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  • Enhanced microbubble contrast agent oscillation following 250kHz insonation. Scientific reports Ilovitsh, T., Ilovitsh, A., Foiret, J., Caskey, C. F., Kusunose, J., Fite, B. Z., Zhang, H., Mahakian, L. M., Tam, S., Butts-Pauly, K., Qin, S., Ferrara, K. W. 2018; 8 (1): 16347

    Abstract

    Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuationcompared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250kHz transmission as compared with the 1MHz center frequency. Following 250kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh-Plesset equation for a clean bubble or the Marmottant model of a lipid-shelledmicrobubble. The expansion ratio reached 30-fold with 250kHz at a peak negative pressure of 400kPa, as compared to a measured expansion ratio of 1.6 fold for 1MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100kPa) for the 250kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75-150kPa. For pressures above 150kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid-shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation.

    View details for PubMedID 30397280

  • Unimicellar hyperstars as multi-antigen cancer nanovaccines displaying clustered epitopes of immunostimulating peptides BIOMATERIALS SCIENCE Kakwere, H., Ingham, E. S., Allen, R., Mahakian, L. M., Tam, S. M., Zhang, H., Silvestrini, M. T., Lewis, J. S., Ferrara, K. W. 2018; 6 (11): 2850?58

    View details for DOI 10.1039/c8bm00891d

    View details for Web of Science ID 000448822800005

  • Unimicellar hyperstars as multi-antigen cancer nanovaccines displaying clustered epitopes of immunostimulating peptides. Biomaterials science Kakwere, H., Ingham, E. S., Allen, R., Mahakian, L. M., Tam, S. M., Zhang, H., Silvestrini, M. T., Lewis, J. S., Ferrara, K. W. 2018

    Abstract

    Unimicellar hyperstar macromolecular chimeras displaying multiple melanoma peptide antigens were prepared primarily via a combination of click chemistry and esterification reactions starting from a biodegradable hyperbranched polymer template. Solubilization of the hyperstars in aqueous solution afforded a multi-antigen unimicellar cancer nanovaccine of about 20 nm. The nanovaccine showed good biocompatibility and uptake by dendritic cells in vitro. An in vivo evaluation of the nanovaccine therapeutic efficacy against melanoma in mice implanted with B16OVA tumors revealed significantly greater T-cell recruitment and improved survival rates for mice treated with nanovaccine and adjuvant compared to non-treated mice.

    View details for PubMedID 30229768

  • In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles BIOMATERIALS Zhang, H., Ingham, E. S., Gagnon, M. J., Mahakian, L. M., Liu, J., Foiret, J. L., Willmann, J. K., Ferrara, K. W. 2017; 118: 63?73

    Abstract

    Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non-targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3-conjugated MBs by 84%, n = 4, p < 0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2-8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies.

    View details for PubMedID 27940383

    View details for PubMedCentralID PMC5279957

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