| 1. |
- Barrefelt, Åsa, et al.
(författare)
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DYNAMIC MR IMAGING, BIODISTRIBUTION AND PHARMACOKINETICS OF POLYMER SHELLED MICROBUBBLES CONTAINING SPION
- 2014
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Ingår i: NANO. - 1793-2920. ; 9:6, s. 1450069-
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic Resonance Imaging (MRI) is a noninvasive diagnostic method that provides information on morphological and physiological changes of the internal organs over time. Imaging and measurements can be repeated on the same subject, thereby reducing inter-individual variability effects and hence the number of subjects required. A potential MRI contrast agent consisting of microbubbles embedded with superparamagnetic iron oxide nanoparticles (SPION) in the shell (SPION MBs) was injected intravenously into rats to determine their biodistribution and pharmacokinetics using MR imaging. Agarose phantoms containing SPION MBs were scanned using 3 T MRI to construct a standard curve. Rats were injected with SPION MBs, free SPION or plain MBs and scanned dynamically at 3 T using a clinical MR scanner. The relaxation rate (R2*) was studied over time as a measure of the iron oxide concentrations to enable calculation of the pharmacokinetic parameters. The kinetics of SPION MBs in the liver was fitted to a one-compartment model. Furthermore, the biological fate of SPION MBs was examined via a histological survey of tissue samples using Perls' Prussian blue staining and immunohistochemistry (IHC). 1.2 h after injection of SPION MBs, T2* of the liver had decreased to its minimum. The elimination half-life of SPION MBs was 598.2 +/- 97.3 h, while the half-life for SPION was 222.6 +/- 26.4 h. Moreover, our study showed that SPION MBs were taken up by the macrophages in the lungs, spleen and liver. MBs labeled with SPION can be used for MR imaging. Moreover, MRI is a reliable and noninvasive tool that can be utilized in pharmacokinetic investigations of future contrast agents using SPION MBs and SPION in the rat.
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| 2. |
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| 3. |
- Brismar, Torkel B., et al.
(författare)
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Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging
- 2012
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 13:5, s. 1390-1399
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Tidskriftsartikel (refereegranskat)abstract
- Microbubbles (MBs) are commonly used as injectable ultrasound contrast agent (UCA) in modern ultrasonography. Polymer-shelled UCAs present additional potentialities with respect to marketed lipid-shelled UCAs. They are more robust; that is, they have longer shelf and circulation life, and surface modifications are quite easily accomplished to obtain enhanced targeting and local drug delivery. The next generation of UCAs will be required to support not only ultrasound-based imaging methods but also other complementary diagnostic approaches such as magnetic resonance imaging or computer tomography. This work addresses the features of MBs that could function as contrast agents for both ultrasound and magnetic resonance imaging. The results indicate that the introduction of iron oxide nanoparticles (SPIONs) in the poly(vinyl alcohol) shell or on the external surface of the MBs does not greatly decrease the echogenicity of the host MBs compared with the unmodified one. The presence of SPIONs provides enough magnetic susceptibility to the MBs to accomplish good detectability both in vitro and in vivo. The distribution of SPIONs on the shell and their aggregation state seem to be key factors for the optimization of the transverse relaxation rate.
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| 4. |
- Capece, Sabrina, et al.
(författare)
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A general strategy for obtaining biodegradable polymer shelled microbubbles as theranostic devices
- 2013
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Ingår i: Chemical Communications. - 1359-7345 .- 1364-548X. ; 49:51, s. 5763-5765
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Tidskriftsartikel (refereegranskat)abstract
- Fabrication of multifunctional ultrasound contrast agents (UCAs) has been recently addressed by several research groups. A versatile strategy for the synthesis of UCA precursors in the form of biodegradable vesicles with a biocompatible crosslinked polymer shell is described. Upon ultrasound irradiation, acoustic droplet vaporization transforms such particles into microbubbles behaving as UCAs. This proof of concept entails the features of a potential theranostic microdevice.
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| 5. |
- Capese, Sabrina, et al.
(författare)
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A general strategy for the obtainment of biodegradable polymer shelled microbubbles as theranostic device
- 2013
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Konferensbidrag (refereegranskat)abstract
- IntroductionFabrication of multifunctional ultrasound contrast agents (UCAs) has been addressed by many research groups.1,2 Recently a poly(vinyl alcohol) shelled microbubble 3 has shown a remarkable chemical and physical stability and versatility for the surface functionalization, leading to a platform for multimodality imaging (ultrasounds, magnetic resonance, single photon emission computer tomography) and targeting inflammation and tumours4. In this contribution we present a new strategy for the synthesis of UCAs precursors in the form of vesicles with a biodegradable crosslinked polymer shell.MethodsDeposition of methacryloyl-derivative of hydrophilic and biodegradable polymers as dextran (DexMA50) or hyaluronic acid (HAMA30) on a lipid vesicle with a liquid perfluoropentane core, 5,6 followed by a photopolymerization of the methacrylate moiety allows the obtainment of polymer shelled vesicles.ResultsLipid shelled vesicles with a perfluorocarbon (PFC) core (Figure 1a) undergo an acoustic droplet vaporization (ADV),7 upon ultrasounds (US) irradiation, transforming such particles into ultrasound effective microbubbles (Fig 1b). The process is reversible as the US are switched off (Fig 1c). In the “microbubble” state, i.e. during US irradiation, the system is echogenic at low mechanical index, allowing their use as UCAs. In this contribution we show that additional functions can be implemented into the microbubbles. For example, we demonstrated the possibility to obtain shells with a thermoreversible behaviour.ConclusionsThis new class of polymer shelled vesicles/microbubbles entails features desired in a potential theranostic microdevice.
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| 6. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Assessment of ultrasound-induced fracture of polymer-shelled ultrasound contrast agents using superharmonic technique
- 2012
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Konferensbidrag (refereegranskat)abstract
- Ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents. Knowledge of the peak negative pressure at which contrast agents fracture is paramount for the imaging application as well as for local drug delivery. Gasholdning microbubbles encapsulated into biocompatible poly vinyl alcohol shells are of particular interest for their enhanced shelf life and demonstratedchemical versatility. A gas core allows microbubbles to efficiently scatter ultrasound waves. In vitro ultrasound tests showed a sufficient enhancement of the backscattered power (25±1 dB), comparable to the soft tissue attenuation coefficients (0.8±0.04 dB/cm MHz) and phase velocities (1519±2 m/s). At temperature values between 24 and 37 °C the monotonic increase of the attenuation and phase velocity with frequency indicates that thick-shelled microbubbles do not resonate in a typical medical ultrasound frequency range of 1-15 MHz. In fact, they work as an amplifier of the incident acoustic wave. The novel approach based on detection of superharmonics (3f and 4f) is proposed for assessment of the fracture pressure threshold, Pthr. In vitro tests suggests that fatigue, i.e. accumulation of damage within the shell, is the major physical mechanism responsible for the fracturing process. It has been observed that there is a decrease of Pthr from 1.15±0.09 MPa to 0.9±0.05 MPa when the number of cycles in the pulse, N, increases from 6 to 12. It is worth noting that the reported pressure values are within clinically approved safety limits. The main conclusion to be drawn from our study is that superharmonic approach appears to be more sensitive in Pthr assessment than traditional second harmonic imaging. This claim is supported also by images acquired with a commercially available system, where contrast pulse sequencing technique, specific to third harmonic, is required for visualization of thick-shelled microbubbles.
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| 7. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Characterization of Acoustic Properties of PVA-Shelled Ultrasound Contrast Agents
- 2010
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Ingår i: Ultrasound Contrast Agents. - Italia : Springer-Verlag. - 9788847014930 ; , s. 99-108
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This work examines the acoustic behavior of ultrasound contrast agents made of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at three different pH and temperature conditions. Backscattering amplitude, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 oC and 37 oC in a frequency range from 3 MHz to 13 MHz. A significant enhancement of the backscattering amplitude and displaying a weak dependence on temperature were observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. The dependence on system parameters such as the number of cycles, frequency, and exposure of the peak negative pressure, Pthr, at which ultrasound contrast agents fracture was also investigated. The effects of temperature, blood, and, wherever data are available, of the dimension of the microbubbles on Pthr are also considered. The large shell thickness notwithstanding, the results of this investigation show that at room temperature PVA contrast agents fracture at negative peak pressure values within the recommended safety limit. Furthermore, Pthr decreases with increasing temperature, radius of the microbubbles, and number of cycles of the incident wave. In conclusion, these results suggest that PVA-shelled microbubbles may offer a potentially viable system to be employed for both imaging and therapeutic purposes.
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| 8. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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In vitro contrast-enhanced ultrasound measurements of capillary microcirculation : Comparison between polymer- and phospholipid-shelled microbubbles
- 2011
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Ingår i: Ultrasonics. - : Elsevier BV. - 0041-624X .- 1874-9968. ; 51:1, s. 40-48
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Tidskriftsartikel (refereegranskat)abstract
- The focus of contrast-enhanced ultrasound research has developed beyond visualizing the blood pool and its flow to new areas such as perfusion imaging, drug and gene therapy, and targeted imaging. In this work comparison between the application of polymer- and phospholipid-shelled ultrasound contrast agents (UCAs) for characterization of the capillary microcirculation is reported. All experiments are carried out using a microtube as a vessel phantom. The first set of experiments evaluates the optimal concentration level where backscattered signal from microbubbles depends on concentration linearly. For the polymer-shelled UCAs the optimal concentration level is reached at a value of about 2 x 10(4) MB/ml, whereas for the phospholipid-shelled UCAs the optimal level is found at about 1 x 10(5) MB/ml.Despite the fact that the polymer shell occupies 30% of the radius of microbubble, compared to 0.2% of the phospholipid-shelled bubble, approximately 5-fold lower concentration of the polymer UCA is needed for investigation compared to phospholipid-shelled analogues. In the second set of experiments, destruction/replenishment method with varied time intervals ranging from 2 ms to 3 s between destructive and monitoring pulses is employed. The dependence of the peak-to-peak amplitude of backscattered wave versus pulse interval is fitted with an exponential function of the time gamma = A( 1 - exp(-beta t)) where A represents capillary volume and the time constant beta represents velocity of the flow. Taking into account that backscattered signal is linearly proportional to the microbubble concentration, for both types of the UCAs it is observed that capillary volume is linearly proportional to the concentration of the microbubbles, but the estimation of the flow velocity is not affected by the change of the concentration. Using the single capillary model, for the phospholipid-shelled UCA a delay of about 0.2-0.3 s in evaluation of the perfusion characteristics is found while polymer-shelled UCA provide response immediately. The latter at the concentration lower than 3.6 x 10(5) MB/ml have no statistically significant delay (p < 0.01), do not cause any attenuation of the backscattered signal or saturation of the receiving part of the system. In conclusion, these results suggest that the novel polymer-shelled microbubbles have a potential to be used for perfusion evaluation.
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| 9. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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On comparison between polymer- and phospholipid-shelled microbubbles for contrast-enhanced ultrasound measurements of capillary microcirculation.
- 2011
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Ingår i: Proceedings of the 34<sup>th</sup> Scandinavian Symposium on Physical Acoustics.
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Konferensbidrag (refereegranskat)abstract
- The focus of contrast-enhanced ultrasound research has developed beyond visualizing the blood circulation to new areas such as perfusion and molecular imaging, drug and gene therapy. This work compares the application of polymer- and phospholipid-shelled ultrasound contrast agents (UCAs) employed for characterization of the capillary microcirculation. To quantify microcirculation destruction/replenishment technique with varied time intervals between destructive and monitoring pulses is used. The dependence of the peak-to-peak amplitude of backscattered wave versus pulse interval is fitted with an exponential function of the time y=A(1-exp(-βt)) , where A represents capillary volume and the time constant β represents velocity of the flow. Working under assumption that backscattered signal is linearly proportional to the microbubble concentration, for both types of the UCAs it is observed that capillary volume, A, is in linearly relationship with the concentration, and the flow velocity, β, remain unchanged. Using 500 µm diameter microtube as a vessel phantom a delay of about 0.25 s in evaluation of the perfusion characteristics is found for the phospholipid-shelled UCA, while polymer-shelled UCA provide response immediately. In conclusion, these results suggest that the novel polymer-shelled microbubbles have a potential to be used for perfusion evaluation.
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| 10. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevise for myocardial ischemia
- 2013
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Ingår i: European Heart Journal Cardiovascular Imaging.
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Konferensbidrag (refereegranskat)abstract
- Cardiovascular disease (CVD) accounts for 1/3 of total global deaths worldwide. The most widespread CVD is ischemic heart disease. It is the leading cause of death in both genders, equally diagnosed in developed and developing countries with mortality exponentially increasing with age. Efforts of healthcare system should be primary focused on prevention, timely detection, efficient differentiation and instant treatment of the disease.
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