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L'articolo prende spunto da un sogno, nel quale gli abitanti si trovano in un mondo improvvisamente spaccato in due, isolati gli uni dagli altri, per effetto di un cataclisma naturale. Come l'autrice cerca di evidenziare, la crescente tendenza della società occidentale contemporanea verso i processi dissociativi appare collegata alla dinamica di opposizione psichica fra naturale e artificiale, individuo e cosmo, soggetto e comunità.Il taglio, la scissione tra mondi, spazio interno e esterno, sono espressione di un paradigma economico volto al controllo, all'utile, al vantaggio competitivo, che nega il nesso di corrispondenza fra la sfera naturale e spirituale, politica e sociale. La coscienza individuale e collettiva, chiusa nella propria autoreferenzialità, sempre più incapace di integrare i contenuti dell'alterità e molteplicità, è soggetta a processi di scissione psichica, all'attivazione di emozioni, fantasie inconsce: ossessioni identitarie, fanatismi persecutori, infezioni psichiche. Si tratta, invece, di interrogarsi sulle possibilità di azione e collaborazione sociale e politica, di creatività psichica, là dove l'umano, il vivente, l'organico e l'inorganico si imprimono, si fanno natura e storia in una dinamica trasformativa, tra contraddizioni e generazioni.

Adhesion is a key process when ultrasound contrast agents, i.e. microbubbles, approach pathological tissues. A way to accomplish tumour targeting is to tether surface engineered microbubbles to endothelial cells of the up-regulated vascularization of cancer tissues. This can be achieved by coupling the microbubbles surface with the Arginine-Glycine-Aspartate, RGD, sequence. Such molecule interacts with the integrin receptors placed on the endothelial cells. Stability and trajectories of RGD modified lipid shelled MBs have been analysed in vitro using microchannels coated with human umbilical vein endothelial cells, HUVEC. In the microchannels realistic conditions, close to the physiological ones, were reproduced replicating shear rate, roughness comparable to the endothelium and channel size mimicking the postcapillary venules. In these conditions, the analysis of the trajectories close to the walls highlights a substantial difference between the modified MBs and the plain ones. Moreover, MBs adhesion has dynamic features recalling the motion of neutrophils engaged near the substrate such as rolling, translations and transient detachments. These findings are useful for the optimization of in vivo imaging and targeting functions.

Purpose: We investigate the vaporization of phase-change ultrasound contrast agents using photon radiation for dosimetry perspectives in radiotherapy. Methods: We studied superheated perfluorobutane nanodroplets with a crosslinked poly(vinylalcohol) shell. The nanodroplets’ physico-chemical properties, and their acoustic transition have been assessed firstly. Then, poly (vinylalcohol)-perfluorobutane nanodroplets were dispersed in poly(acrylamide) hydrogel phantoms and exposed to a photon beam. We addressed the effect of several parameters influencing the nanodroplets radiation sensitivity (energy/delivered dose/dose rate/temperature). The nanodroplets-vaporization post-photon exposure was evaluated using ultrasound imaging at a low mechanical index. Results: Poly(vinylalcohol)-perfluorobutane nanodroplets show a good colloidal stability over four weeks and remain highly stable at temperatures up to 78 ◦C. Nanodroplets acoustically-triggered phase transition leads to microbubbles with diameters

Significant improvement of phase-change perfluorocarbon microdroplets (MDs) in the vast theranostic scenario passes through the optimization of the MDs composition with respect to synthesis efficiency, stability, and drug delivery capability. To this aim, decafluoropentane (DFP) MDs stabilized by a shell of dimethyldioctadecylammonium bromide (DDAB) cationic surfactant were designed. A high concentration of DDAB-MDs was readily obtained within a few seconds by pulsed high-power insonation, resulting in low polydisperse 1 µm size droplets. Highly positive ζ-potential, together with a long, saturated hydrocarbon chains of the DDAB shell, are key factors to stabilize the droplet and the drug cargo therein. The high affinity of the DDAB shell with cell plasma membrane allows for localized chemotherapeutics delivery by increasing the drug concentration at the tumor cell interface and boosting the uptake. This would turn DDAB-MDs into a relevant drug delivery tool exhibiting high antitumor activity at very low drug doses. In this work, the efficacy of such an approach is shown to dramatically improve the effect of doxorubicin against 3D spheroids of mammalian tumor cells, MDA-MB-231. The use of three-dimensional (3D) cell cultures developed in the form of multicellular tumor spheroids (i.e., densely packed cells in a spherical shape) has numerous advantages compared to 2D cell cultures: in addition to have the potential to bridge the gap between conventional in vitro studies and animal testing, it will improve the ability to perform more predictive in vitro screening assays for preclinical drug development or evaluate the potential of off-label drugs and new co-targeting strategies.

Poly(N-isopropylacrylamide) (PNIPAM) hydrogel microparticles with different core&ndash, shell morphologies have been designed, while maintaining an unvaried chemical composition: a morphology with (i) an un-crosslinked core with a crosslinked shell of PNIPAM chains and (ii) PNIPAM chains crosslinked to form the core with a shell consisting of tethered un-crosslinked PNIPAM chains to the core. Both morphologies with two different degrees of crosslinking have been assessed by confocal microscopy and tested with respect to their temperature responsivity and deformation by applying an osmotic stress. The thermal and mechanical behavior of these architectures have been framed within a Flory&ndash, Rehner modified model in order to describe the microgel volume shrinking occurring as response to a temperature increase or an osmotic perturbation. This study provides a background for assessing to what extent the mechanical features of the microgel particle surface affect the interactions occurring at the interface of a microgel particle with a cell, in addition to the already know ligand/receptor interaction. These results have direct implications in triggering a limited phagocytosis of microdevices designed as injectable drug delivery systems.

Microbubbles are a well-established contrast agent which improves diagnostic ultrasound imaging. During the last decade research has focused on expanding their use to include molecular imaging, targeted therapy and imaging modalities other than ultrasound. However, bioadhesion of targeted microbubbles under physiological flow conditions is still difficult to achieve, the main challenge being connected to the poor stability of lipid microbubbles in the body's circulation system. In this article, we investigate the use of polymeric microbubbles based on a poly (vinyl alcohol) shell as an alternative to lipid microbubbles. In particular, we report on the development of microbubble shell modification, using mild reaction conditions, with the aim of designing a multifunctional platform to enable diagnosis and therapy. Superparamagnetic iron oxide nanoparticles and a near infrared fluorescent probe, indocyanine green, are coupled to the bubbles surface in order to support magnetic resonance and fluorescence imaging. Furthermore, anchoring cyclic arginyl-glycyl-aspartic acid (RGD) peptide, and cyclodextrin molecules, allows targeting and drug loading, respectively. Last but not least, shell topography is provided by atomic force microscopy. These applications and features, together with the high echogenicity of poly (vinyl alcohol) microbubbles, may offer a more stable alternative to lipid microbubbles for the development of a multimodal theranostic platform.

Maximal resection of intrinsic brain tumors is a major prognostic factor for survival. Real-time intraoperative imaging tools, including ultrasound (US), are crucial for maximal resection of such tumors. Microbubbles (MBs) are clinically used in daily practice as a contrast agent for ultrasound and can be further developed to serve combined therapeutic and diagnostic purposes. To achieve this goal, we have developed novel MBs conjugated to specific ligands to receptors which are overexpressed in brain tumors. These MBs are designed to target a tumor tissue, visualize it, and deliver therapeutic molecules into it. The objective of this study was to assess the biodistribution of the test items: We used MBs labeled with indocyanine green (MB-ICG) for visualization and MBs conjugated to a cyclic molecule containing the tripeptide Arg-Gly-Asp (RGD) labeled with ICG (MB-RGD-ICG) to target brain tumor integrins as the therapeutic tools. Male Sprague Dawley rats received a single dose of each MB preparation. The identification of the MB in various organs was monitored by fluorescence microscopy in anesthetized animals as well as real-time US for brain imaging. Equally sized control groups under identical conditions were used in this study. One control group was used to establish fluorescence background conditions (ICG), and two control groups were used to test autofluorescence from the test items (MBs and MB-RGD). ICG with or without MBs (naked or RGD-modified) was detected in the brain vasculature and also in other organs. The pattern, duration, and intensity of the fluorescence signal could not be differentiated between animals treated with ICG alone and animals treated with microbubbles MBs-ICG or MBs-RGD-ICG. Following MB injection, either naked or combined with RGD, there was a sharp rise in the Doppler signal within seconds of injection in the brain. The signal was mainly located at the choroid plexus, septum pellucidum, and the meninges of the brain. The signal subsided within a few minutes. Injection of saline or ICG alone to respective animals did not result in a similar raised signal. Following a single intravenous administration of MB-ICG and MB-RGD-ICG to rats, the MBs were found to be effectively present in the brain.

Real-time intraoperative imaging for brain tumor surgery is crucial for achieving complete resection. We are developing novel lipid-based microbubbles (MBs), engineered with specific ligands, which are able to interact with the integrins overexpressed in the endothelium of the brain tumor vasculature. These MBs are designed to visualize the tumor and to carry therapeutic molecules into the tumor tissue, preserving the ultrasound acoustic properties of the starting plain lipid MBs. The potential toxicity of this novel technology was assessed in rats by intravenous injections of two doses of plain MBs and MBs engineered for targeting and near-infrared fluorescence visualization at two time-points, 10 min and 7 days, for potential acute and chronic responses in rats [(1) MB, (2) MB-ICG, (3) MB-RGD, and (4) MB-ICG-RGD]. No mortality occurred during the 7-day study period in any of the dosing groups. All animals demonstrated a body weight gain during the study period. Minor, mostly reversible changes in hematological and biochemical analysis were observed in some of the treated animals. All changes were reversible by the 7-day time-point. Histopathology examination in the high-dose animals showed development of foreign body granulomatous inflammation. We concluded that the low-dose tested items appear to be safe. The results allow for proceeding to clinical testing of the product.

Hypothesis One of the main assets of crosslinked polymer-shelled microbubbles (MBs) as ultrasound-active theranostic agents is the robustness of the shells, combined with the chemical versatility in modifying the surface with ligands and/or drugs. Despite the long shelf-life, subtle modifications occur in the MB shells involving shifts in acoustic, mechanical and structural properties. Experiments We carried out a long-term morphological and acoustic evolution analysis on elastomeric polyvinyl-alcohol (PVA)-shelled MBs, a novel platform accomplishing good acoustic and surface performances in one agent. Confocal laser scanning microscopy, acoustic spectroscopy and AFM nanomechanics were integrated to understand the mechanism of PVA MBs ageing. The changes in the MB acoustic properties were framed in terms of shell thickness and viscoelasticity using a linearised oscillation theory, and compared to MB morphology and to nanomechanical analysis. Findings We enlightened a novel, intriguing ageing time evolution of the PVA MBs with double behaviour with respect to a crossover time of ∼50 days. Before, significant changes occur in MB stiffness and shell thickness, mainly due to a massive release of entangled PVA chains. Then, the MB resonance frequency increases together with shell thickening and softening. Our benchmark study is of general interest for emerging viscoelastomeric bubbles towards personalised medicine.

The unique performance of a partially hydrophobic derivative of hyaluronic acid, HYADD4, bearing 2–3 hexadecylic side chains every 100 repeating units, enables hydrogels based on this polymer to be suitably used as a viscosupplement to replace synovial fluid in stressed or injured articular joints. This contribution addresses: i) as to whether there is a self-assembly process driving the HYADD4 hydrogel stabilization and ii) what the characteristics of the long-range dynamics governing the macroscopic viscoelastic behavior are, and to what extent these features are different from those present in the parent polymer (i.e., hyaluronic acid). Mesoscale dynamic and static properties are interpreted in the light of “sticky reptation theory” and evaluated in combination with small-angle neutron scattering results.

Targeted drug delivery is a main issue in cancer treatment. Taking advantage of recently developed polyvinyl alcohol (PVA)-based microbubbles, which are characterized by chemical versatility of the polymeric surface thereby allowing coating with different ligands, we set up a strategy for the targeted delivery of the anticancer agent doxorubicin to hepatocarcinoma cells. Such microbubbles are exceptionally efficient ultrasound scatterers and thus represent also an option as potential ultrasound contrast agents. Moreover, the oscillation of microbubbles induced by ultrasound could contribute to favor the release of drugs allocated on shell. Specifically, PVA-based microbubbles were reacted with a galactosylated chitosan complex and loaded with doxorubicin to enable the localization and drug delivery to HepG2 hepatocarcinoma cells overexpressing asialoglycoprotein receptors. We demonstrated selectivity and greater bioadhesive properties of the functionalized microbubbles for tumor cells than to normal fibroblasts, which were influenced by the degree of galactosylation. The presence of galactosylated chitosan did not modify the rate of doxorubicin release from microbubbles, whichwas almost complete within 48h. Cellular uptake of doxorubicin loaded on functionalized microbubbles was higher in HepG2 than in normal fibroblasts, which do not over express the asialoglycoprotein receptors. In addition, doxorubicin loaded onto functionalized microbubbles fully retained its cytotoxic activity. Cells were also irradiated with ultrasound, immediately after exposure to microbubbles. An early enhancement of doxorubicin release and cellular drug uptake associated to a concomitant increase in cytotoxicity was observed in HepG2 cells. Overall, results of the study indicate that galactosylated chitosan microbubbles represent promising devices for the targeted delivery of antitumor agents to liver cancer cells.

Polymeric microbubbles (MBs) are gas filled particles composed of a thin stabilized polymer shell that have been recently developed as valid contrast agents for the combined use of ultrasonography (US), magnetic resonance imaging (MRI) and single photon emission computer tomography (SPECT) imaging. Due to their buoyancy, the commonly available approaches to study their behaviour in complex media are not easily applicable and their use in modern medicine requires such behaviour to be fully elucidated. Here we have used for the first time flow cytometry as a new high throughput approach that allows characterisation of the MB dispersion, prior to and after exposure in different biological media and we have additionally developed a method that allows characterisation of the strongly bound proteins adsorbed on the MBs, to fully predict their biological behaviour in biological milieu.

In this paper we report on the study of the interface of hybrid shell droplets encapsulating decafluoropentane (DFP), which exhibit interesting potentialities for ultrasound (US) imaging. The fabrication of the droplets is based on the deposition of a dextran methacrylate layer onto the surface of surfactants. The droplets have been stabilized against coalescence by UV curing, introducing crosslinks in the polymer layer and transforming the shell into an elastomeric membrane with a thickness of about 300 nm with viscoelastic behaviour. US irradiation induces the evaporation of the DFP core of the droplets transforming the particles into microbubbles (MBs). The presence of a robust crosslinked polymer shell introduces an unusual stability of the droplets also during the core phase transition and allows the recovery of the initial droplet state after a few minutes from switching off US. The interfacial tension of the droplets has been investigated by two approaches, the pendant drop method and an indirect method, based on the determination of the liquid ↔ gas transition point of DFP confined in the droplet core. The re-condensation process has been followed by capturing images of single MBs by confocal microscopy. The time evolution of MB relaxation to droplets was analysed in terms of a modified Church model to account for the structural complexity of the MB shell, i.e. a crosslinked polymer layer over a layer of surfactants. In this way the microrheology parameters of the shell were determined. In a previous paper (Chem. Commun., 2013, 49, 5763–5765) we showed that these systems could be used as ultrasound contrast agents (UCAs). In this work we substantiate this view assessing some key features offered by the viscoelastic nature of the droplet shell.

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.

Targeting is a main feature supporting any controlled drug delivery modality. Recently we developed poly(vinyl alcohol), PVA, based microbubbles as a potential new ultrasound contrast agent featuring an efficient ultrasound backscattering and a good shelf stability. The chemical versatility of the polymeric surface of this device offers a vast variety of coupling modalities useful for coating and specific targeting. We have designed a conjugation strategy on PVA shelled microbubbles to enable the localization and the drug delivery on tumor cells by modifying the surface of this polymeric ultrasound contrast agent (UCA) with oxidized hyaluronic acid (HAox). After the conversion of the microbubbles into microcapsules, the kinetics of the release of doxorubicin, a well-known antitumor drug, from uncoated and HAox-coated PVA microbubbles and microcapsules was investigated. Cytocompatibility and bioadhesive properties of the HA-modified microparticles were then tested on the HT-29 tumor cell line. Cytotoxicity to HT-29 tumor cells of microcapsules after loading with doxorubicin was studied, evidencing the efficacy of the HAox coating for the delivery of the drug to cells. These features are a prerequisite for a theranostic, that is, diagnostic and therapeutic, use of polymer-based UCAs.

Microbubbles (MBs) are used in clinical practice as vascular ultrasound contrast agents, and are gaining popularity as a platform supporting multimodal imaging and targeted therapy, facilitating drug delivery under ultrasound exposure. Here, we report on the in vivo biological impact of newly discovered MBs with promising features as a multimodal theranostic device. The shell of the air-filled MBs is made of the poly(vinyl alcohol) (PVA), a well-established, FDA-approved polymer. Nevertheless, as size, shape and dispersity can significantly impact the biological response of particulate systems, studying their fate after administration is crucial. The safety and the biodistribution of PVA MBs were analysed in vivo and ex vivo by coupling a near infrared (NIR) fluorophore on their shell: MBs accumulated mainly in liver and spleen at 24 hours post-injection with their clearance from the spleen 7 days post-dosing. A possible way of elimination was identified in macrophages ability to engulf MBs both in vitro and in vivo. One month post-dosing, transmission electron microscopy (TEM) highlighted the lack of relevant defects and the elimination of PVA MBs by Kupffer cells. This study is the first successful attempt to fill the lack of knowledge necessary to bring PVA MBs one step closer to their possible clinical use.

The system described in this paper was obtained by soaking calcium alginate (CaAlg) microspheres in a water solution of poly-[(3-acrylamidopropyl)- trimethylammonium chloride-b-N-isopropylacrylamide] [poly(AMPTMA-b-NIPAAM)], a new block co-polymer recently synthesized by atom transfer radical polymerization (ATRP). The block co-polymer is characterized by a lower critical solution temperature (LCST) of 41 °C in aqueous 0.1 M NaCl solution, and can be anchored on the CaAlg microspheres by means of polyion interactions. Polycations (permanently positively charged blocks) and polyanions (free alginate carboxylic groups) interact, leading to microspheres with thermosensitive properties. As an effect of interaction with the microspheres the LCST of the co-polymer is lowered to 36-38 °C. In this temperature range a colloidal water suspension of the microspheres collapses, forming macroscopic aggregates. The new system shows, at human body temperature, an improved ability to carry and deliver both hydrophobic and hydrophilic molecules in comparison with unmodified CaAlg microspheres. The release properties of the microspheres loaded with different model drugs can be appropriately modulated by the amount of the poly(AMPTMA-b-NIPAAM). Furthermore, the microspheres show the interesting capability of retaining the activity of a loaded enzyme (horseradish peroxidase), used as a model protein. The results obtained indicate that the proposed drug delivery system may be suitable for drug depot applications. © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Coupling near‐infrared (NIR) nanoscale absorbing materials with microbubbles (MBs) can generate a multifunctional dual imaging contrast agent. A new approach is presented for a hybrid photoacoustic/ultrasound contrast enhancer where pristine graphene is stably tethered to poly(vinyl alcohol) (PVA)‐based MBs. The main advantages of this approach are i) the preservation of optical and mechanical properties of intact graphene for an efficient photoacoustic (PA) enhancement and ii) the echogenicity and biocompatibility due to the robust anchoring of graphene to the bioinert PVA shell. PVA MBs provide ideal platforms for drug loading and ligand tethering for specific tumor targeting. One of the crucial goals toward this direction is optimizing this system in terms of balance between favorable acoustic/photoacoustic properties, immune shielding, and cytotoxicity. Such a combination strongly depends on the bridging moieties between graphene and the microbubble surface and can be easily tuned by PEGylation. The optimized graphene PVA MBs as contrast agent provide an efficient enhancement in vivo both in ultrasound and photoacoustic modes. The spectrally separable absorbance profile allows to a first demonstration of performing real‐time in vivo multiplexed photoacoustic imaging of graphene PVA MBs, and assessment of their full body biodistribution using a Vevo LAZR‐X photoacoustic imaging system.

Drugs can be delivered by a temperature change-driven shrinking of the nanocarrier followed by the cargo release. This paper describes a different structural response to temperature, performed by nanoparticles of poly(N-isopropylacrylamide) and hyaluronic acid. Around 35 °C, the hydrophobicity of the vinyl polymer drives a core-shell rearrangement with the acrylamide chains confined in the core and the polysaccharide moiety forming the shell. In this arrangement, the nanoparticles enable the active targeting of tumor cells, due to the specific interaction of hyaluronic acid with the CD44 receptors. When doxorubicin-loaded nanoparticles are up-taken, the polysaccharide part degrades in the cytoplasm and the cytotoxic effect of the anticancer drug in colon adenocarcinoma cells has a 2-fold increase with respect to healthy fibroblasts. These core-shell particles have hyaluronic acid as the key factor for the specific targeting of tumor cells and drug release with poly(N-isopropylacrylamide) driving the transition.

Combinations of microbubbles (MBs) and superparamagnetic iron oxide nanoparticles (SPIONs) are used to fabricate dual contrast agents for ultrasound and MRI. This study examines the viscoelastic and oscillation characteristics of two MB types that are manufactured with SPIONs and either anchored chemically on the surface (MBs-chem) or physically embedded (MBs-phys) into a polymer shell. A linearized Church model was employed to simultaneously fit attenuation coefficients and phase velocity spectra that were acquired experimentally. The model predicted lower viscoelastic modulus values, undamped resonance frequencies and total damping ratios for MBs-chem. MBs-chem had a resonance frequency of approximately 13 MHz and a damping ratio of approximately 0.9; thus, MBs-chem can potentially be used as a conventional ultrasound contrast agent with the combined functionality of MRI detection. In contrast, MBs-phys had a resonance frequency and damping of 28 MHz and 1.2, respectively, and requires further modification of clinically available contrast pulse sequences to be visualized. QC 20141117

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.

The combination of superparamagnetic iron oxide nanoparticles with polymeric air-filled microbubbles is used to produce two types of multimodal contrast agents to enhance medical ultrasound and magnetic resonance imaging. The nanoparticles are either covalently linked to the shell or physically entrapped into the shell. In this paper, the characterization of the acoustic properties (backscattered power, fracturing pressure, attenuation and dispersion of the ultrasonic wave) and ultrasound imaging of the two types of magnetic microbubbles are presented. In vitro B-mode images are generated using a medical ultrasound scanner by applying a nonconventional signal processing technique that is suitable to detect polymeric bubbles and based on the combination of multipulse excitation and chirp coding. Even if both types of microbubbles can be considered to be effective ultrasound contrast agents, the different structure of the shell loaded with nanoparticles has a pronounced effect on the echogenicity and the detection sensitivity of the imaging technique. The best results are obtained using microbubbles that are externally coated with nanoparticles. A backscattered power of 20 dB was achieved at lower concentration, and an increment of 8 dB in the contrast-to-tissue ratio was observed with respect to the more rigid microbubbles with particles entrapped into the shell.

Background: A multimodal polymer-shelled contrast agent (CA) with target specific potential was recently developed and tested for its acoustic properties in a single element transducer setup. Since the developed polymeric CA has different chemical composition than the commercially available CAs, there is an interest to study its acoustic response when using clinical ultrasound systems. The aim of this study was therefore to investigate the acoustic response by studying the visualization capability and shadowing effect of three polymer-shelled CAs when using optimized sequences for contrast imaging. Methods: The acoustic response of three types of the multimodal CA was evaluated in a tissue mimicking flow phantom setup by measuring contrast to tissue ratio (CTR) and acoustic shadowing using five image sequences optimized for contrast imaging. The measurements were performed over a mechanical index (MI) range of 0.2-1.2 at three CA concentrations (10(6), 10(5), 10(4) microbubbles/ml). Results: The CTR-values were found to vary with the applied contrast sequence, MI and CA. The highest CTR-values were obtained when a contrast sequence optimized for higher MI imaging was used. At a CA concentration of 106 microbubbles/ml, acoustic shadowing was observed for all contrast sequences and CAs. Conclusions: The CAs showed the potential to enhance ultrasound images generated by available contrast sequences. A CA concentration of 106 MBs/ml implies a non-linear relation between MB concentration and image intensity. QC 20131003

Ultrasound contrast agents (UCA) have been used for years in the clinical field, for applications such as blood pool enhancement, characterization of liver lesions or perfusion imaging [12, 13, 14, 15, 20]. The contrast agents are generally in the form of spherical voids or cavities filled by a gas, called microbubbles (MB). MBs are stabilized by a coating material such as phospholipids, surfactants, denatured human serum albumin or synthetic polymers. As gas is less dense than liquids or solids, sound travels more slowly in gas than it does in liquid. The difference in the sound speed in the microbubbles creates an acoustic mismatch between tissue and blood surrounding a microbubble, making it an efficient reflector of ultrasound energy. The ability to produce strong signals from microbubbles depends on the stability of the gas particle. Stability has been enhanced by varying the gas composition (air, nitrogen, sulphur hexafluoride, perfluorocarbons) and/or by chemical modification of the microbubble shell [20]. As microbubbles stay in the vascular space and have a behavior similar to red blood cells in the microcirculation, they can be used as intravascular tracers. The possibility to introduce a targeting ligand for a specific interaction with its receptor onto the microbubble shell can be a way to selectively accumulate the contrast agent in the deseased region. Moreover, targeted MBs can be used to carry different drugs to the desired sites and release them after their destruction/cavitation with ultrasound radiation or by chemical/enzymatic cleavage.

Background In the present study, we used multimodal imaging to investigate biodistribution in rats after intravenous administration of a new 99mTc-labeled delivery system consisting of polymer-shelled microbubbles (MBs) functionalized with diethylenetriaminepentaacetic acid (DTPA), thiolated poly(methacrylic acid) (PMAA), chitosan, 1,4,7-triacyclononane-1,4,7-triacetic acid (NOTA), NOTA-super paramagnetic iron oxide nanoparticles (SPION), or DTPA-SPION. Methods Examinations utilizing planar dynamic scintigraphy and hybrid imaging were performed using a commercially available single-photon emission computed tomography (SPECT)/computed tomography (CT) system. For SPION containing MBs, the biodistribution pattern of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs was investigated and co-registered using fusion SPECT/CT and magnetic resonance imaging (MRI). Moreover, to evaluate the biodistribution, organs were removed and radioactivity was measured and calculated as percentage of injected dose. Results SPECT/CT and MRI showed that the distribution of 99mTc-labeled ligand-functionalized MBs varied with the type of ligand as well as with the presence of SPION. The highest uptake was observed in the lungs 1 h post injection of 99mTc-labeled DTPA and chitosan MBs, while a similar distribution to the lungs and the liver was seen after the administration of PMAA MBs. The highest counts of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs were observed in the lungs, liver, and kidneys 1 h post injection. The highest counts were observed in the liver, spleen, and kidneys as confirmed by MRI 24 h post injection. Furthermore, the results obtained from organ measurements were in good agreement with those obtained from SPECT/CT. Conclusions In conclusion, microbubbles functionalized by different ligands can be labeled with radiotracers and utilized for SPECT/CT imaging, while the incorporation of SPION in MB shells enables imaging using MR. Our investigation revealed that biodistribution may be modified using different ligands. Furthermore, using a single contrast agent with fusion SPECT/CT/MR multimodal imaging enables visualization of functional and anatomical information in one image, thus improving the diagnostic benefit for patients.