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.

RADIOIODINATION AND PHARMACOKINETICS OF BIVALENT ANALOG OF PRACTOLOL AS MYOCARDIAL IMAGING AGENT

Solid phase exchange radioiodination method was used to label the compound.Pharmacokinetics was studied in rats and the data were dealt with by computer. The results indicate that the compound would be a potential myocardial imaging agent.

pH-responsive metal nanoparticles as high contrast theranostic agents for selective imaging and synergistic cancer therapy

The low signal-to-noise ratio(S/N)and single functionality of fluorescence imaging agents have limited their practical applications.Bright two-photon excitation(2PE)imaging probes are highly desirable in vivo with larger imaging depth,minor autofluorescence background,and less photodamage.Herein,we developed responsive aggregated gold nanoparticles(Au NPs)as high contrast 2PE imaging agents,capable of emitting red fluorescence upon excitation of near-infrared(NIR)laser and possessing a high signal-to-noise ratio(S/N of 2,475).By forming aggregates in situ inside tumor tissue,doxorubicin hydrochloride(DOX)-loaded mix-charged gold nanoparticles(DOX-MC-Au NPs)were utilized to act as selective fluorescence imaging probes and precise therapy agents.These high-contrast theranostic agents offer a promising potential for precise cancer imaging and therapy,which might open a new venue to multifunctional and noninvasive theranostics.

An Efficient Probe for Bacterial Nitroreductase Imaging and Detection Based on NanoLuc-Furimazine Bioluminescent Pair

Comprehensive SummaryThe detection of critical endogenous species, such as bacteria in microenvironments in the body, requires better imaging tools for visualization and monitoring of biological events. Bioluminescence imaging is the most popular strategy for obtaining real-time in living cells and organisms. Herein, we introduced a nitroaryl group on the C-3 position and a hydroxy group at the C-6 phenyl ring on furimazine to report the first bioluminescent probe (7) based on NanoLuc-furimazine bioluminescent pair for the detection of nitroreductase in bacteria. The probe, which possessed up to 560-fold intensity increase with a low detection limit of 16 ng/mL of nitroreductase, has the most efficient uncage efficiency in comparison with other bioluminescent congeners, thus enabling highly selective and sensitive visualization of NTR activity in a panel of clinical priority pathogens. Additionally, imaging of the recombinant strain as well as the NTR from mouse feces indicated the potential of this probe in the application of different mouse disease models.

Fluorinated [2]rotaxanes as sensitive ^(19)F MRI agents: Threading for higher sensitivity

As a promising imaging technology,the low sensitivity of fluorine-19 magnetic resonance imaging(^(19)F MRI)severely hinders its biomedical applications.Herein,we have developed an unprecedented rotaxanebased strategy to improve the sensitivity of^(19)F MRI agents.By threading the fluorinated macrocycle into2-blade pinwheel[2]rotaxanes,the^(19)F longitudinal relaxation rate R1was dramatically increased,resulting in a significant^(19)F MRI signal intensity enhancement of up to 79%.Through comparative molecular dynamics studies using a series of solution and solid-state^(1)H/^(19)F nuclear magnetic resonance(^(1)H/^(19)F NMR)and molecular dynamics simulations,it was found that the formation of mechanical bonds dramatically restricts the motion of the wheel fluorines and thus increasing the R1for higher^(19)F MRI sensitivity.Besides a novel strategy for improving^(19)F MRI sensitivity,this study has established^(19)F NMR/MRI as a valuable technology for monitoring the molecular dynamics of rotaxanes,which may shed new light on high-performance^(19)F MRI agents and molecular devices.

The biological role of the CXCL12/CXCR4 axis in esophageal squamous cell carcinoma

Esophageal cancer is the eighth most common malignant tumor and the sixth leading cause of cancer-related death worldwide.Esophageal squamous cell carcinoma(ESCC)is the main histological type of esophageal cancer,and accounts for 90%of all cancer cases.Despite the progress made in surgery,chemotherapy,and radiotherapy,the mortality rate from esophageal cancer remains high,and the overall 5-year survival rate is less than 20%,even in developed countries.The C-X-C motif chemokine ligand 12(CXCL12)is a member of the CXC chemokine subgroup,which is widely expressed in a variety of tissues and cells.CXCL12 participates in the regulation of many physiological and pathological processes by binding to its specific receptor,C-X-C motif chemokine receptor type 4(CXCR4),where it causes embryonic development,immune response,and angiogenesis.In addition,increasing evidence indicates that the CXCL12/CXCR4 axis plays an important role in the biological processes of tumor cells.Studies have shown that CXCL12 and its receptor,CXCR4,are highly expressed in ESCC.This abnormal expression contributes to tumor proliferation,lymph node and distant metastases,and worsening prognosis.At present,antagonists and imaging agents against CXCL12 or CXCR4 have been developed to interfere with the malignant process and monitor metastasis of tumors.This article summarizes the structure,function,and regulatory mechanism of CXCL12/CXCR4 and its role in the malignancy of ESCC.Current results from preclinical research targeting CXCL12/CXCR4 are also summarized to provide a reference for the clinical diagnosis and treatment of ESCC.

Radiosynthesis of N-^(11) C-meisoindigotin as a novel PET agent for imaging of cyclin-dependent kinases and GSK-3β

Meisoindigotin has been demonstrated as a new type of cancer chemotherapeutic agent.N-^（11）C-meisoindigotin was synthesized by N-^（11）C-methyIation of the isoindigotin precursor with ^（11）C-labelled methyl triflate.The decay corrected radiochemical yields were 15-25%,and the specific radioactivity was 1.0-1.2 Ci/μmol at the end of synthesis.The cellular uptake of[N-^（11）C]-meisoindigotin was evaluated in four different lung cancer cell lines.Our results showed that the A549,GLC-82,95D cell lines exhibited higher uptake than 95C cell line after incubation for 60 min.N-^（11）-meisoindigotin was a promising candidate for further development as a novel PET radiotracer for imaging of cyclin-dependent kinases（CDKs） and GSK-3β.

Recent Advances in Activatable Probes for Molecular Imaging by Stimuli-Controlled Disassembly

Comprehensive Summary,Stimuli-controlled disassembly process has shown promise to direct delivery of probes and/or spatial-temporally control imaging signals for molecular imaging in vivo.Via the disassembly process,well defined nanoprobes with a stimulus-responsive moiety can be controllably converted into small-molecular imaging agents in response to a stimulus,leading to a switch in imaging signals.Moreover,the on-site released small-molecule probes could enhance penetration into the deep tissue for improved imaging of deep-seated molecular targets.Therefore,such a stimuli-controllable disassembly approach has been widely utilized to build activatable molecular imaging probes for the noninvasive detection of various molecular targets in living subjects.In this review article,we first briefly introduce the general principle of stimuli-controlled disassembly.We then summarize the activatable probes based on different internal or external stimulus that has been utilized to control disassembly process.Activatable probes by using multiple stimuli to control cascaded in situ self-assembly and disassembly processes are also discussed.Finally,we close with a conclusion of current challenges and perspective in this field.

磁共振钆靶向对比剂的研究现状及展望

特异性MR靶向对比剂通过与体内特定的靶点结合显示活体分子靶点状态,为临床提供分子水平的信息。选择针对特定靶点的特异性运载体和良好的MR显像剂,是构建良好分子探针的一个关键因素。钆剂作为临床常用的MR对比剂,在构建分子探针上具有诸多优势,目前在MR分子成像领域进行了大量实验研究。就目前研究常用的分子靶点和分子探针,对MR钆靶向对比剂的研究现状及展望进行综述。

Gadolinium-hyaluronic acid nanoparticles as an efficient and safe magnetic resonance imaging contrast agent for articular cartilage injury detection

Accurate detection of cartilage injuries is critical for their proper treatment because these injuries lack the selfhealing ability and lead to joint dysfunction.However,the low longitudinal T1 relaxivity(r1)and non-specificity of contrast agents(such as gadolinium(III)-diethylenetriamine-pentaacetic acid(Gd-DTPA))significantly limit the efficiency of clinical magnetic resonance imaging(MRI)applications.To overcome these drawbacks,we integrated hyaluronic acid(HA)with Gd to synthesize a Gd-DTPA-HA composite,which was subsequently freeze-dried to produce nanoparticles(NPs).The resultant Gd-HA NPs demonstrated a greater r1 value(12.51 mM^-1 s^-1)compared with the bulk Gd-DTPA-HA(8.37 mM^-1 s^-1)and clinically used Gd-DTPA(3.88 mM^-1 s^-1).Moreover,the high affinity of HA to the cartilage allowed these NPs to penetrate deeper beyond the cartilage surface.As a result,Gd-HA NPs considerably increased the quality of cartilage and lesion MR images via their intra-articular injection in vivo.Specifically,2 h after NP administration,the signal-to-noise ratio at the injured cartilage site was 2.3 times greater than the value measured before the injection.In addition,Gd-HA NPs exhibited good biosafety properties due to the absence of adverse effects in the blood or on the main organs.It was also showed that Gd NPs were first metabolized by the kidney and liver and then excreted from the body with urine.Thus,Gd-HA NPs can potentially serve as an efficient MRI contrast agent for improved detection of cartilage injuries.

Characteristics of magnetic Fe_3O_4 nanoparticles encapsulated with human serum albumin

Magnetic nanoparticles （Fe304） were prepared by chemical precipitation method using Fe^2＋ and Fe^3＋ salts with sodium hydroxide in the nitrogen atmosphere. Fe3O4 nanoparticles were coated with human serum albumin（HSA） for magnetic resonance imaging as contrast agent. Characteristics of magnetic particles coated or uncoated were carried out using scanning electron microscopy and X-ray diffraction. Zeta potentials, package effects and distributions of colloid particles were measured to confirm the attachment of HSA on magnetic particles. Effects of Fe3O4 nanoparticles coated with HSA on magnetic resonance imaging were investigated with rats. The experimental results show that the adsorption of HSA on magnetic particles is very favorable to dispersing of magnetic Fe3O4 particles, while the sizes of Fe3O4 particles coated are related to the molar ratio of Fe3O4 to HSA. The diameters of the majority of particles coated are less than 100 nm. Fe3O4 nanoparticle coated with HSA has a good biocompatibility and low toxicity. This new contrast agent has some effects on the nuclear magnetic resonance imaging of liver and the lowest dosage is 20μmol/kg for the demands of diagnosis.

Myocardial perfusion imaging with a contrast agent at a low concentration in the diagnosis of myocardial infarction in the elderly

Objective To evaluate the clinical value of myocardial perfusion imaging with dual-source dual-energy CT and a contrast agent at a low concentration in the diagnosis of myocardial infarction in the elderly.Methods Onestop cardiac imaging with dual-source CT was conducted in 138 elderly patients diagnosed with myocardial infarction between October 2015 and May 2016.The

A Bioorthogonal-Activated Fluorescence Turn-On Probe Based on Nitrone-Modified 1,8-Naphthalimide for Live-Cell Imaging

A nitrone-modified 1,8-naphthalimide was desig ned as a novel bioorthog on alactivated turn-on probe based on strain-promoted alkyne-nitrone cycloadditio n(SPANC).The bioorthog onal cycloadducts were subseque ntly tran sformed into fluoresce nt rearra nge-ment products by photo-accelerati on,which exhibited sign ificant fluoresce nee enhan ceme nt,large stokes shift,and high fluores-cence qua ntum yield.DFT calculati ons were performed to elucidate the fluoresce nee OFF-ON mecha nism.This fluoroge nic strategy was successfully applied to labeling of proteins and visualizing mitochondria in live cells in real time.

Syntheses of Two Potential Ligands for Tc-99m Labeling as Diagnosis Agents of Alzheimer's Disease

Two types of ligands-biphenyl and stilbene derivatives, -which can be labeled with Tc-99m for the diagnosis of Alzheimer' s disease (AD) have been synthesized successfully. The key steps in these two syntheses involved Suzuki reaction and Wittig reaction respectively. The new discovered debromination reaction may be expanded to the compounds with double or triple bond adjacent to the carbon atom bearing the bromine atoms. These types of syntheses provide a route to a series of biphenyl and stilbene derivatives that will benefit the search of new imaging agents for AD.

Cell-assembled （Gd-DOTA）i-triphenylphosphonium （TPP） nanoclusters as a T2 contrast agent reveal in vivo fates of stem cell transplants

A simple and straightforward strategy for magnetic resonance imaging （MRI） of stem cell transplants in terms of their viability, migration and homing, and differentiation has been pursued over the years. Herein we couple Gd-DOTA with triphenylphosphonium （TPP） to yield small molecule （Gd-DOTA）i-TPP （i = 1,4） agents and show that labeling cells with （Gd-DOTA）i-TPP via electro- poration （EP） results in two distinct cellular distributions of （Gd-DOTA）i-TPP： freely and evenly distributed in the cytosol or cell-assembled nanoclusters in the cytoplasm. The two distinct cellular distributions contribute in different ways to MRI signals in vitro and in vivo. Importantly, we present a detailed interpretation of MRI results based on the signal intensity equation and cellular longitudinal （T1-） and transverse （Ta-） relaxation rates of water protons. We demonstrate that cell-assembled （Gd-DOTA）i-TPP nanoclusters not only promote its intracellular retention time but also induce significant MRI signal reduction, which act as an excellent T2 contrast agent and allows for unambiguous reporting of in vivo viability and migration of cell transplants under T2-weighted MRI over a long period. Notably,（Gd-DOTA）i-TPP agents released as a result of exocytosis or cell death induce signal enhancement in the surrounding tissue such that the labeled cells can be unambiguously discriminated from its host tissue. The labeling and imaging strategy provides abundant information on the in vivo fates of stem cell transplants. The strategy features a single contrast, single imaging mode with dual signal output.

Fabrication of carbon coated gadolinia particles for dual-mode magnetic resonance and fluorescence imaging

In the present study,we report a fabrication of dual-mode carbon coated gadolinia C@Gd_(2)O_(3)particles by a facile hydrothermal synthesis method without using any organic solvents.The prepared C@Gd_(2)O_(3)particles have a core-shell structure and a narrow size distribution in the range of 261±27 nm.The fluorescent properties of the prepared C@Gd_(2)O_(3)particles were accessed by a room-temperature photoluminescence study,while the longitudinal relaxivity(r1)was examined by using a clinical 1.5 T MRI scanner.A murine fibroblast L-929 cell line was used to examine the cytotoxicity and capability of the prepared C@Gd_(2)O_(3)particles for the fluorescent labeling.The obtained results show that the prepared C@Gd_(2)O_(3)particles could be used as a dual-mode contrast agent for magnetic resonance and fluorescence imaging.

Milk exosomes:Nature’s abundant nanoplatform for theranostic applications

Exosomes are a unique subpopulation of naturally occurring extracellular vesicles which are smaller intracellular membrane nanoparticle vesicles.Exosomes have proven to be excellent nanocarriers for carrying lipids,proteins,mRNAs,non-coding RNAs,and DNAs,and disseminating long-distance intercellular communications in various biological processes.Among various cell-line or biological fluid derived exosomes,milk exosomes are abundant in nature and exhibit many nanocarrier characteristics favorable for theranostic applications.To be an effective delivery carrier for their clinical translation,exosomes must inbuilt loading,release,targeting,and imaging/tracking characteristics.Considering the unmet gaps of milk exosomes in theranostic technology it is essential to focus the current review on drug delivery and imaging applications.This review delineates the efficiency of exosomes to load therapeutic or imaging agents and their successful delivery approaches.It is emphasized on possible modifications of exosomes towards increasing the stability and delivery of agents.This article also summarizes the specific applications and the process of developing milk exosomes as a future pharmaceutical drug delivery vehicle.

Revealing Formaldehyde Fluxes in Alzheimer's Disease Brain by an Activity-Based Fluorescence Probe

Formaldehyde(FA)plays critical roles in Alzheimer's disease and the associations between FA and Alzheimer's disease(AD)are still obscure.To reveal FA fluxes in the Alzheimer's disease brain,an activity-based fluorescence probe NP-FA with superb blood-brain barrier permeable abilities was exquisitely designed.The probe responded to FA with significant fluorescence increases(F/F0=81),thus laying the foundation for the sensitive detection of FA in cuvette and in vivo.Moreover,the probe also possessed some fasci-nating performances,including endoplasmic reticulum(ER)-targeting abilities,good one-photon/two-photon absorption properties,and appropriate hydrophobicity property(log P=2.34±0.05).As a result,the probe can readily reflect the overproduction of FA con-tent in live cells under ER stress by high-fidelity two-photon imaging.More interestingly,ex vivo imaging of AD brains and two-photon imaging of AD slice tissues visually disclosed that the FA level of AD brain is much higher than that of the normal brain.This work afforded a specific activity-based probe for the imaging of FA in the AD mouse brains,which could be further extended to FA-related studies in Alzheimer's disease.

From Fluorescent Probes to the Theranostics Platform

Since the advent of fluorescent probes,they have been widely used in the field of life sciences.Fluorescent probes can not only light up the cells,tissues and organs,but also be used to explore the bio-distribution of specific types of disease markers.Therefore,the development of new fluorescent probes capable of recognition of bio-markers is extremely important for the diagnosis of the related diseases.Herein,we focus on our recent works experienced the evolution from the beginning of simply fluorescent probes to the construction of theranostics platform.We have developed a series of new fluorescent probes for the detecting and imaging of reactive oxygen species(ROS)and specific enzymes in vitro and in living cells.With the shift of the fluorescence signal from visible to near-infrared region,we expanded the application of the fluorescent probes from in vitro to in vivo.Very recently,we further constructed theranostics platforms to combine the diagnosis immediately with the corresponding treatment.