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.

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.

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.

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.

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.