| 1. |
- Ahmed, Mona, et al.
(författare)
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Cellular Uptake of Plain and SPION-Modified Microbubbles for Potential Use in Molecular Imaging
- 2017
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Ingår i: Cellular and Molecular Bioengineering. - : SPRINGER. - 1865-5025 .- 1865-5033. ; 10:6, s. 537-548
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Tidskriftsartikel (refereegranskat)abstract
- Both diagnostic ultrasound (US) and magnetic resonance imaging (MRI) accuracy can be improved by using contrast enhancement. For US gas-filled microbubbles (MBs) or silica nanoparticles (SiNPs), and for MRI superparamagnetic or paramagnetic agents, contribute to this. However, interactions of MBs with the vascular wall and cells are not fully known for all contrast media. We studied the in vitro interactions between three types of non-targeted air-filled MBs with a polyvinyl-alcohol shell and murine macrophages or endothelial cells. The three MB types were plain MBs and two types that were labelled (internally and externally) with superparamagnetic iron oxide nanoparticles (SPIONs) for US/MRI bimodality. Cells were incubated with MBs and imaged by microscopy to evaluate uptake and adhesion. Interactions were quantified and the MB internalization was confirmed by fluorescence quenching of non-internalized MBs. Macrophages internalized each MB type within different time frames: plain MBs 6 h, externally labelled MBs 25 min and internally labelled MBs 2 h. An average of 0.14 externally labelled MBs per cell were internalized after 30 min and 1.34 after 2 h; which was 113% more MBs than the number of internalized internally labelled MBs. The macrophages engulfed these three differently modified new MBs at various rate, whereas endothelial cells did not engulf MBs. Polyvinyl-alcohol MBs are not taken up by endothelial cells. The MB uptake by macrophages is promoted by SPION labelling, in particular external such, which may be important for macrophage targeting.
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| 2. |
- 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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| 3. |
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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Acoustic properties of polymer-shelled ultrasound contrast agents. Bulk volume vs. microcapillary
- 2009
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Ingår i: 16th International Congress on Sound and Vibration 2009, ICSV 2009. - Krakow. - 9781615677368 ; , s. 2515-2522
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Konferensbidrag (refereegranskat)abstract
- The focus of contrast-enhanced ultrasound research has developed beyond detecting the blood pool to new areas such as perfusion imaging, drug and gene therapy, and targeted imaging. Polymer-shelled microbubbles are proposed as a new generation of ultrasound contrast agents (UCAs) which fulfil the requirements of these applications. With a shelf-life of several months and possibility to conjugate pharmacological molecules to their surface, these UCAs will allow not only to enhance the contrast of ultrasound images, but also to function as carriers of drugs to be delivered locally. In this study, the results of an experimental investigation of three types of UCAs stabilized by thick poly vinyl alcohol (PVA) shell are presented. These UCAs are synthesized from a PVA aqueous solution under varied pH values and temperature. The UCAs differ from each other in their average diameter, shell thickness and polydispersity. Knowledge of the peak negative pressure at which the solid shell fractures is paramount for a proper use of UCAs. Therefore, the dependence of this quantity on temperature and number of cycles in the incident pulse is examined. Much of the blood volume resides in the microcirculation, with capillaries playing a particularly important role in patho-physiology and drug delivery. In this sense in vitro characterization of the UCAs oscillation was moved from bulk volume to the capillary scale, where tissue-bubble interaction takes place. The main conclusion to be drawn from these results is that the shell of the UCAs begin to fracture at values of mechanical index (MI) approved for clinical applications. The fatigue, i.e. the accumulation of damage within the shell of the UCAs, is found to play an important role in fracturing the shell. Finally adhesion of the UCAs to the elastic wall is studied and correlated with estimates of the shell’s visco-elastic constants. Open questions arising from this comparison are briefly discussed.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Characterization of acoustic properties of PVA-shelled ultrasound contrast agents : linear properties (Part I)
- 2009
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Ingår i: Ultrasound in Medicine and Biology. - : Elsevier BV. - 0301-5629 .- 1879-291X. ; 35:7, s. 1127-1138
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Tidskriftsartikel (refereegranskat)abstract
- This work examines the linear acoustic behavior of ultrasound contrast agents made of three types of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at different pH and temperature conditions. Back-scattered power, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 degrees C and 37 degrees C in a frequency range from 3 MHz to 13 MHz. Enhancement of the backscattered power higher than 20 dB and displaying a weak dependence on temperature was observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. A modified version of the Church model, which accounts for the dispersion of the dynamic modulus of the PVA shells, was developed to simultaneously fit the attenuation and phase velocity data at 24 degrees C. The frequency dependence of the storage modulus was found to be that of semiflexible polymeric networks. On the other hand, the frequency dependence of the dynamic loss modulus suggests that additional mechanisms, which may be related to the finite dimensions of the shell and/or to its inhomogeneity, may play a significant role in the dissipation of the acoustic energy. For the microbubbles of interest, this model predicts frequency dependent resonance frequency higher than 100 MHz.
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