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PubMed2006

Spatial and acoustic pressure dependence of microbubble-mediated gene delivery targeted using focused ultrasound.

BACKGROUND: Ultrasound/microbubble-mediated gene delivery has the potential to be targeted to tissue deep in the body by directing the ultrasound beam following vector administration. Application of this technology would be minimally invasive and benefit from the widespread clinical experience of using ultrasound and microbubble contrast agents. In this study we evaluate the targeting ability and spatial distribution of gene delivery using focused ultrasound. METHODS: Using a custom-built exposure tank, Chinese hamster ovary cells in the presence of SonoVue microbubbles and plasmid encoding beta-galactosidase were exposed to ultrasound in the focal plane of a 1 MHz transducer. Gene delivery and cell viability were subsequently assessed. Characterisation of the acoustic field and high-resolution spatial analysis of transfection were used to examine the relationship between gene delivery efficiency and acoustic pressure. RESULTS: In contrast to that seen in the homogeneous field close to the transducer face, gene delivery in the focal plane was concentrated on the ultrasound beam axis. Above a minimum peak-to-peak value of 0.1 MPa, transfection efficiency increased as acoustic pressure increased towards the focus, reaching a maximum above 1 MPa. Delivery was microbubble-dependent and cell viability was maintained. CONCLUSIONS: Gene delivery can be targeted using focused ultrasound and microbubbles. Since delivery is dependent on acoustic pressure, the degree of targeting can be determined by appropriate transducer design to modify the ultrasound field. In contrast to other physical gene delivery approaches, the non-invasive targeting ability of ultrasound makes this technology an attractive option for clinical gene therapy.

Acoustics↗
PubMed2006

Selective laser nano-thermolysis of human leukemia cells with microbubbles generated around clusters of gold nanoparticles.

BACKGROUND AND OBJECTIVE: Previously reported studies on laser nano-thermolysis of cancerous cells demonstrated insufficient efficacy and specificity of malignant cell damage. Safety, that is, absence of damage to normal cells in the course of the laser thermolysis was also low due to less than optimal protocol of cancer cell targeting with nanoparticles (NP). The objective of this study was two-fold: to optimize NP targeting to real tumor (human) cells and to better understand physical mechanisms of cell damage for improved control of the laser ablation. STUDY DESIGN/MATERIALS AND METHODS: We have suggested (1) two-stage targeting method to form clusters of light-absorbing gold NPs selectively in target cells, and (2) the cell damage mechanism through laser-induced generation of vapor bubbles around NP clusters. Experimental investigation of laser nano-thermolysis of leukemia cells was performed using 30 nm spherical gold nanoparticles as a light absorbing agent, and photothermal and fluorescent microscopies as well as flow cytometry as methods to monitor microbubble formation and resulting damage of leukemia cells in human bone marrow specimens. RESULTS: NP clusters were formed and visualized using fluorescence microscopy at cell membranes and in cytoplasm of B-lymphoblasts. Laser irradiation of cells (532 nm, 10 nanoseconds, 0.6 J/cm2) induced microbubbles selectively in leukemia cells with large clusters, but not in cells with single NPs or small clusters. Quantitative analysis demonstrated that only 0.1%-1.5% of tumor cells and 77%-84% of normal bone marrow cells survived laser pulse. CONCLUSIONS: Two-stage cell targeting method permits formation of NP clusters selectively in diagnosis-specific tumor cells. The clusters serve as effective sources of photothermally-induced microbubbles, which kill individual target cells after a single laser pulse. The laser fluence threshold for generation of microbubbles is inversely proportional to the volume of NP clusters.

Cell Death↗
PubMed2005

Analysis of different contrast enhancement patterns after microbubble-based contrast agent injection in liver hemangiomas with atypical appearance on baseline scan.

BACKGROUND: We describe different possible enhancement patterns in liver hemangiomas with atypical appearance on baseline ultrasound after microbubble-based contrast agent injection. METHODS: From a series of 253 consecutive lesions that were indeterminate on baseline ultrasound and then scanned after injection of air-filled microbubble contrast agent, 65 focal liver lesions were retrospectively selected on the basis of a diagnosis of liver hemangioma on multiphase contrast-enhanced computed tomography (n = 23), magnetic resonance imaging (n = 27), or histology (n = 15). Each lesion was scanned during arterial phase (30 s after microbubble injection) and late phase (5 min after injection). On-site sonologists performed retrospective assessment of contrast-enhancement patterns by consensus. RESULTS: Centripetal fill-in preceded (n = 50) or not preceded (n = 3) by peripheral nodular/rim-like enhancement was the prevalently observed contrast-enhancement pattern, equivalent to the typical enhancement pattern of liver hemangiomas on contrast-enhanced computed tomography or magnetic resonance imaging. In the remaining lesions, additional enhancement patterns (diffuse contrast enhancement with rapid fill-in and a late hyper-isoechoic appearance, n = 6; peripheral nodular enhancement with a late hypoechoic appearance, n = 3; or persistent heterogeneous and hyperechoic appearance, n = 3) were observed. CONCLUSION: Different contrast-enhancement patterns are possible in atypical liver hemangiomas after microbubble injection. Typical centripetal fill-in is the prevalent pattern and its evidence allows diagnosis.

Adult↗
PubMed2005

Intracellular delivery of Bak BH3 peptide by microbubble-enhanced ultrasound.

PURPOSE: To investigate the possibility of intracellular delivery of Bak BH3 peptide using sonoporation effect by microbubble-enhanced ultrasound. METHODS: HeLa and BJAB cells were exposed to 1.696-Mhz focused ultrasound with 2% microbubble contrast agents (OPTISON). Cell-impermeable calcein was used as an indicator for successful sonoporation, and propidium iodide staining was used for cell viability assessment. Peptides were also exposed to ultrasound with OPTISON and analyzed with mass spectrometry for evaluation of stability under ultrasound exposure. The effect of transduced Bak BH3 peptide was evaluated by the cell viability of successfully sonoporated cells. RESULTS: Bak BH3 peptides did not undergo mechanical degradation with microbubble-enhanced ultrasound exposure. With the increase of acoustic energy exposure, the sonoporation efficiency saturated both in BJAB and HeLa cells, while direct cell death rate by ultrasound exposure tended to increase. When BJAB cells were treated with 100 microM Bak BH3 peptides, and ultrasound exposure with ultrasound contrast agents (OPTISON), an increased 35% cell death was confirmed. On the other hand, although HeLa cells had a similar trend, they failed to exhibit statistical significance. CONCLUSIONS: Our results suggest that microbubble-enhanced focused ultrasound peptide transduction is possible. Further optimization of ultrasound exposure conditions may be necessary.

Antineoplastic Agents↗
PubMedDate not supplied

Targeted vascular delivery of antisense molecules using intravenous microbubbles.

OBJECTIVE: Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind the antisense to the c-myc protooncogene (anti-c-myc) which prevents neointimal hyperplasia following vascular endothelial injury. The microbubbles also adhere to sites of damaged vascular endothelium and thus may be a method of systemically targeting delivery of anti-c-myc. METHODS: Laser scanning microscopy was performed on the aorta of 10 mice (five which were complement depleted) that received intravenous FITC-PESDA following aortic endothelial injury. C-myc expression was quantified following selective intracoronary injury in nine pigs that received intravenous (IV) anti-c-myc bound to PESDA. Finally, neointimal formation was measured following intracoronary stent deployment in 30 pigs that received either IV anti-c-myc alone or the same dose bound to PESDA. RESULTS: Fluorescent microscopy confirmed selective PESDA microbubble adherence to aortic endothelium in all mice with aortic injury. This binding was nearly abolished when serum complement was depleted prior to injury. C-myc expression at the site of coronary endothelial injury was significantly lower in pigs treated with systemic anti-c-myc bound to PESDA. There was a 33% reduction in % stenosis and a 28% reduction in intimal area at 45 days post-stent deployment in pigs that received IV antisense plus PESDA. The stent margins also had reduced neointimal formation. CONCLUSION: Systemic administration of anti-c-myc bound to PESDA microbubbles may be a good method for preventing coronary neointimal formation within and around implanted stents.

Analysis of Variance↗
PubMed2004

Surface phase behavior and microstructure of lipid/PEG-emulsifier monolayer-coated microbubbles.

Langmuir trough methods and fluorescence microscopy were combined to investigate the phase behavior and microstructure of monolayer shells coating micron-scale bubbles (microbubbles) typically used in biomedical applications. The monolayer shell consisted of a homologous series of saturated acyl chain phospholipids and an emulsifier containing a single hydrophobic stearate chain and polyethylene glycol (PEG) head group. PEG-emulsifier was fully miscible with expanded phase lipids and phase separated from condensed phase lipids. Phase coexistence was observed in the form of dark condensed phase lipid domains surrounded by a sea of bright, emulsifier-rich expanded phase. A rich assortment of condensed phase area fractions and domain morphologies, including networks and other novel structures, were observed in each batch of microbubbles. Network domains were reproduced in Langmuir monolayers under conditions of heating-cooling followed by compression-expansion, as well as in microbubble shells that underwent surface flow with slight compression. Domain size decreased with increased cooling rate through the phase transition temperature, and domain branching increased with lipid acyl chain length at high cooling rates. Squeeze-out of the emulsifier at a surface pressure near 35 mN/m was indicated by a plateau in Langmuir isotherms and directly visualized with fluorescence microscopy, although collapse of the solid lipid domains occurred at much higher surface pressures. Compression of the monolayer past the PEG-emulsifier squeeze-out surface pressure resulted in a dark shell composed entirely of lipid. Under certain conditions, the PEG-emulsifier was reincorporated upon subsequent expansion. Factors that affect shell formation and evolution, as well as implications for the rational design of microbubbles in medical applications, are discussed.

Lipids↗
PubMed2005

Treatment of ischemic limbs based on local recruitment of vascular endothelial growth factor-producing inflammatory cells with ultrasonic microbubble destruction.

OBJECTIVES: We sought to clarify the mechanism for neovascularization by ultrasonic microbubble destruction (US/MB) and its ability to improve the function of ischemic limbs. BACKGROUND: In tissue, US/MB can cause capillary rupture, leading to angiogenesis and arteriogenesis. METHODS: Seven days after removal of the femoral artery (day 0) in mice, microbubble/ultrasound treatment was performed by intermittent insonation (1.6 MHz, mechanical index 1.1) to the ischemic limbs after intravenous infusion of phospholipid-stabilized microbubbles BR14 (US/MB group). Effects were compared with those in untreated mice with ischemic limbs (control group). RESULTS: Immunostaining of the treated muscles revealed a greater leukocyte (CD45-positive cell) count in the US/MB group on days 3 and 7. These cells included F4/80-positive cells (macrophages) and CD3-positive cells (T-lymphocytes), both of which were immunoreactive to vascular endothelial growth factor (VEGF) antibody. Muscular VEGF content by Western blotting was elevated in the US/MB group on day 3, which declined but remained greater until day 21. The US/MB group showed a greater capillary density by alkaline phosphatase stain on day 7 without further increase at day 21. Surface vascularity of the muscles and blood flow were greater in the US/MB group on day 7, which further increased by day 21. Moreover, the US/MB group showed a two-fold longer treadmill time compared with the untreated control group on day 21. None of these favorable effects were observed in mice treated with ultrasound only or microbubbles only. CONCLUSIONS: Ultrasonic destruction of microbubbles delivered to the ischemic limbs can recruit inflammatory cells producing VEGF, which is followed by neovascularization and functional improvement, and thus has a therapeutic potential.

Animals↗
PubMed2006

The effects of albumin-coated microbubbles in DNA delivery mediated by therapeutic ultrasound.

The application of therapeutic ultrasound (TUS) in combination with contrast agents (USCA) to mediate gene delivery relies on the understanding of the bioeffects involved. The objective of this study was to evaluate the various bioeffects generated by albumin-coated microbubbles: Optison, an USCA, when applied with TUS operated for 10-30 min, on cells and on DNA transfection. This study reveals that Optison microbubbles were still acoustically active after long-term TUS application of 30 min. Optison enhances TUS-gene transfection by increasing the number of plasmids in the cells and also by distributing the plasmids to more cells, without significant decrease in cell viability. Optison also interacts with the DNA to further enhance transfection in a mechanism not necessarily involving cavitation. However, Optison affects mainly the cell cytoplasmatic membrane, without interfering with DNA intracellular trafficking. Using high-resolution scanning electron microscopy (HRSEM), the bioeffects on cell membrane induced by TUS-Optison were observed, demonstrating that Optison lead to a rougher surface, characterized by depressions that are reversible within 24-h post TUS. These effects are different from those observed when only TUS was applied. The findings from this study suggest that albumin-coated microbubbles enhances transfection when using TUS for 10-30 min, and that microbubbles play a major role in elevating cell transfection level and efficiency.

Albumins↗
PubMed2005

Microbubble-enhanced ultrasound for gene transfer into living skin equivalents.

BACKGROUND: Gene transfer to skin is an attractive therapeutic approach because of the accessibility of the skin and the high rate of cure for many cutaneous diseases. However, safety concerns over viral vectors and the low efficiency of most non-viral gene transfer techniques have encumbered their clinical application for gene transfer. By contrast, efficient gene transfers into various cell types using microbubble-enhanced ultrasound has been reported. OBJECTIVES: The purpose of this study was to investigate whether ultrasound with microbubble enhancement allowed effective transfer of foreign genes into living skin equivalents (LSEs). METHODS: Microbubbles and plasmid DNA encoding green fluorescent protein (GFP) were added to the dermal-epidermal junctions of LSEs, which were then exposed to ultrasound. The LSEs were harvested at different time points to investigate transgene expression using confocal laser microscopy. Transfected LSEs were also transplanted onto nude mice, and the in vivo transgene expression was observed. RESULTS: From days 2 to 7 after transfection, most GFP-positive cells continued to migrate upward from the basal layer, while other GFP-positive cells lagged behind or remained in the basal layer on days 5 and 7. Transfection resulted in 20-30% GFP-positive cells. Multiple transfections further increased the percentage of transfected cells and resulted in multi-layer transgene expression. Grafts from the transfected LSEs survived on nude mice and continued to express GFP up to 2 weeks post-transplantation. CONCLUSION: Gene transfer into LSE using ultrasound with microbubble enhancement is an effective alternative to viral and non-viral methods.

Animals↗
PubMedDate not supplied

Molecular imaging with contrast ultrasound and targeted microbubbles.

There is growing interest in the development of methods for imaging cellular and molecular mediators of cardiovascular diseases. Techniques for imaging molecular and cellular alterations have been explored for essentially all noninvasive cardiac imaging modalities. Molecular imaging with contrast-enhanced ultrasound relies on the detection of novel site-targeted microbubble contrast agents. These microbubbles are retained within regions of a specific disease process, thereby allowing phenotypic characterization of tissue. As microbubbles are pure intravascular tracers, the disease processes assessed must be characterized by antigens that are expressed within the vascular compartment. Accordingly, the pathologic states that have been targeted include inflammation, neoplasms, angiogenesis, and thrombus formation, all of which are mediated in part by molecular events within the vascular space. This review describes (1) different strategies that have been used to target microbubbles to regions of disease, (2) the unique challenges for imaging targeted ultrasound contrast agents, and (3) some of the early experience imaging molecular events in animal models of disease.

Animals↗
PubMed2006

Difference frequency and its harmonic emitted by microbubbles under dual frequency excitation.

Vibro-acoustography is an elasticity imaging method that uses two ultrasound beams of slightly different frequency to excite an object and detects the resulting acoustic emission (AE) at the difference frequency. This method is especially sensitive to bubbles due to their nonlinearity. This study explores the harmonic acoustic emission (HAE) at twice the difference frequency emitted from bubbles. A perturbation method based on the dynamic bubble equation is used to derive the AE and HAE from a single bubble excited by dual frequency waves. Simulation shows that HAE is generated only by microbubbles whose resonant frequencies match the incident ultrasound frequencies. In contrast, AE is more sensitive to resonance at the difference frequency, which is relevant to sub-millimeter bubbles. This finding was confirmed by experiments where HAE was produced from Optison microbubbles, but not from larger air bubbles which are off resonance at the incident ultrasound frequency. In conclusion, harmonic acoustic emission is present for microbubbles. It is very sensitive to the size of the bubble and may be used for selective detection of microbubbles.

Albumins↗
PubMed2004

Effects of ultrasound-targeted microbubble destruction on cardiac gene expression.

Ultrasound (US) contrast agents are increasingly used in diagnostic echocardiography. Recent studies have suggested unanticipated effects of microbubble destruction. This study was designed to evaluate gene regulation caused by US-mediated destruction of microbubbles in the heart. During IV infusion of Optison trade mark, triggered US was applied to rat hearts to destroy microbubbles. A control group received only saline and US. RNA was isolated from hearts 24 and 72 h after treatment. Analysis with a deeply representative murine cardiac-specific microarray was used to identify regulated genes. Real-time polymerase chain reaction (PCR) was then applied to verify regulated genes. Microarray analysis revealed only 5 regulated genes in the 24-h group and 4 in the 72-h group. Of these genes, only carbonic anhydrase was significantly upregulated in the 24-h Optison trade mark group (4.3 fold; p = 0.0005) when examined in individual animals by real-time PCR. By this very sensitive technique, the bioeffects of microbubble destruction are negligible.

Albumins↗
PubMed2004

Ultrasound-induced encapsulated microbubble phenomena.

When encapsulated microbubbles are subjected to high-amplitude ultrasound, the following phenomena have been reported: oscillation, translation, coalescence, fragmentation, sonic cracking and jetting. In this paper, we explain these phenomena, based on theories that were validated for relatively big, free (not encapsulated) gas bubbles. These theories are compared with high-speed optical observations of insonified contrast agent microbubbles. Furthermore, the potential clinical applications of the bubble-ultrasound interaction are explored. We conclude that most of the results obtained are consistent with free gas bubble theory. Similar to cavitation theory, the number of fragments after bubble fission is in agreement with the dominant spherical harmonic oscillation mode. Remarkable are our observations of jetting through contrast agent microbubbles. The pressure at the tip of a jet is high enough to penetrate any human cell. Hence, liquid jets may act as remote-controlled microsyringes, delivering a drug to a region-of-interest. Encapsulated microbubbles have (potential) clinical applications in both diagnostics and therapeutics.

Acoustics↗
PubMed2005

Advantages in using multifrequency excitation of contrast microbubbles for enhancing echo particle image velocimetry techniques: initial numerical studies using rectangular and triangular waves.

Accurate measurement of velocity profiles, multiple velocity vectors and local shear stress in arteries is very important for a variety of cardiovascular diseases. We have recently developed an ultrasound based velocimetry technique, termed echo particle image velocimetry (echo PIV). This method takes advantage of the nonlinear backscatter characteristics of ultrasound contrast microbubbles when exposed to certain ultrasonic forcing conditions. Preliminary in vitro, animal and clinical studies have shown significant promise of this method for measuring multiple velocity components with good temporal (up to 2 ms) and spatial (<1 mm) resolution. However, there is still difficulty in maximizing the nonlinearity of bubble backscatter using conventional Gaussian-pulse excitation techniques because: (1) significant harmonic components may not be produced at modest pressure amplitudes; and (2) the higher incident pressure amplitudes required to induce nonlinear behavior may cause bubble destruction. We present here a potential solution to this problem through the use of multifrequency excitation, where rectangular and triangular pulses with four harmonics are used to drive the bubble. The nonlinear behavior of the microbubble, as well as fragility and backscatter, were studied through numerical modeling via a modified Rayleigh-Plesset equation. Results show that the rectangular wave is effective in improving the visibility of microbubbles, with effective scattering cross-section area significantly higher (up to 35 times) than the widely-used Gaussian waveform. However, velocity and acceleration analysis of the bubble wall shows that the rectangular wave may threaten bubble stability. Due to lower wall velocity and acceleration, the triangular wave should decrease the potential for bubble destruction yet maintain relatively high second harmonic backscatter components. The impact of higher harmonics was studied by examining backscatter differences from incident rectangular and triangular pulses with four and two harmonics. Results indicate that a two-frequency excitation (which may be easier to implement practically) may be sufficient to induce nonlinear behavior of the microbubbles at modest incident pressures. These predictions provide support for the use of multifrequency driving to enhance echo PIV applications.

Acoustics↗
PubMed2006

Effects of simultaneous application of ultrasound and microbubbles on intracerebral hemorrhage in an animal model.

Microbubble-enhanced sonothrombolysis (MEST) may be an alternative therapeutic option in ischemic stroke. Clinical study of the efficacy of MEST as an adjunct stroke therapy, before imaging with CT or MRI, requires experimental data on the safety of this approach in the presence of hemorrhagic stroke. We, therefore, investigated the effect of diagnostic transcranial ultrasound combined with microbubbles (US + MB) in an experimental animal model of intracerebral hemorrhage (ICH). ICH was induced in anesthetized rats by intracerebral collagenase injection. Transcranial ultrasound (2 MHz, mechanical index 1.3, 1051 kPa) was applied 3 h after ICH induction to rat brains for 30 min during a continuous IV infusion of sulfur hexafluoride microbubbles (SonoVue). The size of cerebral hemorrhage, the extent of brain edema, and the amount of apoptosis were compared with those from control rats with ICH but without US + MB. Results showed no significant effect of US + MB on hemorrhage size (control 23.3 +/- 10.7 mm(3), US + MB 20.3 +/- 5.8 mm(3)), on the extent of brain edema (control 3.3 +/- 2.0%, US +MB 3.5 +/- 1.9%), or on the rate of apoptosis (control 5.2 +/- 1.5%, US + MB 5.2 +/- 1.0%). We conclude that diagnostic ultrasound in combination with microbubbles does not cause additional damage to the rat brain during ICH in our experimental set-up. This finding provides support for the use of MEST as an early stroke therapy.

Animals↗
PubMed2006

Myocardium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via an angiogenic response.

Application of ultrasound-mediated destruction of microbubbles (US + Bubble) to skeletal muscle creates capillary ruptures leading to leakage of the cell components. We studied whether US + Bubble combined with bone-marrow-derived mononuclear cells (BM-MNCs) infusion enables the targeted delivery of endothelial-lineage cells into the myocardium and improves cardiac function of the cardiomyopathy model due to the paucity of neocapillary formation. Pulsed US was applied to the anterior chest of BIOTO2 cardiomyopathy hamsters for 90 s after the intravenous injection of microbubble (Optison) followed by infusion of BM-MNCs. Cardiac samples from US + microbubble + BM-MNCs (US + Bubble + BM), US + Bubble, US + BM without Bubble, and saline infusion control groups were analyzed 12 weeks after treatment. Labeled BM-MNCs transplanted by US + Bubble were found to be mainly localized in the microvessels, but not by US stimulation without microbubble (121.2 +/- 24.5 vs. 2.80 +/- 1.30 cells/mm2, P < 0.001). Capillary densities in US + Bubble + BM group were increased 1.7-fold (P < 0.05) over the control, and neither US + Bubble nor US + BM enhanced neocapillary formation. 99mTc-Tetrofosmin scintigraphy revealed that blood perfusion area in the US + Bubble + BM group was 48% greater than the control (P < 0.01). US + Bubble stimulation induces the expression of adhesion molecules (VCAM-1 and ICAM-1) in capillaries, and the US + Bubble-mediated supply of BM-MNCs increased the myocardial content of VEGF and bFGF. The left ventricular wt/body wt, area of cardiac fibrosis, and apoptotic cell numbers in the US + Bubble + BM group significantly (P < 0.05) decreased by 82%, 73%, and 64% relative to the control, respectively. The cardiac function in myopathic hamsters (assessed by fractional shortening) was markedly improved 36% (P < 0.05) by US + Bubble + BM treatment. Targeted delivery of BM-MNCs by US + Bubble to the myocardium of the cardiomyopathic hamster increased the capillary densities and regional blood flow and inhibited cardiac remodeling, resulting in the prevention of heart failure. This non-invasive cell delivery system may be useful as a novel efficient approach for angiogenic cell therapy to the myocardium.

Angiogenesis Inducing Agents↗
PubMed2006

Tethering functional ligands onto shell of ultrasound active polymeric microbubbles.

Hollow (air-filled) microparticles, i.e., microbubbles, provide a promising novel vehicle for both local delivery of therapeutic agents and simultaneous diagnostic ultrasound echo investigations. In this paper, we describe the synthetic routes for decorating the polymeric shell of a poly(vinyl alcohol)-based microbubble with low and high molecular weight ligands with pharmacological relevance. Investigations on physical properties of microbubbles and surface chemical coupling with different cargo molecules such as L-cysteine, L-lysine, poly(L-lysine), chitosan, and beta-cyclodextrin were carried out by CD and NMR spectroscopies, confocal laser scanning microscopy, and microcalorimetry. The in vitro cytotoxicity and biocompatibility of the polymer microbubbles have been also determined toward different cell lines. The results are discussed in terms of the features shown by this device, i.e., injectability, long shelf life, ease of preparation, biocompatibility, loading and cargo capacities, and functional properties.

Cell Line, Tumor↗
PubMed2004

Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound.

Although gene therapy might become a promising approach for central nervous system diseases, the safety issue is a serious consideration in human gene therapy. To overcome this problem, we developed an efficient gene transfer method into the adult rat brain based on plasmid DNA using a microbubble-enhanced ultrasound method, since microbubble-enhanced ultrasound has shown promise for transfecting genes into other tissues such as blood vessels. Using the microbubble-enhanced ultrasound method, luciferase expression was increased approximately 10-fold as compared to injection of naked plasmid DNA alone. Interestingly, the site of gene expression was limited to the site of insonation with intracisternal injection, in contrast to previous studies using viruses. Expression of the reporter gene, Venus, was readily detected in the central nervous system. The transfected cells were mainly detected in meningeal cells with intracisternal injection, and in glial cells with intrastriatal injection. There was no obvious evidence of tissue damage by microbubble-enhanced ultrasound. Overall, the present study demonstrated the feasibility of efficient plasmid DNA transfer into the central nervous system, providing a new option for treating various diseases such as tumors.

Animals↗