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Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging
KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.ORCID iD: 0000-0002-3699-396X
KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.ORCID iD: 0000-0002-9604-0511
Show others and affiliations
2012 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 13, no 5, 1390-1399 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2012. Vol. 13, no 5, 1390-1399 p.
Keyword [en]
Ultrasound Contrast Agents, Iron-Oxide Nanoparticles, Active Polymeric Microbubbles, Coated Microbubbles, Acoustic Properties, Induced Fracture, In-Vitro, Part I, Delivery, Shell
National Category
Medical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-96726DOI: 10.1021/bm300099fISI: 000303951600019Scopus ID: 2-s2.0-84861134310OAI: oai:DiVA.org:kth-96726DiVA: diva2:532848
Note

QC 20150626

Available from: 2012-06-12 Created: 2012-06-11 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Ultrasound Contrast Agents Loaded with Magnetic Nanoparticles: Acoustic and Mechanical Characterization
Open this publication in new window or tab >>Ultrasound Contrast Agents Loaded with Magnetic Nanoparticles: Acoustic and Mechanical Characterization
2013 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

The current methodologies in body scanning diagnostic uses different simultaneous imaging modalities like Ultrasound (US), magnetic resonance imaging (MRI), single photon emission tomography (SPECT) and positron emission tomography (PET). The field requires combination of different modalities for effective use in clinical diagnostics. Such incorporation of different modalities has already been achieved. For example, PET-CT hybrid scanner is designed to acquire align functional and anatomical images and recently US-MRI scanner has successfully shown to improve diagnosis of prostate cancer. The non ionizing radiation hybrid US-MRI is of great interest in health care industry. Further these US and MRI modalities uses different contrast agents like micro-sized gas bubbles (MBs) encapsulated by surfactant for US and superparamagnetic nanoparticles for MRI imaging modalities to further enables new diagnostic opportunities and therapeutic applications. Recently in our 3MiCRON project, we have developed the multimodal contrast agent that could be supported for both US and MRI. This was achieved by coating the magnetic nanoparticles to the poly vinyl alcohol (PVA) surfactant shelled MBs. The nanoparticles in the shell effect the structure can alter the MBs performance as an ultrasound contrast agent. The present thesis is conducted to examine the acoustic and mechanical properties of such multimodal contrast agents.

These multimodal contrast agents were prepared by coating the surface of PVA-shelled MBs by two following strategies: (1) The superparamagnetic iron oxide (Fe3O4) nano-particles (SPIONs) were chemically anchored to the surface of poly vinyl alcohol (PVA) shelled MBs namely MBs-chem and (2) in the second strategy the SPIONs were physical entrapped into the PVA shell while formation of PVA surface on the gas bubble were named as MBs-phys. To understand the scattering efficiency and viscoelastic properties of these modified agents, we investigated the backscattering power, attenuation coefficient and phase velocity measurements. Our acoustic experimental results indicate that both the modified MBs and non-modified plain PVA-shelled ultrasound contrast agents have the same echogenic response. The investigation of mechanical properties of modified MBs revealed that the attached SPIONs on the PVA shell has reduced the stiffness of MBs-chem shell, while, the SPIONs inside the shell has increased MBs-phys stiffness. As a result, MBs-chem exhibits soft shell behavior under ultrasound exposure than both MBs-phys. Finally, the images were obtained through the MRI investigations at the department of Radiology, Karolinksa Institute, has demonstrated that both MB types have enough magnetic susceptibility that further provides good detectability in vitro and in vivo. As an outlook, the modified magnetic gas bubbles, i.e. both MBs-chem and MBs-phys can be proposed as a potential contrast agent for both US and MR imaging and can be further utilized in potential therapeutic applications.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2013. viii, 40 p.
Series
Trita-STH : report, ISSN 1653-3836 ; 2013:6
Keyword
Ultrasound contrast agents, SPION nanoparticles, harmonic oscillation, backscattering power, attenuation coefficient, phase velocity, nonlinear equation of motion
National Category
Medical Engineering
Identifiers
urn:nbn:se:kth:diva-134616 (URN)978-91-7501-951-2 (ISBN)
Presentation
2013-12-06, Room 7B, Alfred Nobels Allé 8 Flemingsberg, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20131126

Available from: 2013-11-26 Created: 2013-11-26 Last updated: 2013-11-26Bibliographically approved
2. Nano-Engineered Contrast Agents: Toward Multimodal Imaging and Acoustophoresis
Open this publication in new window or tab >>Nano-Engineered Contrast Agents: Toward Multimodal Imaging and Acoustophoresis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diagnostic ultrasound (US) is safer, quicker and cheaper than other diagnostic imaging modalities. Over the past two decades, the applications of US imaging has been widened due to the development of injectable, compressible and encapsulated microbubbles (MBs) that provide an opportunity to improve conventional echocardiographic imaging, blood flow assessment and molecular imaging. The encapsulating material is manufactured by different biocompatible materials such as proteins, lipids or polymers. In current research, researchers modify the encapsulated shell with the help of advanced molecular chemistry techniques to load them with dyes (for fluorescent imaging), nanoparticles and radioisotopes (for multimodal imaging) or functional ligands or therapeutic gases (for local drug delivery). The echogenicity and the radial oscillation of MBs is the result of their compressibility, which undoubtedly varies with the encapsulated shell characteristics such as rigidity or elasticity.

In this thesis, we present acoustic properties of novel type of polyvinyl alcohol (PVA)-shelled microbubble (PVA-MB) that was further modified with superparamagnetic iron oxide nanoparticles (SPIONs) to work as a dual-modal contrast agent for magnetic resonance (MR) imaging along with US imaging. Apparently, the shell modification changes their mechanical characteristics, which affects their acoustic properties. The overall objective of the thesis is to investigate the acoustic properties of modified and unmodified PVA-MBs at different ultrasound parameters.

The acoustic and mechanical characterization of SPIONs modified PVA-MBs revealed that the acoustical response depends on the SPION inclusion strategy. However they retain the same structural characteristics after the modification. The modified MBs with SPIONs included on the surface of the PVA shell exhibit a soft-shelled behavior and produce a higher echogenicity than the MBs with the SPIONs inside the PVA shell. The fracturing mechanism of the unmodified PVA-MBs was identified to be different from the other fracturing mechanisms of conventional MBs. With the interaction of high-pressure bursts, the air gas core is squeezed out through small punctures in the PVA shell. During the fracturing, the PVA-MBs exhibit asymmetric (other modes) oscillations, resulting in sub- and ultra-harmonic generation. Exploiting the US imaging at the other modes of the oscillation of the PVA-MBs would provide an opportunity to visualize very low concentrations of (down to single) PVA-MBs. We further introduced the PVA-MBs along with particles mimicking red blood cells in an acoustic standing-wave field to observe the acoustic radiation force effect. We observed that the compressible PVA-MBs drawn toward pressure antinode while the solid blood phantoms moved toward the pressure node. This acoustic separation method (acoustophoresis) could be an efficient tool for studying the bioclearance of the PVA-MBs in the body, either by collecting blood samples (in-vitro) or by using the extracorporeal medical procedure (ex-vivo) at different organs.

Overall, this work contributes significant feedback for chemists (to optimize the nanoparticle inclusion) and imaging groups (to develop new imaging sequences), and the positive findings pave new paths and provide triggers to engage in further research. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. x, 53 p.
Series
TRITA-STH : report, ISSN 1653-3836 ; 2015:5
Keyword
Nano-engineered microbubbles, SPION nanoparticles, Acoustic characterization of MBs, Fracturing mechanism of MBs, Opto-acoustics, Acoustophoresis
National Category
Medical Laboratory and Measurements Technologies Medical Image Processing Nano Technology Signal Processing Polymer Technologies
Research subject
Physics; Järnvägsgruppen - Ljud och vibrationer; Technology and Health
Identifiers
urn:nbn:se:kth:diva-172397 (URN)978-91-7595-648-0 (ISBN)
Public defence
2015-09-22, 3221, Alfred Nobels Álle 8, Hudding, 09:00 (English)
Opponent
Supervisors
Projects
3MiCRON
Funder
EU, FP7, Seventh Framework Programme, 245572
Note

QC 20150827

Available from: 2015-08-26 Created: 2015-08-20 Last updated: 2015-08-27Bibliographically approved
3. Structural studies of microbubbles and molecular chaperones using transmission electron microscopy
Open this publication in new window or tab >>Structural studies of microbubbles and molecular chaperones using transmission electron microscopy
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultrasound contrast agents (CAs) are typically used in clinic for perfusion studies (blood flow through a specific region) and border delineating (differentiate borders between tissue structures) during cardiac imaging. The CAs used during ultrasound imaging usually consist of gas filled microbubbles (MBs) (diameter 1-5 μm) that are injected intravenously into the circulatory system. This thesis partially involves a novel polymer-shelled ultrasound CA that consists of air filled MBs stabilized by a polyvinyl alcohol (PVA) shell. These MBs could be coupled with superparamagnetic iron oxide nanoparticles (SPIONs) in order to serve as a combined CA for ultrasound and magnetic resonance imaging. The first three papers (Paper A-C) in this thesis investigate the structural characteristic and the elimination process of the CA.

In Paper A, two types (PVA Type A and PVA Type B) of the novel CA were analyzed using transmission electron microscopy (TEM) images of thin sectioned MBs. The images demonstrated that the SPIONs were either attached to the PVA shell surface (PVA Type A) or embedded in the shell (PVA Type B). The average shell thickness of the MBs was determined in Paper B by introducing a model that calculated the shell thickness from TEM images of cross-sectioned MBs. The shell thickness of PVA Type A was determined to 651 nm, whereas the shell thickness of PVA Type B was calculated to 637 nm. In Paper C, a prolonged blood elimination time was obtained for PVA-shelled MBs compared to the lipid-shelled CA SonoVue used in clinic. In addition, TEM analyzed tissue sections showed that the PVA-shelled MBs were recognized by the macrophage system. However, structurally intact MBs were still found in the circulation 24 h post injection. These studies illustrate that the PVA-shelled MBs are stable and offer large chemical variability, which make them suitable as CA for multimodal imaging.

This thesis also involves studies (Paper D-E) of the molecular chaperones (Hsp21 and DNAJB6). The small heat shock protein Hsp21 effectively protects other proteins from unfolding and aggregation during stress. This chaperone ability requires oligomerization of the protein. In Paper D, cryo-electron microscopy together with complementary structural methods, obtained a structure model which showed that the Hsp21 dodecamer (12-mer) is kept together by paired C-terminal interactions.The human protein DNAJB6 functions as a very efficient suppressor of polyglutamine (polyQ) and amyloid-β42 (Aβ42) aggregation. Aggregation of these peptides are associated with development of Huntington’s (polyQ) and Alzheimer’s (Aβ42) disease. In Paper E, a reconstructed map of this highly dynamic protein is presented, showing an oligomer with two-fold symmetry, indicating that the oligomers are assembled by two subunits.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. xiii, 58 s p.
Series
TRITA-STH : report, ISSN 1653-3836 ; 2016:3
Keyword
Transmission electron microscopy, Contrast agent, Microbubble, Polyvinyl alcohol, Single particle analysis, Heat shock protein, Molecular chaperone
National Category
Structural Biology
Research subject
Technology and Health
Identifiers
urn:nbn:se:kth:diva-186882 (URN)978-91-7729-020-9 (ISBN)
Public defence
2016-06-08, Hörsalen plan 4 Novum, Blickagången 6, 141 57, Huddinge, 10:00 (English)
Opponent
Supervisors
Note

QC 20160527

Available from: 2016-05-27 Created: 2016-05-16 Last updated: 2016-05-27Bibliographically approved

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Grishenkov, DmitryHärmark, JohanHebert, Hans

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