Advanced Ultrasound in Diagnosis and Therapy ›› 2019, Vol. 3 ›› Issue (3): 62-75.doi: 10.37015/AUDT.2019.190812
• Review Article • Previous Articles Next Articles
Vishal Thumar, MDa, Ji-Bin Liu, MDb, John Eisenbrey, PhDb*()
Received:
2019-05-07
Online:
2019-09-30
Published:
2019-09-05
Contact:
John Eisenbrey, PhD,
E-mail:John.Eisenbrey@jefferson.edu
Vishal Thumar, MD, Ji-Bin Liu, MD, John Eisenbrey, PhD. Applications in Molecular Ultrasound Imaging: Present and Future. Advanced Ultrasound in Diagnosis and Therapy, 2019, 3(3): 62-75.
Figure 2
Illustration of a drug-loaded liposome with an aqueous core and gas bubbles in the lipid bilayer (can also be confined within the inner lipid layer in the same component as the aqueous core). Hydrophilic drugs can be loaded within the aqueous core and hydrophobic drugs can be loaded within the lipid bilayer."
Figure 3
In vivo tumor targeting. Images were taken at the indicated time points (0, 1, 30, and 40 min) after nanobubbles were injected into the transplanted SK-BR-3 tumors injected with Herceptin-conjugated nanobubbles (NBs-Her; A) or unconjugated nanobubbles (NBs-Blank; B) and in the transplanted MDA-MB-231 tumors injected with NBs-Her (C) or NBs-Blank (D) (Reprinted with permission from reference [13])"
Figure 4
Schematic of the microbubble-based, ultrasound-assisted PDT strategy. (A) Preparation of PGL-MB and its transformation from microbubbles to nanoparticles under exposure to low-frequency ultrasound (LFUS); (B) Experimental process of in vivo PDT under the guidance of CEUS imaging, followed by ultrasound targeted microbubble destruction (UTMD). (Reprinted with permission from reference [22])"
Figure 5
In vivo CEUS and fluorescence imaging in a subcutaneous PC-3 tumor model. (A) In vivo CEUS in a subcutaneous PC-3 tumor model. CEUS imaging of the tumor site before (pre) and after intravenous administration (i.v.) of PGL-MBs; (B) Fluorescence imaging in vivo at different time points after intravenous administration of PGL-MBs, with or without LFUS (400 kPa, 3 min) exposure. Tumors are circled with yellow dashed lines; (C) Images of organs excised at 24 h after injection. Organs of tumor-bearing mice without PGL-MBs injection were excised as negative controls; (D) Quantitative analysis of fluorescence intensity for the excised organs (n = 3). (Reprinted with permission from reference [22])"
Figure 8
Isotype and endoglin-targeted ultrasound molecular imaging of a nude mouse with subcutaneous HB. (A) Intensity graph for the traced regions of interest prior to and after the destruction pulse (pink region). The region on the left of the column is prior to destruction, and on the right of it is after destruction. The change in intensity following the destruction pulse is an index of the amount of specific binding. The linearized signal prior to the destruction pulse represents bound and circulating microbubbles (MB) and tissue signal. The linearized signal after the destruction pulse corresponds to the MB that were still in circulation and to any residual tissue-echoes, and does not represent the binding process. The ΔTE was computed by subtracting the mean intensity detected after the destructive pulse from that prior to the destructive pulse; (B) Parametric imaging. The scale bar of ΔTE is on the right corner of the map; (C) ΔTE of isotype and endoglin-targeted MB. ΔTE=TEfd - TEpd. n=4; **P < 0.001. TE, targeted enhancement; ΔTE, differential TE; fd, following destruction; pd, prior to destruction; MB, microbubbles. (Reprinted with permission from reference [30])"
Figure 9
Ultrasound contrast agents able to target a molecular signature on the surface of cancer cells could be a promising strategy for improved cancer detection. The diagram demonstrates application of CA-125-targeted echogenic lipid and surfactant-stabilized nanobubbles (smaller than 200 nm mean hydrodynamic diameter) for targeting CA-125 positive OVCAR-3 tumors in mice. Targeted or non-targeted nanobubbles were injected into mice (via tail vein) bearing either CA-125 positive or negative flank ovarian tumors. Tumors were imaged with contrast harmonic imaging at 12 MHz, and time-intensity curves and histology were utilized to compare tumor distribution and pharmacokinetics of the contrast agents. (Reprinted with permission from reference [37])"
Figure 11
Molecular ultrasound imaging with VEGF targeted microbubbles detected response of anti-angiogenic therapy in mice with clear-cell cancer. Method for obtaining anechoic regions in a peak intensity image (A). The green dots outline the tumor. The image is blurred using a Gaussian filter to eliminate dark areas in speckle (B). The regions below a predetermined intensity threshold are selected as anechoic (C). Note: these are single frames in a 3D volume, so the process will be performed for each slice in the volume. (Reprinted with permission from reference [64])"
Figure 12
Representative targeted ultrasound (US) images for intracellular adhension molecule-1 (ICAM-1) and normalized intensity difference (NID) in each group. (A) Representative targeted ultrasound (US) images of ICAM-1-targeted microbubbles (MBICAM-1) and control microbubbles (MBCON) in ischemia-reperfusion injury (IRI) rats and control rats. US signal after MBICAM-1 in IRI liver was substantially higher than that in control liver and was significantly higher compared with MBCON in IRI liver and normal liver; (B) The normalized intensity differences (NIDs) were calculated as the ratio of subtraction using the destruction-replenishment method (n = 3, *P = 0.048, IRI group compared with control group after MBICAM-1 administration). (Reprinted with permission from reference [66])"
Figure 13
Representative targeted ultrasound (US) images evaluating different degrees of ischemia-reperfusion injury (IRI). Targeted US imaging signal was weakest in the control liver (A) and strongest in the moderate to severe IRI liver (C) compared with that in the mild IRI liver (B); (D) The normalized intensity difference (NID) in each group. (*P < 0.001 mild IRI group vs control group, #P = 0.002) moderate to severe IRI group vs mild IRI group, &P < 0.001 moderate to severe IRI group vs control group). (Reprinted with permission from reference [66])"
Figure 14
Schematic illustration of the image and analysis protocol (A). After monitoring for 4 min, targeted MBs were considered to adhere to the tumor site firmly. Blank MBs or DPMC were destroyed by the Flash mode of the ultrasound system. The process was monitored, starting from injection to at least 30 s after Flash destruction. The video intensity (VI) from adherent MBs (Targeted VI) was assessed by calculating the average pre- and post-destruction VI, and subtracting average post- from pre-destruction intensity. Ultrasound molecular images representing intensity from adherent blank MBs or DPMC displayed as color maps overlaid on B-mode images (B). Yellow line represents the region of interest (ROI). Image signals are quantitatively presented (***P<0.001) (C). (Reprinted with permission from reference [71])"
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