Use of Radioiodinated Peptide Arg-Arg-Leu Targeted to Neovascularization as well as Tumor Cells in Molecular Tumor Imaging

Objective： To explore a tumor peptide imaging agent Arginine-Arginine-Leucine （Tyr-Cys-Gly-Gly-Arg-Arg- Leu-Gly-Gly-Cys, tripeptide RRL [tRRL]） that targeted to tumor cells and tumor-derived endothelial cells （TDECs） and primarily investigate the possible relationship between tRRL and vascular endothelial growth factor receptor 2 （VEGFR-2）. Methods： The tRRL sequence motif was identified as a tumor molecular marker specifically binding to TDECs. Tyrosine was conjugated to the amino terminal of RRL （Cys-Gly-Gly-Arg-Arg-Leu-Gly-Gly-Cys） for labeling with radionuclide iodine-131 （1311-tRRL）. The uptake ability and molecular binding of tRRL to tumor cells and angiogenic endothelium were studied using flow cytometry and radioactivity counter in vitro. Whether VEGFR-2 is the binging site of tRRL was investigated. Biodistribution and single-photon emission computed tomography （SPECT） imaging of 131-tRRL were used to evaluate the effectiveness of this new imaging agent to visualize varied tumor xenografts in nude mice. Results： In vitro cellular uptake experiments revealed that tRRL could not only adhere to tumor angiogenic endothelial cells but also largely accumulate in malignant tumor cells. VEGFR-2, which is highly expressed on TDECs, was probably not the solely binding ligand for tRRL targeted to tumor angiogenic endothelium, 131-tRRL mainly accumulated in tumors in vivo, not other organs at 24 h after injection. SPECT imaging with 131-tRRL clearly visualized tumors in nude mice, especially at 24 h. Conclusion： Radioiodinated tRRL offers a noninvasive of tumors targeted to neovascularization, and may be a carrier. nuclear imaging method for functional molecular imaging promising candidate for tumor radioimmunotherapeutic carrier,

^(99m)Tc-AMD3100:A novel potential receptor-targeting radiopharmaceutical for tumor imaging

The chemokine CXCR4 receptor is over-expressed in a wide variety of tumors.In this study,AMD3100,which was a prototype non-peptide antagonist of CXCR4 receptor,was labeled with;Tc.;Tc-AMD3100 was verified by thin layer radio chromatography（TLRC）.The tumor-localizing properties of;Tc-AMD3100 were evaluated and proved in mice bearing Hep-G2 tumor xenograft.;Tc-AMD3100 was a promising,novel receptor-specific radiopharmaceutical with potential application in the imaging of human tumors.

Near-infrared dye-loaded magnetic nanoparticles as photoacoustic contrast agent for enhanced tumor imaging

Objective: Photoacoustic(PA) tomography(PAT) has attracted extensive interest because of its optical absorption contrast and ultrasonic detection. This study aims to develop a biocompatible and biodegradable PA contrast agent particularly promising for clinical applications in human body.Methods: In this study, we presented a PA contrast agent: 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)](DSPE-PEG)-coated superparamagnetic iron oxide(SPIO) nanoparticles(NPs) loaded with indocyanine green(ICG). We used ICG and SPIO NPs because both drugs are approved by the U.S. Food and Drug Administration. Given the strong absorption of near-infrared laser pulses, SPIO@DSPE-PEG/ICG NPs with a uniform diameter of ~28 nm could significantly enhance PA signals.Results: We demonstrated the contrast enhancement of these NPs in phantom and animal experiments, in which the in vivo circulation time of SPIO@DSPE-PEG/ICG NPs was considerably longer than that of free ICG. These novel NPs also displayed a high efficiency of tumor targeting.Conclusions: SPIO@DSPE-PEG/ICG NPs are promising PAT contrast agents for clinical applications.

pH Induced Self-assembly of AIE Fluorescent Probe for Tumor Imaging

This work reported an AIE fluorescent probe for tumor imaging based on the p H induced self-assembly strategy. The fluorescent probe was composed of an acid-responsive soluble copolymer PEG-b-PAMA-DMMA with a maleic acid amide group and an anionic soluble aggregation-induced emission fluorogen(AIEgen) TPE-2SO_(3)^(-). The polymer could be transformed into a protonated amine-containing polymer after the hydrolysis of maleic acid amide in acidic tumor microenvironment, which would be further self-assembled with TPE-2SO_(3)^(-)to form aggregated nanoparticles. The transition of TPE-2SO_(3)^(-)from dispersed state to aggregated state led to an obvious increase in fluorescence intensity due to its AIE characteristics.

Tumor Imaging by a^(99m)TcO_(4)^(−)-Labeled Cationic Polymeric Network

Technetium-99m(^(99m)Tc)is the most used(>80%)radionuclide in the clinical nuclear diagnostic imaging procedure.The traditional approach to preparing ^(99m)Tc-based imaging agents utilizes stannous chloride(SnCl_(2))for the reduction of noncomplexing pertechnetate(^(99m)TcO_(4)^(−))to low-valent Tc[e.g.,Tc(IV)].This process,however,is difficult to control precisely and usually results in toxic SnCl_(2) residue and remaining 99mTc(VII),both of which are destructive to humans.Herein,we report a new strategy for preparing^(99m)TcO_(4)^(−)-labeled agents without adding any reductants.The deliberately designed nanoscale cationic polymeric network(SCU-CPN-3)shows excellent affinity for^(99m)TcO_(4)^(−)even at trace levels originating from the strong p-πinteraction with^(99m)TcO_(4)^(−).Impressively,record-fast labeling kinetics are observed,where almost quantitative labeling efficacy(>96%)can be achieved within 1 min,giving rise to a short labeling time and simple operation using a clinical kit.Both single-photon emission computed tomography(SPECT)images and ex vivo biodistribution of different tumor model analyses verify the potential feasibility of this strategy for tumor imaging.

FOLATE-TARGETED OPTICAL AND MAGNETIC RESONANCE DUAL-MODALITY PCL-b-PEG MICELLES FOR TUMOR IMAGING

A biodegradable tumor targeting nano-probe based on poly（ε-caprolactone）-b-poly（ethylene glycol） block copolymer （PCL-b-PEG）micelle functionalized with a magnetic resonance imaging （MRI） contrast agent diethylenetriaminepentaacetic acid-gadolinium （DTPA-Gd＋） on the shell and a near-infrared （NIR） dye in the core for magnetic resonance and optical dual-modality imaging was prepared. The longitudinal relaxivity （rl） of the PCL-b-PEG- DTPA-Gd3＋ micelle was 13.4 （mmol/L）^-1s^-1, three folds of that of DTPA-Gd3＋, and higher than that of many polymeric contrast agents with similar structures. The in vivo optical imaging of a nude mouse bearing xenografied breast tumor showed that the dual-modality micelle preferentially accumulated in the tumor via the folic acid-mediated active targeting and the passive accumulation by the enhanced permeability and retention （EPR） effect. The results indicated that the dualmodality micelle is a promising nano-probe for cancer detection and diagnosis.

In vivo bioorthogonal labeling of rare-earth doped nanoparticles for improved NIR-II tumor imaging by extracellular vesiclemediated targeting

The development of efficient contrast agents for tumor-targeted imaging remains a critical challenge in the clinic.Herein,we proposed a tumor-derived extracellular vesicle(EV)-mediated targeting approach to improve in vivo tumor imaging using ternary downconversion nanoparticles(DCNPs)with strong near infrared II(NIR-II)luminescence at 1,525 nm.The EVs were metabolically engineered with azide group,followed by in vivo labeling of DCNPs through copper-free click chemistry.By taking advantage of the homologous targeting property of tumor derived EVs,remarkable improvement in the tumor accumulation(6.5%injection dose(ID)/g)was achieved in the subcutaneous colorectal cancer model when compared to that of individual DCNPs via passive targeting(1.1%ID/g).Importantly,such bioorthogonal labeling significantly increased NIR-II luminescence signals and prolonged the retention at tumor sites.Our work demonstrates the great potential of EVs-mediated bioorthogonal approach for in vivo labeling of NIR-II optical probes,which provides a robust tool for tumor-specific imaging and targeted therapy.

Extracellular Milieu and Membrane Receptor Dual-Driven DNA Nanorobot for Accurate in Vivo Tumor Imaging

Precise diagnostic approaches have great potential in cancer intervention and prognosis.Although diverse DNA nanoprobes have been reported for tumor diagnosis,precise tumor imaging in vivo still encounters a great challenge due to the scarcity of exquisite design methodology.Herein,by assembling three programmable modules on a DNA triangular prism,we engineered a DNA nanorobot for simultaneous recognition of extracellular pH and cancer cell membrane receptor in an intelligent manner.Since the design uses two heterogeneous types of biomarkers as inputs,pH-RE not only could discriminate target tumor cells from similar cell mixtures with a recognition accuracy as high as 98.8%,but also could perform precise tumor imaging in living mice by intravenous injection.We expect that this extracellular pH and membrane receptor dual-driven DNA nanorobot will facilitate the establishment of a novel design paradigm for precise cancer diagnosis and therapy.

Laser spectroscopy imaging technique coupled withnanomaterials for cancer diagnosis: A review

Laser spectroscopic imaging techniques have received tremendous attention in the-eld of cancer diagnosis due to their high sensitivity,high temporal resolution,and short acquisition time.However,the limited tissue penetration of the laser is still a challenge for the in vivo diagnosis of deep-seated lesions.Nanomaterials have been universally integrated with spectroscopic imaging techniques for deeper cancer diagnosis in vivo.The components,morphology,and sizes of nanomaterials are delicately designed,which could realize cancer diagnosis in vivo or in situ.Considering the enhanced signal emitting from the nanomaterials,we emphasized their combination with spectroscopic imaging techniques for cancer diagnosis,like the surface-enhanced Raman scattering(SERS),photoacoustic,fluorescence,and laser-induced breakdown spectroscopy(LIBS).Applications ofthe above spectroscopic techniques offer new prospectsfor cancer diagnosis.

In situ Activatable Peptide-based Nanoprobes for Tumor Imaging

Owing to its excellent biological properties,peptide has been widely used in the design of nanoprobes capable of enhancing tumor imaging signals.In recent years,a number of peptide-based nanoprobes with strong loading capacity and great biocompatibility have been developed for precision tumor imaging by coupling peptide motifs with different imaging agents.It is worth noting that,compared with“always on”mode,the use of stimulus-mediated in situ activatable mode to design and control the self-assembly or nanostructure transformation of peptide-based nanoprobes in vivo can achieve the significant improvement of imaging efficiency.Herein,we summarize the recent progress of in situ activatable peptide-based nanoprobes for tumor imaging in diverse imaging modes,including magnetic resonance imaging(MRI),fluorescence imaging(FI),photoacoustic imaging(PAI),radionuclide imaging(RI)and multimodal imaging.Finally,we briefly prospect the challenges and potential development directions of this field.

Imaging tumor hypoxia:Blood-borne delivery of imaging agents is fundamentally different in hypoxia subtypes

Dedicated to the memory of Professor Briton Chance on the ccasion of his 100th birthday(July24 th,2013),and remembering mary erciting discussions on the orygenation of breast cancer,ontumor hyporia in general and imaging of the orygenation status of malignant tumors.Hypoxic tissue subvolumes are a hallmark feat ure of solid malignant tumors,relevant for cancertherapy and patient outcome because they increase both the intrinsic aggressiveness of tumor cells and their resist ance to several commonly used anticancer strategies.Pathogenetic mech-anisms leading to hypoxia are diverse,may coexist within the same tumor and are commonlygrouped according to the duration of their ffects.Chronic hypoxia is mainly caused by difusionlimitations resulting from enlarged intercapilary distances and adverse difusion geometriesand--to a lsser extent--by hypoxemia,compromised perfusion or long-lasting microregionalfow stops.Conversely,acute hypoxia preferentilly results from transient disruptions in per.fusion.While each of these features of the tumor microenvironment can contribute to a criticalreduction of oxy gen availability,the delivery of imaging agents(as well as nutrients and anti-cancer agents)may be compromised or remain unaffected,Thus,a critial appraisal of the ffectsof the various mechanisms leading to hypoxia with regard to the blood-bome delivery of imagingagents is necessary to judge their ability to correctly represent the hypoxic phenotype of solidmalignancies.

Application of ^(18) F-FDG PET/CT Imaging in Diagnosing Bladder Tumor Metastasis Lesions

Bladder tumor is the most common malignant tumor in urinary system and always com- panied with lymph node metastasis. The accurate staging plays a significant role in treatment for bladder tumor and prognostic evaluation, and the distant metastasis predicts worse prognosis. The objective of this study was to assess the clinical significance of 18F-FDG PET/CT imaging in diagnosing bladder tumor metastasis lesions. A retrospective analysis of 60 patients with bladder tumor from October 2008 to May 2010 was done. The patients were stratified based on the imaging technique. Among all 60 cases, besides the primary lesion, 81 suspected lesions were spotted and 73 confirmed as metastasis, including 50 lymph node metastases, 22 distant metastases, and 1 bone metastasis. For PET/CT imaging, its sensitivity was 94.5%, specificity 87.5%, positive predictive value 98.6%, negative predictive value 63.6% and accuracy 93.8% respectively. For CT, its sensitivity was 82.2%, specificity 50%, positive predictive value 93.8%, negative predictive value 23.5% and accuracy 79% respectively. PET/CT im- aging was superior to CT in sensitivity, specificity and accuracy. In conclusion, 18F-FDG PET/CT imaging is more significant in diagnosing bladder tumor metastasis lesions.

A Review of Research on Accurate Segmentation of Multimodal Tumor Images

Accurate segmentation of tumor images is a key core technology for the diagnosis and treatment of tumor diseases.In this paper,we analyze a variety of novel and targeted algorithms to solve these problems,summarize,and elaborate the method based on multimodal tumor image processing given the characteristics of serious grayscale inhomogeneity,texture instability,and diversity complexity of tumor images.

Multimodality imaging in nanomedicine and nanotheranostics

Accurate diagnosis of tumors needs much detailed information. However, available single imaging modality cannot provide complete or comprehensive data. Nanomedicine is the application of nanotechnology to medicine, and multimodality imaging based on nanoparticles has been receiving extensive attention. This new hybrid imaging technology could provide complementary information from different imaging modalities using only a single injection of contrast agent. In this review, we introduce recent developments in multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine. Most of the reviewed studies are based on the intrinsic properties of nanoparticles and their application in clinical imaging technology. The imaging techniques include positron emission tomography, single-photon emission computed tomography, computerized tomography, magnetic resonance imaging, optical imaging, and ultrasound imaging.

Early Tumor Diagnosis in Brain MR Images via Deep Convolutional Neural Network Model

Machine learning based image analysis for predicting and diagnosing certain diseases has been entirely trustworthy and even as efficient as a domain expert’s inspection.However,the style of non-transparency functioning by a trained machine learning system poses a more significant impediment for seamless knowledge trajectory,clinical mapping,and delusion tracing.In this proposed study,a deep learning based framework that employs deep convolution neural network(Deep-CNN),by utilizing both clinical presentations and conventional magnetic resonance imaging(MRI)investigations,for diagnosing tumors is explored.This research aims to develop a model that can be used for abnormality detection over MRI data quite efficiently with high accuracy.This research is based on deep learning and Deep-CNN was deployed to examine the MR brain image for tracing the tumor.The system runs on Tensor flow and uses a feature extraction module in DeepCNN to elicit the factors of that part of the image from where underlying issues are identified and subsequently succeeded in prediction of the disease in the MR image.The results of this study showed that our model did not have any adverse effect on classification,achieved higher accuracy than the peers in recent years,and attained good detection outcomes including case of abnormality.In the future work,further improvement can be made by designing models that can drastically reduce the parameter space without affecting classification accuracy.

Advances on Tumor Image Segmentation Based on Artificial Neural Network

Image technology is applied more and more to help doctors to improve the accuracy of tumor diagnosis as well as researchers to study tumor characteristics. Image segmentation technology is an important part of image treatment. This paper summarizes the advances of image segmentation by using artificial neural network including mainly the BP network and convolutional neural network (CNN). Many CNN models with different structures have been built and successfully used in segmentation of tumor images such as supervised and unsupervised learning CNN. It is shown that the application of artificial network can improve the efficiency and accuracy of segmentation of tumor image. However, some deficiencies of image segmentation by using artificial neural network still exist. For example, new methods should be found to reduce the cost of building the marked data set. New artificial networks with higher efficiency should be built.

Pancreatic Neuroendocrine Neoplasms: Correlation between MR Features and Pathological Tumor Grades

This study investigated the accuracy of MRI features in differentiating the pathological grades of pancreatic neuroendocrine neoplasms（PNENs）. A total of 31 PNENs patients were retrospectively evaluated, including 19 cases in grade 1, 5 in grade 2, and 7 in grade 3. Plain and contrastenhanced MRI was performed on all patients. MRI features including tumor size, margin, signal intensity, enhancement patterns, degenerative changes, duct dilatation and metastasis were analyzed. Chi square tests, Fisher＇s exact tests, one-way ANOVA and ROC analysis were conducted to assess the associations between MRI features and different tumor grades. It was found that patients with older age, tumors with higher TNM stage and without hormonal syndrome had higher grade of PNETs（all P〈0.05）. Tumor size, shape, margin and growth pattern, tumor pattern, pancreatic and bile duct dilatation and presence of lymphatic and distant metastasis as well as MR enhancement pattern and tumor-topancreas contrast during arterial phase were the key features differentiating tumors of all grades（all P〈0.05）. ROC analysis revealed that the tumor size with threshold of 2.8 cm, irregular shape, pancreatic duct dilatation and lymphadenopathy showed satisfactory sensitivity and specificity in distinguishing grade 3 from grade 1 and grade 2 tumors. Features of peripancreatic tissue or vascular invasion, and distant metastasis showed high specificity but relatively low sensitivity. In conclusion, larger size, poorlydefined margin, heterogeneous enhanced pattern during arterial phase, duct dilatation and the presence of metastases are common features of higher grade PNENs. Plain and contrast-enhanced MRI provides the ability to differentiate tumors with different pathological grades.

Evaluating the tumor stratification with a lysosomal pH sensitive-probe by fluorescence lifetime imaging

Owing to the anaerobic metabolism in the tumor,abundant acidic metabolites are produced and accumulated in the cells.Therefore,the cells in different tumor layers are directly linked to the pH micro-environment.Nevertheless,due to the lack of robust tools,the high-efficient evaluation of the acidic micro-environment of tumor stratification faces the challenge of accurate diagnosis.We designed a new pH sensitive fluorescent lifetime probe target to lysosomes.As we expected,the fluorescence lifetime of PLN possesses a good linear fit to the pH value,which could detect the pH change at a single lysosome level in real time,and then evaluate the different acidity of tumor stratification.The probe PLN is successfully used to evaluate the tumor stratification by fluorescence lifetime imaging microscopy(FLIM)for the first time,which is of great significance in the preoperative diagnosis of clinical tumor treatment or evaluation of drug delivery effect.

HISTOLOGIC GRADE, AND CONTENT AND IMAGE ANALYSIS OF SOFT TISSUE TUMORS

Flow cytometry and image analysis technique were used to quantltate the nuclei of various soft tissue tumors. A single representing section from soft tissue sarcoma was used for histologic grading. Histologlc and cytometric comparative analyses showed that all 21 benign tumors were diploid. Among 62 cases of soft tissue sarcoma, 45(73%) were aneuploid. There was a significant difference in the nuclear area between benign and malignant tumors (P<0. 01), dlploid and aneuploid tumors (P<0. 05). The two new techniques are valuable In cellular quantitative measurement for soft tissue tumors.

PANCREATO-BILIARY TUMOR: MR DIAGNOSIS AND RESECTABILITY ASSESSMENT

Objective: TO evaluate the clinical value of MR multi-imaging technique in diagnosing and assessing the resectability of pancreato-biliary tumor. Methods The prospective diagnosis and resectability of 17 patients with suspicious pancreato-biliary tumors were evaluated. Surgical findings and pathologic results confirmed pancreatic adenocarcinoma in 11 cases, cholangiocarcinoma in 4, and non-neoplastic lesion in 2. MR multi-imaging protocol, including MR cross-sectional imaging, us cholangiopancreatography (MRCP ), and three-dimensional dynamic contrast-enhanced MR portography (3D DCE MRP), were performed in all patients. Results MR multi-imaging technique allowed-correct diagnosing 15 of 17 (88. 2% ) patients with pancreato-biliary tumors. The accuracy in detecting the range of tumor invasion was 64. 4%. The sensitivity, speificity, accuracy, positive, and negative predictive value of MR multi-imaging technique in assessing the resectability of pancreato-biliary tumors were 83. 3%, 77. 8%, 80. 0%, 71. 4%, and 87. 5%, respectively. Conclusion MR multi-imaging technique can not only improve the diagnostic ability of pancreato-biliary tumor, but also assess the surgical reartability of the tumor. With the fast development of MR techniques, the diagnosing and pre-operative assessment of aoncreato-biliary tumor may be more simplified and efficient by using the non-invasive "all-in-one" method.