Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0-37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70-150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.

BACKGROUND: Primarily used as ultrasound contrast agents, microbubbles have recently emerged as a versatile therapeutic vector that can be \'burst\' to deliver payloads in the presence of suitably optimised ultrasound fields. Ultrasound-stimulated microbubbles (USMB) have recently demonstrated improvements in treatment outcomes across a variety of clinical applications. This scoping review investigates whether this potential translates into the context of radiation therapy by evaluating the application of this technology across all three phases of radiation action.
METHODS: Primary research articles, excluding poster presentations and conference proceedings, were identified through systematic searches of the PubMed NCBI/Medline, Embase/OVID, Web of Science and CINAHL/EBSCOhost databases, with additional articles identified via manual Google Scholar searching. Articles were dual screened for inclusion using the Covidence systematic review platform and classified against all three phases of radiation action.
RESULTS: Overall, 57 eligible publications from a total of 1389 identified articles were included in the review, with studies dating back to 2012. Study heterogeneity prevented formal statistical analysis; however, most articles reported improved outcomes using USMB in the presence of radiation compared to that of radiation alone. These improvements appear to result from the use of USMB as either a biovascular disruptor causing tumour cell damage via indirect mechanisms, or as a localised treatment vector that directly increases tumour cell uptake of other therapeutic and physical agents designed to enhance radiation action.
CONCLUSIONS: USMB demonstrate exciting potential to enhance the effects of radiation treatments due to their versatility and capacity to target all three phases of radiation action.

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Intratumoral injections have the potential for enhanced cancer treatment efficacy while reducing costs and systemic exposure. However, intratumoral drug injections can result in substantial off-target leakage and are invisible under standard imaging modalities like ultrasound (US) and x-ray. A thermosensitive poloxamer-based gel for drug delivery was developed that is visible using x-ray imaging (computed tomography (CT), cone beam CT, fluoroscopy), as well as using US by means of integrating perfluorobutane-filled microbubbles (MBs). MBs content was optimized using tissue mimicking phantoms and ex vivo bovine livers. Gel formulations less than 1% MBs provided gel depositions that were clearly identifiable on US and distinguishable from tissue background and with minimal acoustic artifacts. The cross-sectional areas of gel depositions obtained with US and CT imaging were similar in studies using ex vivo bovine liver and postmortem in situ swine liver. The gel formulation enhanced multimodal image-guided navigation, enabling fusion of ultrasound and x-ray/CT imaging, which may enhance targeting, definition of spatial delivery, and overlap of tumor and gel. Although speculative, such a paradigm for intratumoral drug delivery might streamline clinical workflows, reduce radiation exposure by reliance on US, and boost the precision and accuracy of drug delivery targeting during procedures. Imageable gels may also provide enhanced temporal and spatial control of intratumoral conformal drug delivery.

Quasi-3D plasmonic nanostructures are in high demand for their ability to manipulate and enhance light-matter interactions at subwavelength scales, making them promising building blocks for diverse nanophotonic devices. Despite their potential, the integration of these nanostructures with optical sensors and imaging systems on a large scale poses challenges. Here, a robust technique for the rapid, scalable, and seamless replication of quasi-3D plasmonic nanostructures is presented straight from their production wafers using a microbubble process. This approach not only simplifies the integration of quasi-3D plasmonic nanostructures into a wide range of standard and custom optical imaging devices and sensors but also significantly enhances their imaging and sensing performance beyond the limits of conventional methods. This study encompasses experimental, computational, and theoretical investigations, and it fully elucidates the operational mechanism. Additionally, it explores a versatile set of options for outfitting nanophotonic devices with custom-designed plasmonic nanostructures, thereby fulfilling specific operational criteria.

Ozone-based advanced oxidation processes (AOPs) have emerged a promising avenue for water treatment, offering effective removal of micropollutants. Recent research underscores the potential of ozone microbubbles to enhance ozone mass transfer during water treatment, particularly when combined with pre-treatment steps. This study aimed to evaluate the efficacy of three different combined processes (chlorine/KMnO4/PAC pre-treatment followed by ozonation) in removing atrazine, a common micropollutant from natural source water. Results revealed that all combined processes achieved higher atrazine removal rates compared to individual pre-treatment or ozonation methods. Notably, the highest atrazine removal rates were observed under alkaline pH conditions, with treatment outcomes influenced by oxidant dose and pH levels. Among the combined processes, chlorine pre-treatment followed by ozonation emerged as the most effective approach, achieving a removal rate of 59.7% that exceeded the sum of individual treatments. However, this treatment efficacy was affected by water quality parameters, particularly the presence of organic matter and elevated ammonia nitrogen concentration (> 0.5 mg/L). This study highlights the potential for utilizing ozone micro/nanobubbles to enhance ozone mass transfer and offers valuable insights for optimizing the combined application of pre-treatment and ozonation strategies for efficient atrazine removal from natural water sources.

Molecular ultrasound imaging with actively targeted microbubbles (MB) proved promising in preclinical studies but its clinical translation is limited. To achieve this, it is essential that the actively targeted MB can be produced with high batch-to-batch reproducibility with a controllable and defined number of binding ligands on the surface. In this regard, poly (n-butyl cyanoacrylate) (PBCA)-based polymeric MB have been used for US molecular imaging, however, ligand coupling was mostly done via hydrolysis and carbodiimide chemistry, which is a multi-step procedure with poor reproducibility and low MB yield. Herein, we developed a single-step coupling procedure resulting in high MB yields with minimal batch-to-batch variation. Actively targeted PBCA-MB were generated using an aminolysis protocol, wherein amine-containing cRGD was added to the MB using lithium methoxide as a catalyst. We confirmed the successful conjugation of cRGD on the MB surface, while preserving their structure and acoustic signal. Compared to the conventional hydrolysis protocol, aminolysis resulted in higher MB yields and better reproducibility of coupling efficiency. Optical imaging revealed that under flow conditions, cRGD- and rhodamine-labelled MB, generated by aminolysis, specifically bind to tumor necrosis factor-alpha (TNF-α) activated endothelial cells in vitro. Furthermore, US molecular imaging demonstrated a markedly higher binding of the cRGD-MB than of control MB in TNF-α activated mouse aortas and 4T1 tumors in mice. Thus, using the aminolysis based conjugation approach, important refinements on the production of cRGD-MB could be achieved that will facilitate the production of clinical-scale formulations with excellent binding and ultrasound imaging performance.

Ferroptosis, triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DOX-induced cardiomyopathy (DIC), and thus limits the use of doxorubicin (DOX) in clinic. Here, we further showed that cardiac ferroptosis induced by DOX in mice was attributed to up-regulation of Hmox1, as knockdown of Hmox1 effectively inhibited cardiomyocyte ferroptosis. To targeted delivery of siRNA into cardiomyocytes, siRNA-encapsulated exosomes were injected followed by ultrasound microbubble targeted destruction (UTMD) in the heart region. UTMD greatly facilitated exosome delivery into heart. Consistently, UTMD assisted exosomal delivery of siHomox1 nearly blocked the ferroptosis and the subsequent cardiotoxicity induced by doxorubicin. In summary, our findings reveal that the upregulation of HMOX1 induces ferroptosis in cardiomyocytes and UTMD-assisted exosomal delivery of siHmox1 can be used as a potential therapeutic strategy for DIC.

Sonoporation-based delivery has great promise for noninvasive drug and gene therapy. After short-term membrane resealing, the long-term function recovery of sonoporated cells affects the efficiency and biosafety of sonoporation-based delivery. It is necessary to identify the key early biological signals that influence cell fate and to develop strategies for manipulating the long-term fates of sonoporated cells. Here, we used a customized experimental platform with a single cavitating microbubble induced by a single ultrasound pulse (frequency: 1.5 MHz, pulse length:13.33 μs, peak negative pressure: ∼0.40 MPa) to elicit single-site reversible sonoporation on a single HeLa cell model. We used a living-cell microscopic imaging system to trace the long-term fates of sonoporated HeLa cells in real-time for 48 h. Fluorescence from intracellular propidium iodide and Fluo-4 was used to evaluate the degree of sonoporation and intracellular calcium fluctuation (ICF), respectively. Changes in cell morphology were used to assess the long-term cell fates (i.e., proliferation, arrest, or death). We found that heterogeneously sonoporated cells had different long-term fates. With increasing degree of sonoporation, the probability of normal (proliferation) and abnormal fates (arrest and death) in sonoporated cells decreased and increased, respectively. We identified ICF as an important early event for triggering different long-term fates. Reversibly sonoporated cells exhibited stronger proliferation and restoration at lower extents of ICF. We then regulated ICF dynamics in sonoporated cells using 2-APB or BAPTA treatment to reduce calcium release from intracellular organelles and enhance intracellular calcium clearance, respectively. This significantly enhanced the proliferation and restoration of sonoporated cells and reduced the occurrence of cell-cycle arrest and death. Finally, we found that the long-term fates of sonoporated cells at multiple sites and neighboring cells were also dependent on the extent of ICF, and that 2-APB significantly enhanced their viability and reduced death. Thus, using a single HeLa cell model, we demonstrated that regulating intracellular calcium can effectively enhance the proliferation and restoration capabilities of sonoporated cells, therefore rescuing the long-term viability of sonoporated cells. These findings add to our understanding of the biophysical process of sonoporation and help design new strategies for improving the efficiency and biosafety of sonoporation-based delivery.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.
OBJECTIVE: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.
METHODS: The ALS mouse model with the SOD1G93A mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.
RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.
CONCLUSIONS: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.