Tumor Molecular Imaging with Nanoparticles

Molecular imaging(MI)can provide not only structural images using traditional imaging techniques but also functional and molecular information using many newly emerging imaging techniques.Over the past decade,the utilization of nanotechnology in MI has exhibited many significant advantages and provided new opportunities for the imaging of living subjects.It is expected that multimodality nanoparticles(NPs)can lead to precise assessment of tumor biology and the tumor microenvironment.This review addresses topics related to engineered NPs and summarizes the recent applications of these nanoconstructs in cancer optical imaging,ultrasound,photoacoustic imaging,magnetic resonance imaging(MRI),and radionuclide imaging.Key challenges involved in the translation of NPs to the clinic are discussed.

A NEAR-INFRARED FLUORESCENT DEOXYGLUCOSE DERIVATIVE FOR OPTICAL IMAGING OF EXPERIMENTAL ARTHRITIS

The purpose of this study is to investigate whether a near-infrared fluorescence(NIRF)probe,Cy5.5-d-glucosamine(Cy5.5-2DG),can image arthritis in collagen-induced arthritic(CIA)mice.The presence of arthritis was verified by both visual examination and micro-computed tomography(MicroCT)imaging.CIA mice were imaged by a micro-positron emission tomography(MicroPET)scanner one hour after intravenous injection of 2-deoxy-2-[18F]fluoro-d-glucose([18F]FDG).After radioactivity of[18F]FDG decayed away,Cy5.5-2DG was injected into a lateral tail vein of the mice.Arthritic tissue targeting and retention of Cy5.5-2DG in CIA mice were evaluated and quantified by an optical imaging system.Inflammatory tissue in CIA mice was clearly visualized by[18F]FDG-MicroPET scan.NIRF imaging of Cy5.5-2DG in the same mice revealed that the pattern of localization of Cy5.5-2DG in the arthritic tissue was very similar to that of[18F]FDG.Quantification analysis further showed that[18F]FDG uptake in arthritic tissues at one hour post-injection(p.i.)and Cy5.5-2DG uptakes at different time points p.i.were all well correlated(r2 over 0.65).In conclusion,Cy5.5-DG can detect arthritic tissues in living mice.The good correlation between the[18F]FDG uptake and Cy5.5-2DG accumulation in the same arthritic tissue warrants further investigation of Cy5.5-2DG as an approach for assessment of anti-inflammatory treatments.

Antimicrobial peptides and the gut microbiome in inflammatory bowel disease

Antimicrobial peptides(AMP)are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells,Paneth cells,as well as immune cells in the gastrointestinal(GI)tract.They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections.Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease(IBD)and converge on the function of AMP,the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years.In this frontier article,we discuss the function and mechanisms of AMP in the GI tract,examine the interaction of AMP with the gut microbiome,explore the role of AMP in the pathogenesis of IBD,and review translational applications of AMP in patients with IBD.

visual bone marrow mesenchymal stem cell transplantation in the repair of spinal cord injury

An important factor in improving functional recovery from spinal cord injury using stem cells is maximizing the number of transplanted cells at the lesion site. Here, we established a contusion model of spinal cord injury by dropping a weight onto the spinal cord at T7_8. Superparamagnet- ic iron oxide-labeled bone marrow mesenchymal stem cells were transplanted into the injured spinal cord via the subarachnoid space. An outer magnetic field was used to successfully guide the labeled cells to the lesion site. Prussian blue staining showed that more bone marrow mesen- chymal stem cells reached the lesion site in these rats than in those without magnetic guidance or snperparamagnetic iron oxide labeling, and immunofluorescence revealed a greater number of complete axons at the lesion site. Moreover, the Basso, Beattie and Bresnahan （BBB） locomotor rating scale scores were the highest in rats with superparamagnetic labeling and magnetic guid- ance. Our data confirm that superparamagnetic iron oxide nanoparticles effectively label bone marrow mesenchymal stem cells and impart sufficient magnetism to respond to the external magnetic field guides. More importantly, superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells can be dynamically and non-invasively tracked in vivo using magnetic resonance imaging. Superparamagnetic iron oxide labeling of bone marrow mesenchymal stem cells coupled with magnetic guidance offers a promising avenue for the clinical treatment of spinal cord injury.

Deep-Tissue Photothermal Therapy Using Laser Illumination at NIR-Ⅱa Window

Photothermal therapy(PTT)using near-infrared(NIR)light for tumor treatment has triggered extensive attentions because of its advantages of noninvasion and convenience.The current research on PTT usually uses lasers in the first NIR window(NIR-I;700–900 nm)as irradiation source.However,the second NIR window(NIR-II;1000–1700 nm)especially NIRIIa window(1300–1400 nm)is considered much more promising in diagnosis and treatment as its superiority in penetration depth and maximum permissible exposure over NIR-I window.Hereby,we propose the use of laser excitation at 1275 nm,which is approved by Food and Drug Administration for physical therapy,as an attractive technique for PTT to balance of tissue absorption and scattering with water absorption.Specifically,CuS-PEG nanoparticles with similar absorption values at 1275 and 808 nm,a conventional NIR-I window for PTT,were synthesized as PTT agents and a comparison platform,to explore the potential of 1275 and 808 nm lasers for PTT,especially in deep-tissue settings.The results showed that 1275 nm laser was practicable in PTT.It exhibited much more desirable outcomes in cell ablation in vitro and deep-tissue antitumor capabilities in vivo compared to that of 808 nm laser.NIR-IIa laser illumination is superior to NIR-I laser for deep-tissue PTT,and shows high potential to improve the PTT outcome.

Highly Integrated Multiplexing and Buffering Electronics for Large Aperture Ultrasonic Arrays

Large aperture ultrasonic arrays can be implemented by tiling together multiple pretested modules of high-density acoustic arrays with closely integrated multiplexing and buffering electronics to form a larger aperture with high yield.These modular arrays can be used to implement large 1.75D array apertures capable of focusing in elevation for uniform slice thickness along the axial direction which can improve image contrast.An important goal for large array tiling is obtaining high yield and sensitivity while reducing extraneous image artifacts.We have been developing tileable acoustic-electric modules for the implementation of large array apertures utilizing Application Specific Integrated Circuits(ASICs)implemented using 0.35μm high voltage(50 V)CMOS.Multiple generations of ASICs have been designed and tested.The ASICs were integrated with high-density transducer arrays for acoustic testing and imaging.The modules were further interfaced to a Verasonics Vantage imaging system and were used to image industry standard ultrasound phantoms.The first-generation modules comprise ASICs with both multiplexing and buffering electronics on-chip and have demonstrated a switching artifact which was visible in the images.A second-generation ASIC design incorporates low switching injection circuits which effectively mitigate the artifacts observed with the first-generation devices.Here,we present the architecture of the two ASIC designs and module types as well imaging results that demonstrate reduction in switching artifacts for the second-generation devices.

Erratum to “Highly Integrated Multiplexing and Buffering Electronics for Large Aperture Ultrasonic Arrays”

In the article titled“Highly Integrated Multiplexing and Buffering Electronics for Large Aperture Ultrasonic Arrays”[1],there was an error in figure 7.The figure should show as per the submitted files.

双定向超声对比剂在体评价肿瘤血管形成

目的研制并验证双定向超声对比剂(imagingagent),即将微气泡(MBs)附着到血管内皮生长因子受体2(vascular endothelial growth factor receptor,VEGFR2)

靶向微泡成像显示肿瘤新生血管:微型PET动态扫描评估小鼠体内的生物学分布

目的通过微型PET对活体小鼠的动态扫描来评价肿瘤血管内皮生成因子受体2(VEGFR2)相关的微泡靶向肿瘤新生血管在小鼠体内的分布。材料与方法

Photoacoustic detection of follicular thyroid carcinoma using targeted Nano-Au-Tripods

Follicular thyroid carcinoma(FTC)is the second most common form of thyroid malignancy,and it is associated with more aggressive growth and worse long-term survival outcomes relative to papillary thyroid carcinoma(PTC).Reliable approaches to preoperative FTC detection,however,remain to be established.Herein,a targeted Affibody-Au-Tripod nanoprobe was developed and successfully utilized to facilitate the targeted photoacoustic imaging(PAI)of epidermal growth factor receptor(EGFR)-positive cells and tumors.These Affibody-Au-Tripods were found to be highly sensitive and specific for cells expressing EGFR when used as a PA contrast agent in vitro,and studies conducted in an FTC-133 subcutaneous tumor model system in mice further revealed that these Affibody-Au-Tripods were able to specifically target these EGFR-expressing tumors while providing a strong photoacoustic signal in vivo.Importantly,these nanoprobes exhibited negligible cytotoxicity and robust chemical and physical stability,making Affibody-Au-Tripods promising candidates for targeted PAI-based FTC diagnosis.In addition,these nanoprobes have the potential to facilitate the individualized treatment of patients harboring EGFRpositive tumors.

PET probes beyond ^(18)F-FDG

During the past several decades,positron emission tomography（PET） has been one of the rapidly growing areas of medical imaging;particularly,its applications in routine oncological practice have been widely recognized.At present,^18F-fluorodeoxyglucose（^18F-FDG） is the most broadly used PET probe.However,^18F-FDG also suffers many limitations.Thus,scientists and clinicians are greatly interested in exploring and developing new PET imaging probes with high affinity and specificity.In this review,we briefly summarize the representative PET probes beyond ^18F-FDG that are available for patients imaging in three major clinical areas（oncology,neurology and cardiology）,and we also discuss the feasibility and trends in developing new PET probes for personalized medicine.

从小动物到大动物的人间质干细胞基因表达成像

目的采用临床PET／CT扫描，评价植入猪心肌内的人间质干细胞（MSCs）报告基因成像的可行性。材料与方法动物实验方案经实验动物保护学术委员会批准。采用不同剂量的含有巨细胞病毒（CMV）启动子的腺病毒进行人MSCs的转导，CMV启动子诱导变异的1型单纯疱疹病毒胸腺嘧啶脱氧核苷激酶的报告基因（Ad—CMV—HSV1-sr39tk）在细胞培养中确定其特征。

Biological imaging without autofluorescence in the second near-infrared region

Fluorescence imaging is capable of acquiring anatomical and functional infor- mation with high spatial and temporal resolution. This imaging technique has been indispensable in biological research and disease detection/diagnosis. Imaging in the visible and to a lesser degree, in the near-infrared （NIR） regions below 900 nm, suffers from autofluorescence arising from endogenous fluorescent molecules in biological tissues. This autofluorescence interferes with fluorescent molecules of interest, causing a high background and low detection sensitivity. Here, we report that fluorescence imaging in the 1,500-1,700-nm region （termed ＂NIR-IIb＂） under 808-nm excitation results in nearly zero tissue autofluorescence, allowing for background-free imaging of fluorescent species in otherwise notoriously autofluorescent biological tissues, including liver. Imaging of the intrinsic fluorescence of individual fluorophores, such as a single carbon nanotube, can be readily achieved with high sensitivity and without autofluorescence background in mouse liver within the 1,500-1,700-nm wavelength region.

InAs/InP/ZnSe Core/Shell/Shell Quantum Dots as Near-Infrared Emitters:Bright,Narrow-Band,Non-Cadmium Containing,and Biocompatible

High quality InAs/InP/ZnSe core/shell/shell quantum dots have been grown by a one-pot approach.This engineered quantum dots with unique near-infrared(NIR)fluorescence,possessing outstanding optical properties,and the biocompatibility desired for in vivo applications.The resulting quantum dots have significantly lower intrinsic toxicity compared to NIR emissive dots containing elements such as cadmium,mercury,or lead.Also,these newly developed ultrasmall non-Cd containing and NIR-emitting quantum dots showed signifi cantly improved circulation half-life and minimal reticuloendothelial system(RES)uptake.

Differential Responses of Transplanted Stem Cells to Diseased Environment Unveiled by a Molecular NIR-II Cell Tracker

Stem cell therapy holds high promises in regenerative medicine.The major challenge of clinical translation is to precisely and quantitatively evaluate the in vivo cell distribution,migration,and engraftment,which cannot be easily achieved by current techniques.To address this issue,for the first time,we have developed a molecular cell tracker with a strong fluorescence signal in the second near-infrared(NIR-II)window(1,000-1,700 nm)for real-time monitoring of in vivo cell behaviors in both healthy and diseased animal models.The NIR-II tracker(CelTrac1000)has shown complete cell labeling with low cytotoxicity and profound long-term tracking ability for 30 days in high spatiotemporal resolution for semiquantification of the biodistribution of transplanted stem cells.Taking advantage of the unique merits of CelTrac1000,the responses of transplanted stem cells to different diseased environments have been discriminated and unveiled.Furthermore,we also demonstrate CelTrac1000 as a universal and effective technique for ultrafast real-time tracking of the cellular migration and distribution in a 100μm single-cell cluster spatial resolution,along with the lung contraction and heart beating.As such,this NIR-II tracker will shift the optical cell tracking into a single-cell cluster and millisecond temporal resolution for better evaluating and understanding stem cell therapy,affording optimal doses and efficacy.

124I原位标记有机黑色素纳米粒子的制备及初步分子影像研究

探索了有机黑色素纳米粒子对一种目前最有潜力的新型PET成像核素的原位标记方法,制备出新型多功能纳米探针,并进行初步的分子影像研究.以自然存在的黑色素(Melanin)为原料,利用超声破碎法制备超微粒径(5.5nm)黑色素纳米粒子(MNPs),并使用两端具有氨基的PEG3500对其表面进行修饰,获得具有较好水分散性和氨基活性基团的新型PEG-MNP纳米载体.采用动态光散射(DLS)、透射电镜(TEM)、红外光谱(FTIR)以及核磁氢谱(1HNMR)对纳米粒子进行充分形貌表征.而后使用溴代琥珀酰亚胺(NBS)作为氧化剂进行长半衰期核素^124I的原位标记,获得了相应的具有PET成像功能的^124I-PEG-MNP纳米载体.而后使用游离^124I、^124I-PEG-MNP分别进行正常昆明小鼠Micro-PET成像对比研究,同时构建胰腺癌荷瘤鼠模型BxPC3,并进行^124I-PEG-MNP肿瘤成像研究.结果显示,长半衰期核素^124I对PEG-MNP的标记率可达99%以上,且体外稳定性良好.Micro-PET图像显示,^124I-PEG-MNP在小鼠体内未见脱标现象,体内放射性分布与游离^124I成像差异明显.通过基于选定甲状腺及肝脏感兴趣区(RegionofInterest,ROI)的半定量分析表明,经过^124I标记后的PEG-MNP纳米粒子,与原有^124I的代谢学行为具有显著的统计学差异(P<0.001).同时,^124I-PEG-MNP利用自身的实体瘤高通透性和滞留效应(EPR)在肿瘤部位有明显的富集,并在肿瘤部位滞留超过48h.上述研究表明,有机纳米粒子PEG-MNP具备标记单质长半衰期核素的能力,并可用于肿瘤模型PET显像,为其进一步构建长循环多模态成像探针提供实验依据.