Huan Qin

Gadolinium(III)-gold nanorods for MRI and photoacoustic imaging dual-modality detection of macrophages in atherosclerotic inflammation

AIM One of the features of high-risk atherosclerotic plaques is the preponderance of macrophages. Gadolinium(III)-gold nanorods (Gd(III)-GNRs) have been developed as a dual-modality probe for MRI and photoacoustic imaging (PAI) to trace macrophages for determining the degree of inflammation. MATERIALS & METHODS Gd(III)-GNRs were utilized for MRI and PAI dual-modality detection of macrophages in living mice and ex vivo simulated macrophage-rich plaque. RESULTS Gd(III)-GNRs were shown to be endocytosed by macrophages in vitro. Macrophages labeled with Gd(III)-GNRs were detected by both PAI and MRI. With Gd(III)-GNRs, it is possible to institute a multiscale complementary imaging protocol: MRI can screen to identify the location of the probe-phagocytosed macrophages, and intravascular PAI provides a subsequent precise morphology to quantify the infiltration area and invasion depth of macrophages in the arterial wall. CONCLUSION This new dual-modality nanoparticle approach has promise for enabling quantitative detection of macrophages in atherosclerotic plaques.

Fluorescence Quenching Nanoprobes Dedicated to In Vivo Photoacoustic Imaging and High‐Efficient Tumor Therapy in Deep‐Seated Tissue

Photoacoustic imaging (PAI) and photoacoustic (PA) therapy have promising applications for treating tumors. It is known that the utilization of high-absorption-coefficient probes can selectively enhance the PAI target contrast and PA tumor therapy efficiency in deep-seated tissue. Here, the design of a probe with the highest availability of optical-thermo conversion by using graphene oxide (GO) and dyes via π-π stacking interactions is reported. The GO serves as a base material for loading dyes and quenching dye fluorescence via fluorescence resonance energy transfer (FRET), with the one purpose of maximum of PA efficiency. Experiments verify that the designed fluorescence quenching nanoprobes can produce stronger PA signals than the sum of the separate signals generated in the dye and the GO. Potential applications of the fluorescence quenching nanoprobes are demonstrated, dedicating to enhance PA contrast of targets in deep-seated tissues and tumors in living mice. PA therapy efficiency both in vitro and in vivo by using the fluorescence quenching nanoprobes is found to be higher than with the commonly used PA therapy agents. Taken together, quenching dye fluorescence via FRET will provide a valid means for developing high-efficiency PA probes. Fluorescence quenching nanoprobes are likely to become a promising candidate for deep-seated tumor imaging and therapy.

Microwave-induced thermoacoustic computed tomography with a clinical contrast agent of NMG2[Gd(DTPA)]

NMG2[Gd(DTPA)], a clinical contrast agent, was investigated for microwave-induced thermoacoustic computed tomography (CT). Due to ionic conduction and magnetic dipole rotation in the presence of microwave field, microwave energy absorbed by NMG2[Gd(DTPA)] would be transformed to thermoacoustic signals based on the thermoelastic effect. The experimental results demonstrated that NMG2[Gd(DTPA)] at a concentration of 10 mM provided effective enhancement compared with water. The enhancement of NMG2[Gd(DTPA)] for thermoacoustic CT was further demonstrated in invivo tumor-bearing mouse. The theory and experimental results indicate that the clinically available NMG2[Gd(DTPA)] will promote the medical applications of thermoacoustic CT.

Thermally confined shell coating amplifies the photoacoustic conversion efficiency of nanoprobes

Efficient probes/contrast agents are highly desirable for good-performance photoacoustic (PA) imaging, where the PA signal amplitude of a probe is dominated by both its optical absorption and the conversion efficiency from absorbed laser energy to acoustic waves. Nanoprobes have a unique micromechanism of PA energy conversion due to the size effect, which, however, has not been quantitatively demonstrated and effectively utilized. Here, we present quantitative simulations of the PA signal production process for plasmonmediated nanoprobes based on the finite element analysis method, which were performed to provide a deep understanding of their PA conversion micromechanism. Moreover, we propose a method to amplify the PA conversion efficiency of nanoprobes through the use of thermally confined shell coating, which allows the active control of the conversion efficiency beyond that of conventional probes. Additionally, we deduced the dependence of the conversion efficiency on the shell properties. Gold-nanoparticles/polydimethylsiloxane nanocomposites were experimentally synthesized in the form of gel and microfilms to verify our idea and the simulation results agreed with the experiments. Our work paves the way for the rational design and optimization of nanoprobes with improved conversion efficiency.

Inflammation-targeted gold nanorods for intravascular photoacoustic imaging detection of matrix metalloproteinase-2 (MMP2) in atherosclerotic plaques

Elevated expression of matrix metalloproteinase-2 (MMP2) is one of the clinical features of high-risk atherosclerotic plaques. Many methods such as fluorescence imaging methods have been used to detect MMP2 for evaluating plaque vulnerability. However, so far no imaging method has been able to resolve the expression of MMP2 with high fidelity and resolution beyond microscopic depths. In this study, gold nanorods conjugated with MMP2 antibody (AuNRs-Abs) were developed as a highly efficient photoacoustic imaging (PAI) probe for mapping MMP2 in atherosclerotic plaques. AuNRs-Abs could specifically target MMP2 as demonstrated by scanning electron microscope and immunofluorescence imaging. After labeling with AuNRs-Abs, area of distribution of MMP2 from the surface to the depths of the atherosclerotic plaques was revealed using intravascular PAI. AuNRs-Abs has the ability to enable quantitative detection of MMP2 in atherosclerotic plaques.

In vivo cell characteristic extraction and identification by photoacoustic flow cytography.

We present a photoacoustic flow cytography with fast cross-sectional (B-scan) imaging to precisely identify specific cells in vivo. The B-scan imaging speed of the system is up to 200 frame/s with a lateral resolution of 1.5 μm, which allows to dynamically image the flowing cells within the microvascular. The shape, size and photoacoustic intensity of the target cells are extracted from streaming images and integrated into a standard pattern to distinguish cell types. Circulating red blood cells and melanoma cells in blood vessels are simultaneously identified on melanoma-bearing mouse model. The results demonstrate that in vivo photoacoustic flow cytography can provide cells characteristics analysis and cell types visual identification, which will be applied for noninvasively monitoring circulating tumor cells (CTCs) and analyzing hematologic diseases.

In vivo fast variable focus photoacoustic microscopy using an electrically tunable lens

Fast focusing scan over a large depth range is challenging in photoacoustic microscopic imaging. In this paper, a fast variable focus photoacoustic microscopy (VF-PAM) with a large range of imaging depth was presented by using an electrically tunable lens (ETL). The ETL controlled the divergence angle of the laser beam for fast and continuous focus-shifting in depth direction with the shifting time of 15 ms, and 2.82 mm focus-shifting range with a 1 µm shifting accuracy was achieved by combining the ETL with a 0.3 NA plan microscope objective lens. Carbon fibers imaging verified the depth imaging ability of the system, in vivo microvasculature of mouse ear and brain tissues of the mouse imaging further demonstrated the focusing scan ability in biomedical application. The fast VF-PAM system allows substantial shortening of the focus-shifting time, which will be more conducive to studying living biological tissue, and will promote the development of in vivo noninvasive PA depth imaging without mechanical scan.

Dextran-coated Fe3O4 magnetic nanoparticles as a contrast agent in thermoacoustic tomography for hepatocellular carcinoma detection

Microwave-induced thermoacoustic tomography can provide a novel imaging modality for clinical detection. Significant progress has been made in the past several years in microwave-induced thermoacoustic tomography. In this paper, we investigate the feasibility of using dextran-coated Fe3O4 magnetic nanoparticles as a contrast agent in thermoacoustic tomography for hepatocellular carcinoma detection. Dextran-coated Fe3O4 magnetic nanoparticles administered intravenously are phagocytosed by resident Kupffer cells in normal reticuloendothelial system (RES) within the liver, but are not retained in tumor tissue. Consequently, there are significant differences in thermoacoustic signal intensity between normal RES and tumors, which result in increased lesion conspicuity and detectability. This provides the improvement of lesion-to-liver contrast for thermoacoustic tomography. A fast thermoacoustic computed tomography system with a multielement linear transducer array was used to image cancerous liver tissue with circular scanning. The results show that the system can provide molecular imaging with functionalized contrast agents for high-contrast detecting hepatocellular carcinoma and has the potential to become a novel approach for clinical diagnosis in the future.

Phage display-derived oligopeptide-functionalized probes for in vivo specific photoacoustic imaging of osteosarcoma

Specific detection of various tumor types remains crucial for designing effective treatment strategies. We demonstrate photoacoustic imaging (PAI) using high-affinity and high-specificity peptide-based probes for accurate and specific diagnosis of osteosarcoma. Herein, two new tumor-specific oligopeptides, termed PT6 and PT7, were identified using phage display-based screening on an osteosarcoma cell line (UMR-106). The identified oligopeptides were able to detect clinical osteosarcoma samples on tissue microarrays. Oligopeptide-conjugated PEGylated gold nanorods (PGNR) were designed to specifically target UMR-106 cells. More importantly, PAI revealed that both PGNR-PT6 and PGNR-PT7 could bind selectively to subcutaneous UMR-106 xenografts after systemic administration and enhance the contrast of osteosarcoma images by 170% and 230%, respectively, compared to tumor-bearing mice injected with PGNRs conjugated to scrambled oligopeptides. PAI employing PGNRs conjugated to specifically designed nanoprobes may provide a new method for tumor type-specific diagnosis of osteosarcoma.

Multi-parametric imaging of the invasiveness-permissive acidic microenvironment in human glioma xenografts

Gliomas, the intrinsic tumors of the brain, are currently incurable because they are extremely invasive. The infiltrative nature of gliomas makes them difficult to completely excise and leads to a high recurrence rate. Acidification of extracellular microenvironment plays an important role in the invasion, migration and metastasis of solid tumors. To elucidate the relationship between acidic microenvironment and the invasiveness of gliomas, multi-parametric imaging studies were conducted between a highly invasive orthotopic (ortho.) human U87MG glioma xenograft and a lowly invasive subcutaneous (s.c.) U87MG xenograft. In vivo optical imaging showed higher overall acidity of the ortho. tumor than that of the s.c. tumor after administration of a pH responsive near-infrared (NIR) fluorescence probe. Positron emission tomography/computed tomography (PET/CT) imaging demonstrated higher glucose uptake in the ortho. tumor after injection of [18F]-fluorodeoxyglucose (18F-FDG). Photoacoustic microscopy imaging (PAM) revealed a higher vascular density but a more aberrant vessel morphology in the ortho. tumor. Immunofluorescence microscopic imaging indicated significantly up-regulated acidification associated enzymes in the gliomas than in normal brain tissue. This work not only reveals the acidity correlated glioma invasiveness, but also shows the promise for curbing glioma invasiveness by neutralizing intratumoral acidity via down-regulation of glucose uptake, normalizing tumor vasculatures or blocking the acidification associated metabolic/physiological processes.