title: Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevice.
abstract: The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with nitric oxide (NO) for integrated therapeutic and diagnostic applications (ie, theranostics) of myocardial ischemia. We used gas-filled MBs with an average diameter of 4 μm stabilized by a biocompatible shell of polyvinyl alcohol. In vitro acoustic tests showed sufficient enhancement of the backscattered power (20 dB) acquired from the MBs' suspension. The values of attenuation coefficient (0.8 dB/cm MHz) and phase velocities (1,517 m/s) were comparable with those reported for the soft tissue. Moreover, polymer MBs demonstrate increased stability compared with clinically approved contrast agents with a fracture threshold of about 900 kPa. In vitro chemiluminescence measurements demonstrated that dry powder of NO-loaded MBs releases its gas content in about 2 hours following an exponential decay profile with an exponential time constant equal to 36 minutes. The application of high-power ultrasound pulse (mechanical index =1.2) on the MBs resuspended in saline decreases the exponential time constant from 55 to 4 minutes in air-saturated solution and from 17 to 10 minutes in degassed solution. Thus, ultrasound-triggered release of NO is achieved. Cytotoxicity tests indicate that phagocytosis of the MBs by macrophages starts within 6-8 hours. This is a suitable time for initial diagnostics, treatment, and monitoring of the therapeutic effect using a single injection of the proposed multifunctional MBs.
authors.affiliation: Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden ; Department of Medical Engineering, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden ; Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Grishenkov
authors.affiliation: Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden ; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gonon
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Harmark
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cerroni
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Gaio
authors.initials: G
authors.lastname: Paradossi
authors.affiliation: Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden ; Department of Medical Engineering, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden ; Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Janerot-Sjoberg
mesh_terms: D002626:Chemistry, Pharmaceutical; D003287:Contrast Media / Q000009:adverse effects / Q000737:chemistry*; D004864:Equipment and Supplies; D005740:Gases; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects; D045423:Microbubbles; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000188:drug therapy; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology*; D010316:Particle Size; D010587:Phagocytosis; D011208:Powders; D000068936:Theranostic Nanomedicine; D014465:Ultrasonics / Q000379:methods*
chemical_list: D003287:Contrast Media; D005740:Gases; D011208:Powders; D009569:Nitric Oxide
keywords: contrast agent; microbubbles; myocardial ischemia; nitric oxide; ultrasound