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Abstract. This study investigates a photoacoustic/ultrasound dual-modality contrast agent, including extending its applications from image-contrast enhancement to combined diagnosis and therapy with site-specific targeting. The contrast agent comprises albumin-shelled microbubbles with encapsulated gold nanorods (AuMBs). The gas-filled microbubbles, whose diameters range from submicrometer to several micrometers, are not only echogenic but also can serve as drug-delivery vehicles. The gold nanorods are used to enhance the generation of both photoacoustic and photothermal signals. The optical absorption peak of the gold nanorods is tuned to 760 nm and is invariant after microbubble encapsulation. Dual-modality contrast enhancement is first described here, and the applications to cellular targeting and laser-induced thermotherapy in a phantom are demonstrated. Photoacoustic imaging can be used to monitor temperature increases during the treatment. The targeting capability of AuMBs was verified, and the temperature increased by 26°C for a laser power of 980 mW, demonstrating the potential of combined diagnosis and therapy with the dual-modality agent. Targeted photo-or acoustic-mediated delivery is also possible.

Plasmonic photothermal therapy (PPTT) using plasmonic nanoparticles as efficient photoabsorbing agents has been proposed previously. One critical step in PPTT is to effectively deliver gold nanoparticles into the cells. This study demonstrates that the delivery of gold nanorods (AuNRs) can be greatly enhanced by combining the following three mechanisms: AuNRs encapsulated in protein-shell microbubbles (AuMBs), molecular targeting, and sonoporation employing acoustic cavitation of microbubbles (MBs). Both in vitro and in vivo tests were performed. For molecular targeting, the AuMBs were modified with anti-VEGFR2. Once bound to the angiogenesis markers, the MBs were destroyed by ultrasound to release the AuNRs and the release was confirmed by photoacoustic measurements. Additionally, acoustic cavitation was induced during MB destruction for sonoporation (i.e., increase in transient cellular permeability). The measured inertial cavitation dose was positively correlated with the temperature increase at the tumor site. The quantity of AuNRs delivered into the cells was also determined by measuring the mass spectrometry and observed using third-harmonic-generation microscopy and two-photon fluorescence microscopy. A temperature increase of 20°C was achieved in vitro. The PPTT results in vivo also demonstrated that the temperature increase (>45°C) provided a sufficiently high degree of hyperthermia. Therefore, synergistic delivery of AuNRs was demonstrated.

This paper introduces the SNR-dependent coherence factor (CF), which can be used for adaptive side lobe suppression in ultrasound (US) and photoacoustic (PA) imaging. Previous methods employed the minimum-variance distortionless response (MVDR)-based CF to achieve remarkable resolution improvement (by MVDR) and to suppress side lobes (by CF). However, the SNR is often low when using an unfocused acoustic beam (e.g., high-frame-rate imaging) and in PA imaging (limited laser energy), giving such an approach suboptimal performance in these applications because noise also lowers the coherence and thus affects the effectiveness of the side lobe suppression by these CF-based methods. To overcome this problem, the proposed method takes into account the local SNR in the CF formulation so that the contrast can be restored even when the SNR is low. We tested this method with both high-frame-rate US imaging and PA imaging. Simulations show that the proposed method performs well even when the SNR is as low as -10 dB. Compared with the conventional CF, the contrast (CR) and contrast-to-noise ratio (CNR) in clinical US imaging can be improved by an average of 27.2% in CR and 11.1% in CNR with the proposed method, whereas in PA imaging, the lateral resolution could be restored and the image contrast was elevated by 17 dB.

Hypoechogenicity has been described qualitatively and is potentially subject to intra- and inter-observer variability. The aim of this study was to clarify whether quantitative echoic indexes (EIs) are useful for the detection of malignant thyroid nodules. Overall, 333 participants with 411 nodules were included in the final analysis. Quantification of echogenicity was performed using commercial software (AmCAD-UT; AmCad BioMed, Taiwan). The coordinates of three defined regions, the nodule, thyroid parenchyma, and strap muscle regions, were recorded in the database separately for subsequent analysis. And the results showed that ultrasound echogenicity (US-E), as assessed by clinicians, defined hypoechogenicity as an independent factor for malignancy. The EI, adjusted EI (EIN-T; EIN-M) and automatic EI(N-R)/R values between benign and malignant nodules were all significantly different, with lower values for malignant nodules. All of the EIs showed similar percentages of sensitivity and specificity and had better accuracies than US-E. In conclusion, the proposed quantitative EI seems more promising to constitute an important advancement than the conventional qualitative US-E in allowing for a more reliable distinction between benign and malignant thyroid nodules.

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