Spatial ultrasound modulation by digitally controlling microbubble arrays.
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ABSTRACT:
SUBMITTER: Ma Z
PROVIDER: S-EPMC7484750 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We developed a method to spatially control gene expression following nonviral delivery of DNA. This method includes surface-modifying DNA nanocarriers with heparin to inhibit passive gene transfer in both the target and the off-target tissues and using ultrasound-targeted microbubble destruction (UTMD) to selectively activate heparin-inhibited gene transfer at the target site. We observed that the engraftment of heparin onto the surface of cationic liposomes reduced off-target gene expression in the liver, a major site of nanoplex accumulation, by more than 700-fold compared to the nonheparinized PEGylated liposomes. We further observed that tumor-directed UTMD increased gene transfer with heparin-modified nanoplexes by more than 10-fold. This method augmented tumor-to-liver selectivity of gene expression by 4000-fold compared to controls. We conclude that heparinization of DNA nanocarriers in conjunction with localized activation of gene transfer by UTMD may enable greater spatial control over genetic therapy.
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Project description:RationaleMicrobubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld.ObjectiveTo develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging.Methods and resultsMicrobubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab')2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification.ConclusionsTargeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)-(iii) desired for clinical applications.
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Project description:GoalTo develop a low-cost magnetic resonance imaging (MRI)-free transcranial focused ultrasound (FUS) system for microbubble-mediated therapy.MethodsA 128-element 11 MHz array for skull localization was integrated within a 256-module multi-frequency (306/612/1224 kHz) dual-mode phased array. The system's transcranial transmit and receive performance was evaluated with ex-vivo human skullcaps using phase aberration corrections calculated from computed tomography (CT)-based simulations via ultrasound-based (USCT) and landmark-based (LMCT) registrations, and a gold-standard fixed source emitter (FSE)-based method.ResultsDisplacement and rotation registration errors of 1.4 ± 0.4 mm and 2.1 ± 0.2 ° were obtained using USCT, resulting in sub-millimeter transmit targeting errors driven at 306 kHz (0.9 ± 0.2 mm) and 612 kHz (0.9 ± 0.3 mm), and source localization errors of 1.0 ± 0.3 mm and 0.6 ± 0.2 mm at receive frequencies of 306 kHz and 612 kHz, respectively (mean ± SD). Similar errors were obtained using LMCT and no significant differences between these two approaches were found on either transmit (p = 0.64/0.99) or receive (p = 0.45/0.36) at 306 kHz/612kHz. During volumetric multi-point exposures, approximately 70% and 60% of the transmit frames in which microbubble activity was detected via FSE were recovered using USCT when imaging at the second-harmonic and half-harmonic, respectively, compared to 60% and 69% using LMCT.ConclusionThis low-cost ultrasound-guided transcranial FUS system affords USCT skull registration with accuracy comparable to LMCT methods.SignificanceSuch systems have great potential to advance the adoption of microbubble-mediated FUS brain therapy by improving access to the technology.
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Project description:Melanoma is one of the most aggressive types of cancer, and its incidence has increased rapidly in the past few decades. In this study, we investigated a novel treatment approach, the use of low-intensity ultrasound (2.3 W/cm2 at 1 MHz)-mediated Optison microbubble (MB) destruction (UMMD) to treat melanoma in a flank tumor model. The effect of UMMD was first evaluated in the melanoma cell line B16 F10 (B16) in vitro and then in mice inoculated with B16 cells. MB+B16 cells were exposed to US in vitro, resulting in significant cell death proportional to duty cycle (R2 = 0.74): approximately 30%, 50%, 80% and 80% cell death at 10%, 30%, 50% and 100% DC respectively. Direct implantation of tumors with MBs, followed by sonication, resulted in retarded tumor growth and improved survival (p = 0.0106). Immunohistochemical analyses confirmed the significant changes in expression of the cell proliferation marker Ki67 (p = 0.037) and a microtubule-associated protein 2 (p = 0.048) after US + MB treatment. These results suggest that UMMD could be used as a possible treatment approach in isolated melanoma and has the potential to translate to clinical trials.
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Project description:Effective removal or dissolution of large blood clots remains a challenge in clinical treatment of acute thrombo-occlusive diseases. Here we report the development of an intravascular microbubble-mediated sonothrombolysis device for improving thrombolytic rate and thus minimizing the required dose of thrombolytic drugs. We hypothesize that a sub-megahertz, forward-looking ultrasound transducer with an integrated microbubble injection tube is more advantageous for efficient thrombolysis by enhancing cavitation-induced microstreaming than the conventional high-frequency, side-looking, catheter-mounted transducers. We developed custom miniaturized transducers and demonstrated that these transducers are able to generate sufficient pressure to induce cavitation of lipid-shelled microbubble contrast agents. Our technology demonstrates a thrombolysis rate of 0.7?±?0.15 percent mass loss/min in vitro without any use of thrombolytic drugs.
| S-EPMC5471247 | biostudies-literature
Project description:The PtIV prodrug iproplatin has been actively loaded into liposomes using a calcium acetate gradient, achieving a 3-fold enhancement in drug concentration compared to passive loading strategies. A strain-promoted cycloaddition reaction (azide- dibenzocyclooctyne) was used to attach iproplatin-loaded liposomes L(Pt) to gas-filled microbubbles (M), forming an ultrasound-responsive drug delivery vehicle [M-L(Pt)]. Ultrasound-triggered release of iproplatin from the microbubble-liposome construct was evaluated in cellulo. Breast cancer (MCF-7) cells treated with both free iproplatin and iproplatin-loaded liposome-microbubbles [M-L(Pt)] demonstrated an increase in platinum concentration when exposed to ultrasound. No appreciable platinum uptake was observed in MCF-7 cells following treatment with L(Pt) only or L(Pt)+ultrasound, suggesting that microbubble-mediated ultrasonic release of platinum-based drugs from liposomal carriers enables greater control over drug delivery.
| S-EPMC8634767 | biostudies-literature
Project description:Ultrasound imaging presents many positive attributes, including safety, real-time imaging, universal accessibility, and cost. However, inherent difficulties in discrimination between soft tissues and tumors prompted development of stabilized microbubble contrast agents. This presents the opportunity to develop agents in which drug is entrapped in the microbubble shell. We describe preparation and characterization of theranostic poly(lactide) (PLA) and pegylated PLA (PEG-PLA) shelled microbubbles that entrap gemcitabine, a commonly used drug for pancreatic cancer (PDAC). Entrapping 6 wt% gemcitabine did not significantly affect drug activity, microbubble morphology, or ultrasound contrast activity compared with unmodified microbubbles. In vitro microbubble concentrations yielding ≥ 500nM entrapped gemcitabine were needed for complete cell death in MIA PaCa-2 PDAC drug sensitivity assays, compared with 62.5 nM free gemcitabine. In vivo administration of gemcitabine-loaded microbubbles to xenograft MIA PaCa-2 PDAC tumors in athymic mice was well tolerated and provided substantial tumoral image enhancement before and after destructive ultrasound pulses. However, no significant differences in tumor growth were observed among treatment groups, in keeping with the in vitro observation that much higher doses of gemcitabine are required to mirror free gemcitabine activity. STATEMENT OF SIGNIFICANCE: The preliminary results shown here are encouraging and support further investigation into increased gemcitabine loading. Encapsulation of gemcitabine within polylactic acid (PLA) microbubbles does not damage its activity towards pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) cells. Excellent imaging and evidence of penetration into the highly desmoplastic PDAC tumors is demonstrated. Microbubble destruction was confirmed in vivo, showing that elevated mechanical index shatters the microbubbles for enhanced delivery. The potential to slow PDAC growth in vivo is shown, but higher gemcitabine concentrations are required. Current efforts are directed at increasing drug loading by inclusion of drug-carrying nanoparticles for effective in vivo treatment.
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Project description:It is now well established that for tumour growth and survival, tumour vasculature is an important element. Studies have demonstrated that ultrasound-stimulated microbubble (USMB) treatment causes extensive endothelial cell death leading to tumour vascular disruption. The subsequent rapid vascular collapse translates to overall increases in tumour response to various therapies. In this study, we explored USMB involvement in the enhancement of hyperthermia (HT) treatment effects. Human prostate tumour (PC3) xenografts were grown in mice and were treated with USMB, HT, or with a combination of the two treatments. Treatment parameters consisted of ultrasound pressures of 0 to 740 kPa, the use of perfluorocarbon-filled microbubbles administered intravenously, and an HT temperature of 43°C delivered for various times (0-50 minutes). Single and multiple repeated treatments were evaluated. Tumour response was monitored 24 hours after treatments and tumour growth was monitored for up to over 30 days for a single treatment and 4 weeks for multiple treatments. Tumours exposed to USMB combined with HT exhibited enhanced cell death (p<0.05) and decreased vasculature (p<0.05) compared to untreated tumours or those treated with either USMB alone or HT alone within 24 hours. Deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and cluster of differentiation 31 (CD31) staining were used to assess cell death and vascular content, respectively. Further, tumours receiving a single combined USMB and HT treatment exhibited decreased tumour volumes (p<0.05) compared to those receiving either treatment alone when monitored over the duration of 30 days. Additionally, tumour response monitored weekly up to 4 weeks demonstrated a reduced vascular index and tumour volume, increased fibrosis and lesser number of proliferating cells with combined treatment of USMB and HT. Thus in this study, we characterize a novel therapeutic approach that combines USMB with HT to enhance treatment responses in a prostate cancer xenograft model in vivo.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death worldwide. Poor drug delivery to tumours is thought to limit chemotherapeutic treatment efficacy. Sonoporation combines ultrasound (US) and microbubbles to increase the permeability of cell membranes. We assessed gemcitabine uptake combined with sonoporation in vitro in three PDAC cell lines (BxPC-3, MIA PaCa-2 and PANC-1). Cells were cultured in hypoxic bioreactors, while gemcitabine incubation ± sonoporation was conducted in cells with operational or inhibited nucleoside membrane transporters. Intracellular active metabolite (dFdCTP), extracellular gemcitabine, and inactive metabolite (dFdU) concentrations were measured with liquid chromatography tandem mass spectrometry. Sonoporation with increasing US intensities resulted in decreasing extracellular gemcitabine concentrations in all three cell lines with inhibited membrane transporters. In cells with inhibited membrane transporters, without sonoporation, dFdCTP concentrations were reduced down to 10% of baseline. Sonoporation partially restored gemcitabine uptake in these cells, as indicated by a moderate increase in dFdCTP concentrations (up to 37% of baseline) in MIA PaCa-2 and PANC-1. In BxPC-3, gemcitabine was effectively inactivated to dFdU, which might represent a protective mechanism against dFdCTP accumulation in these cells. Intracellular dFdCTP concentrations did not change significantly following sonoporation in any of the cell lines with operational membrane transporters, indicating that the gemcitabine activation pathway may have been saturated with the drug. Sonoporation allowed a moderate increase in gemcitabine transmembrane uptake in all three cell lines, but pre-existing nucleoside transporters were the major determinants of gemcitabine uptake and retention.
| S-EPMC7076495 | biostudies-literature
Project description:High-intensity ultrasound (US) ablation produces deeper myocardial lesions than radiofrequency ablation. The presence of intravascular microbubble (MB) contrast agents enhances pulsed-wave US ablation via cavitation-related histotripsy, potentially facilitating ablation in persistently perfused/conducting myocardium. US ablation catheters were developed and tested in the presence of MBs using ex vivo and in vivo models. High-frame-rate videomicroscopy and US imaging of gel phantom models confirmed MB destruction by inertial cavitation. MB-facilitated US ablation in an ex vivo perfused myocardium model generated shallow (2 mm) lesions and, in an in vivo murine hindlimb model, reduced perfusion by 42% with perivascular hemorrhage and inflammation, but no myonecrosis.
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