Theranostic Trigger‐Responsive Carbon Monoxide‐Generating Microbubbles

Small, vol. 18, pp. e2200924

Abstract

Carbon monoxide (CO) is a gaseous signaling molecule that modulates inflammation, cell survival, and recovery after myocardial infarction. However, handling and dosing of CO as a compressed gas are difficult. Here, light-triggerable and magnetic resonance imaging (MRI)-detectable CO release from dimanganese decacarbonyl (CORM-1) are demonstrated, and the development of CORM-1-loaded polymeric microbubbles (COMB) is described as an ultrasound (US)- and MRI-imageable drug delivery platform for triggerable and targeted CO therapy. COMB are synthesized via a straightforward one-step loading protocol, present a narrow size distribution peaking at 2 µm, and show excellent performance as a CORM-1 carrier and US contrast agent. Light irradiation of COMB induces local production and release of CO, as well as enhanced longitudinal and transversal relaxation rates, enabling MRI monitoring of CO delivery. Proof-of-concept studies for COMB-enabled light-triggered CO release show saturation of hemoglobin with CO in human blood, anti-inflammatory differentiation of macrophages, reduction of hypoxia-induced reactive oxygen species (ROS) production, and inhibition of ischemia-induced apoptosis in endothelial cells and cardiomyocytes. These findings indicate that CO-generating MB are interesting theranostic tools for attenuating hypoxia-associated and ROS-mediated cell and tissue damage in cardiovascular disease.

Authors 14

1. Vertika Pathak Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

2. Karolin Roemhild Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

   Institute of Pathology Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

3. Nicolas Groß‐Weege Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

4. Teresa Nolte Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

5. Stephan Ruetten Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Electron Microscopy Institute of Pathology Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

6. Eva Miriam Buhl Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Electron Microscopy Institute of Pathology Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

7. Asmaa El Shafei Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

8. Marek Weiler Aachen

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

9. Lukas Märtin Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Intensive Care Medicine Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

10. Gernot Marx Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Intensive Care Medicine Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

11. Volkmar Schulz Aachen

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

12. Fabian M. Kiessling corresponding Aachen

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

13. Twan Lammers corresponding Aachen

    Utrecht University · RWTH Aachen University · University of Twente

    Affiliation as printed

    Department of Pharmaceutics Utrecht University Utrecht 3584CG The Netherlands

    Department of Targeted Therapeutics University of Twente Enschede 7522 NB The Netherlands

    Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

    Department of Pharmaceutics, Utrecht University, Utrecht, 3584CG The Netherlands

    Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

14. Patrick Koczera corresponding Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Intensive Care Medicine Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany

    Institute for Experimental Molecular Imaging Medical Faculty Rheinisch‐Westfälische Technische Hochschule (RWTH) Aachen University Clinic 52074 Aachen Germany