions: Perivascular application of NO-releasing self-assembling nanofiber gels is an effective and simple therapy to prevent neointimal hyperplasia after arterial injury. Our study demonstrates that the PROLI/NO nanofiber gel most effectively prevented neointimal hyperplasia and resulted in less inflammation than the DPTA/NO nanofiber gel. This therapy has great clinical potential to prevent neointimal hyperplasia after open vascular interventions in patients.

Original languageEnglish
Pages (from-to)173-182
Number of pages10
JournalJournal of Vascular Surgery
Volume47
Issue number1
DOIs
Publication statusPublished - Jan 2008

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Nanotechnology
Hyperplasia
Nitric Oxide
Nanofibers
Gels
Inflammation
Vascular Smooth Muscle
Smooth Muscle Myocytes
Heparin
Wounds and Injuries
Cell Death
Cell Proliferation
Psidium
Carotid Artery Injuries

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Kapadia, M. R., Chow, L. W., Tsihlis, N. D., Ahanchi, S. S., Eng, J. W., Murar, J., ... Kibbe, M. R. (2008). Nitric oxide and nanotechnology: A novel approach to inhibit neointimal hyperplasia. Journal of Vascular Surgery, 47(1), 173-182. https://doi.org/10.1016/j.jvs.2007.09.005

Nitric oxide and nanotechnology : A novel approach to inhibit neointimal hyperplasia. / Kapadia, Muneera R.; Chow, Lesley W.; Tsihlis, Nick D.; Ahanchi, Sadaf S.; Eng, Jason W.; Murar, Jozef; Martinez, Janet; Popowich, Daniel A.; Jiang, Qun; Hrabie, Joseph A.; Saavedra, Joseph E.; Keefer, Larry K.; Hulvat, James F.; Stupp, Samuel I; Kibbe, Melina R.

In: Journal of Vascular Surgery, Vol. 47, No. 1, 01.2008, p. 173-182.

Research output: Contribution to journalArticle

Kapadia, MR, Chow, LW, Tsihlis, ND, Ahanchi, SS, Eng, JW, Murar, J, Martinez, J, Popowich, DA, Jiang, Q, Hrabie, JA, Saavedra, JE, Keefer, LK, Hulvat, JF, Stupp, SI & Kibbe, MR 2008, 'Nitric oxide and nanotechnology: A novel approach to inhibit neointimal hyperplasia', Journal of Vascular Surgery, vol. 47, no. 1, pp. 173-182. https://doi.org/10.1016/j.jvs.2007.09.005
Kapadia, Muneera R. ; Chow, Lesley W. ; Tsihlis, Nick D. ; Ahanchi, Sadaf S. ; Eng, Jason W. ; Murar, Jozef ; Martinez, Janet ; Popowich, Daniel A. ; Jiang, Qun ; Hrabie, Joseph A. ; Saavedra, Joseph E. ; Keefer, Larry K. ; Hulvat, James F. ; Stupp, Samuel I ; Kibbe, Melina R. / Nitric oxide and nanotechnology : A novel approach to inhibit neointimal hyperplasia. In: Journal of Vascular Surgery. 2008 ; Vol. 47, No. 1. pp. 173-182.
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title = "Nitric oxide and nanotechnology: A novel approach to inhibit neointimal hyperplasia",
abstract = "Objective: Nitric oxide (NO) has been shown to inhibit neointimal hyperplasia after arterial interventions in several animal models. To date, however, NO-based therapies have not been used in the clinical arena. Our objective was to combine nanofiber delivery vehicles with NO chemistry to create a novel, more potent NO-releasing therapy that can be used clinically. Thus, the aim of this study was to evaluate the perivascular application of spontaneously self-assembling NO-releasing nanofiber gels. Our hypothesis was that this application would prevent neointimal hyperplasia. Methods: Gels consisted of a peptide amphiphile, heparin, and a diazeniumdiolate NO donor (1-[N-(3-Aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate [DPTA/NO] or disodium 1-[(2-Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate [PROLI/NO]). Nitric oxide release from the gels was evaluated by the Griess reaction, and scanning electron microscopy confirmed nanofiber formation. Vascular smooth muscle cell (VSMC) proliferation and cell death were assessed in vitro by 3H-thymidine incorporation and Personal Cell Analysis (PCA) system (Guava Technologies, Hayward, Calif). For the in vivo work, gels were modified by reducing the free-water content. Neointimal hyperplasia after periadventitial gel application was evaluated using the rat carotid artery injury model at 14 days (n = 6 per group). Inflammation and proliferation were examined in vivo with immunofluorescent staining against CD45, ED1, and Ki67 at 3 days (n = 2 per group), and graded by blinded observers. Endothelialization was assessed by Evans blue injection at 7 days (n = 3 per group). Results: Both DPTA/NO and PROLI/NO, combined with the peptide amphiphile and heparin, formed nanofiber gels and released NO for 4 days. In vitro, DPTA/NO inhibited VSMC proliferation and induced cell death to a greater extent than PROLI/NO. However, the DPTA/NO nanofiber gel only reduced neointimal hyperplasia by 45{\%} (intima/media [I/M] area ratio, 0.45 ± 0.07), whereas the PROLI/NO nanofiber gel reduced neointimal hyperplasia by 77{\%} (I/M area ratio, 0.19 ± 0.03, P <.05) vs control (injury alone I/M area ratio, 0.83 ± 0.07; P <.05). Both DPTA/NO and PROLI/NO nanofiber gels significantly inhibited proliferation in vivo (1.06 ± 0.30 and 0.19 ± 0.11 vs injury alone, 2.02 ± 0.20, P <.05), yet had minimal effect on apoptosis. Only the PROLI/NO nanofiber gel inhibited inflammation (monocytes and leukocytes). Both NO-releasing nanofiber gels stimulated re-endothelialization. Conclusions: Perivascular application of NO-releasing self-assembling nanofiber gels is an effective and simple therapy to prevent neointimal hyperplasia after arterial injury. Our study demonstrates that the PROLI/NO nanofiber gel most effectively prevented neointimal hyperplasia and resulted in less inflammation than the DPTA/NO nanofiber gel. This therapy has great clinical potential to prevent neointimal hyperplasia after open vascular interventions in patients.",
author = "Kapadia, {Muneera R.} and Chow, {Lesley W.} and Tsihlis, {Nick D.} and Ahanchi, {Sadaf S.} and Eng, {Jason W.} and Jozef Murar and Janet Martinez and Popowich, {Daniel A.} and Qun Jiang and Hrabie, {Joseph A.} and Saavedra, {Joseph E.} and Keefer, {Larry K.} and Hulvat, {James F.} and Stupp, {Samuel I} and Kibbe, {Melina R.}",
year = "2008",
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doi = "10.1016/j.jvs.2007.09.005",
language = "English",
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pages = "173--182",
journal = "Journal of Vascular Surgery",
issn = "0741-5214",
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TY - JOUR

T1 - Nitric oxide and nanotechnology

T2 - A novel approach to inhibit neointimal hyperplasia

AU - Kapadia, Muneera R.

AU - Chow, Lesley W.

AU - Tsihlis, Nick D.

AU - Ahanchi, Sadaf S.

AU - Eng, Jason W.

AU - Murar, Jozef

AU - Martinez, Janet

AU - Popowich, Daniel A.

AU - Jiang, Qun

AU - Hrabie, Joseph A.

AU - Saavedra, Joseph E.

AU - Keefer, Larry K.

AU - Hulvat, James F.

AU - Stupp, Samuel I

AU - Kibbe, Melina R.

PY - 2008/1

Y1 - 2008/1

N2 - Objective: Nitric oxide (NO) has been shown to inhibit neointimal hyperplasia after arterial interventions in several animal models. To date, however, NO-based therapies have not been used in the clinical arena. Our objective was to combine nanofiber delivery vehicles with NO chemistry to create a novel, more potent NO-releasing therapy that can be used clinically. Thus, the aim of this study was to evaluate the perivascular application of spontaneously self-assembling NO-releasing nanofiber gels. Our hypothesis was that this application would prevent neointimal hyperplasia. Methods: Gels consisted of a peptide amphiphile, heparin, and a diazeniumdiolate NO donor (1-[N-(3-Aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate [DPTA/NO] or disodium 1-[(2-Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate [PROLI/NO]). Nitric oxide release from the gels was evaluated by the Griess reaction, and scanning electron microscopy confirmed nanofiber formation. Vascular smooth muscle cell (VSMC) proliferation and cell death were assessed in vitro by 3H-thymidine incorporation and Personal Cell Analysis (PCA) system (Guava Technologies, Hayward, Calif). For the in vivo work, gels were modified by reducing the free-water content. Neointimal hyperplasia after periadventitial gel application was evaluated using the rat carotid artery injury model at 14 days (n = 6 per group). Inflammation and proliferation were examined in vivo with immunofluorescent staining against CD45, ED1, and Ki67 at 3 days (n = 2 per group), and graded by blinded observers. Endothelialization was assessed by Evans blue injection at 7 days (n = 3 per group). Results: Both DPTA/NO and PROLI/NO, combined with the peptide amphiphile and heparin, formed nanofiber gels and released NO for 4 days. In vitro, DPTA/NO inhibited VSMC proliferation and induced cell death to a greater extent than PROLI/NO. However, the DPTA/NO nanofiber gel only reduced neointimal hyperplasia by 45% (intima/media [I/M] area ratio, 0.45 ± 0.07), whereas the PROLI/NO nanofiber gel reduced neointimal hyperplasia by 77% (I/M area ratio, 0.19 ± 0.03, P <.05) vs control (injury alone I/M area ratio, 0.83 ± 0.07; P <.05). Both DPTA/NO and PROLI/NO nanofiber gels significantly inhibited proliferation in vivo (1.06 ± 0.30 and 0.19 ± 0.11 vs injury alone, 2.02 ± 0.20, P <.05), yet had minimal effect on apoptosis. Only the PROLI/NO nanofiber gel inhibited inflammation (monocytes and leukocytes). Both NO-releasing nanofiber gels stimulated re-endothelialization. Conclusions: Perivascular application of NO-releasing self-assembling nanofiber gels is an effective and simple therapy to prevent neointimal hyperplasia after arterial injury. Our study demonstrates that the PROLI/NO nanofiber gel most effectively prevented neointimal hyperplasia and resulted in less inflammation than the DPTA/NO nanofiber gel. This therapy has great clinical potential to prevent neointimal hyperplasia after open vascular interventions in patients.

AB - Objective: Nitric oxide (NO) has been shown to inhibit neointimal hyperplasia after arterial interventions in several animal models. To date, however, NO-based therapies have not been used in the clinical arena. Our objective was to combine nanofiber delivery vehicles with NO chemistry to create a novel, more potent NO-releasing therapy that can be used clinically. Thus, the aim of this study was to evaluate the perivascular application of spontaneously self-assembling NO-releasing nanofiber gels. Our hypothesis was that this application would prevent neointimal hyperplasia. Methods: Gels consisted of a peptide amphiphile, heparin, and a diazeniumdiolate NO donor (1-[N-(3-Aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate [DPTA/NO] or disodium 1-[(2-Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate [PROLI/NO]). Nitric oxide release from the gels was evaluated by the Griess reaction, and scanning electron microscopy confirmed nanofiber formation. Vascular smooth muscle cell (VSMC) proliferation and cell death were assessed in vitro by 3H-thymidine incorporation and Personal Cell Analysis (PCA) system (Guava Technologies, Hayward, Calif). For the in vivo work, gels were modified by reducing the free-water content. Neointimal hyperplasia after periadventitial gel application was evaluated using the rat carotid artery injury model at 14 days (n = 6 per group). Inflammation and proliferation were examined in vivo with immunofluorescent staining against CD45, ED1, and Ki67 at 3 days (n = 2 per group), and graded by blinded observers. Endothelialization was assessed by Evans blue injection at 7 days (n = 3 per group). Results: Both DPTA/NO and PROLI/NO, combined with the peptide amphiphile and heparin, formed nanofiber gels and released NO for 4 days. In vitro, DPTA/NO inhibited VSMC proliferation and induced cell death to a greater extent than PROLI/NO. However, the DPTA/NO nanofiber gel only reduced neointimal hyperplasia by 45% (intima/media [I/M] area ratio, 0.45 ± 0.07), whereas the PROLI/NO nanofiber gel reduced neointimal hyperplasia by 77% (I/M area ratio, 0.19 ± 0.03, P <.05) vs control (injury alone I/M area ratio, 0.83 ± 0.07; P <.05). Both DPTA/NO and PROLI/NO nanofiber gels significantly inhibited proliferation in vivo (1.06 ± 0.30 and 0.19 ± 0.11 vs injury alone, 2.02 ± 0.20, P <.05), yet had minimal effect on apoptosis. Only the PROLI/NO nanofiber gel inhibited inflammation (monocytes and leukocytes). Both NO-releasing nanofiber gels stimulated re-endothelialization. Conclusions: Perivascular application of NO-releasing self-assembling nanofiber gels is an effective and simple therapy to prevent neointimal hyperplasia after arterial injury. Our study demonstrates that the PROLI/NO nanofiber gel most effectively prevented neointimal hyperplasia and resulted in less inflammation than the DPTA/NO nanofiber gel. This therapy has great clinical potential to prevent neointimal hyperplasia after open vascular interventions in patients.

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