Theranostics; ferritin; IR820; ICG; fluorescence imaging; photoacoustic imaging; photothermal therapy
Matrix metalloproteases (MMPs) have
been found to be highly expressed
in a variety of malignant tumor tissues. Noninvasive visualization
of MMP activity may play an important role in the diagnosis of MMP
associated diseases. Here we report the design and synthesis of a
set of fluorine-19 dendron-based magnetic resonance imaging (MRI)
probes for real-time imaging of MMP-2 activity. The probes have the
following features: (a) symmetrical fluorine atoms; (b) the number
of fluorine atoms can be increased through facile chemical modification;
(c) readily accessible peptide sequence as the MMP-2 substrate; (d)
activatable 19F signal (off/on mode) via paramagnetic metal
ion incorporation. Following optimization for water solubility, one
of the probes was selected to evaluate MMP-2 activity by 19F magnetic resonance spectroscopy (MRS). Our results showed that
the fluorine signal increased by 8.5-fold in the presence of MMP-2.
The specific cleavage site was verified by mass spectrometry. The
selected probe was further applied to detect secreted MMP-2 activity
of living SCC7 squamous cell carcinoma cells. The fluorine signal
was increased by 4.8-fold by MRS analysis after 24 h incubation with
SCC7 cells. This type of fluorine probe can be applied to evaluate
other enzyme activities by simply tuning the substrate structures.
This symmetrical fluorine dendron-based probe design extends the scope
of the existing 19F MRI agents and provides a simple but
robust method for real-time 19F MRI application.
resonance imaging; 19F magnetic resonance spectroscopy; activatable probe; matrix metalloproteases
The purpose of this study was to develop a novel in vivo albumin-labeling method to allow PET of cardiac function after myocardial infarction and vascular leakage and increased permeability in inflammatory diseases and malignant tumors.
To label albumin in vivo, we synthesized a NOTA (1,4,7-triazacyclononane-N,N′, N″-triacetic acid)-conjugated truncated form of Evans blue (NEB). 18F labeling was achieved by the formation of an 18F-aluminum fluoride (18F-AlF) complex, and 64Cu labeling was obtained by a standard chelation method. Sixty-minute dynamic PET imaging was performed on normal mice to evaluate the distribution of 18F-AlF-NEB, which was compared with in vitro–labeled mouse serum albumin (18F-fluorobenzyl-MSA). Electrocardiography-gated PET imaging was performed in a mouse model of myocardial infarction. Both dynamic and static PET scans were obtained in a mouse inflammation model induced by local injection of turpentine to evaluate vascular leakage. Tumor permeability was studied by dynamic and late-point static PET using 64Cu-NEB in a UM-22B xenograft model.
NEB was successfully synthesized, and 18F labeling including work-up took about 20–30 min, with a radiochemical purity greater than 95% without the need for high-performance liquid chromatography purification. Most of the radioactivity was retained in the circulation system at 60 min after injection (26.35 ± 1.52 percentage injected dose per gram [%ID/g]). With electrocardiography-gated PET, ventricles of the heart and major arteries were clearly visualized. The myocardial infarction mice showed much lower left ventricular ejection fraction than the control mice. Inflammatory muscles showed significantly higher tracer accumulation than the contralateral healthy ones. UM-22B tumor uptake of 64Cu-NEB gradually increased with time (5.73 ± 1.11 %ID/g at 1 h and 8.03 ± 0.77 %ID/g at 2 h after injection).
The distribution and local accumulation of serum albumin can be noninvasively visualized and quantified by 18F-AlF-NEB and 64Cu-NEB PET. The simple labeling and broad applications make these imaging probes attractive for clinical translation.
serum albumin; in vivo labeling; Evans blue; PET; vascular permeability
receptor 4 and stromal-cell-derived factor 1 have been
found to be related to the initiation of neuroinflammation in ischemic
brain. Herein, we aimed to monitor the changes of neuorinflammation
after AMD3100 treatment using a translocator protein (TSPO) specific
PET tracer in a mouse model of stroke. The transient MCAO model was
established with Balb/C mice. The success of the model was confirmed
by magnetic resonance imaging and FDG PET. The treatment started the
same day after surgery via daily intraperitoneal injection of 1 mg
of AMD3100/kg for three consecutive days. [18F]DPA-714
was used as the TSPO imaging tracer. In vivo PET
was performed at different time points after surgery in both control
and treated mice. Ex vivo histological and immunofluorescence
staining of brain slices was performed to confirm the lesion site
and inflammatory cell activation. The TSPO level was also evaluated
using Western blotting. Longitudinal PET scans revealed that the level
of [18F]DPA-714 uptake was significantly increased in the
ischemic brain area with a peak accumulation at around day 10 after
surgery, and the level of uptake remained high until day 16. The in vivo PET data were consistent with those from ex vivo immunofluorescence staining. After AMD3100 treatment,
the signal intensity was significantly decreased compared with that
of normal saline-treated control group. In conclusion, TSPO-targeted
PET imaging using [18F]DPA-714 can be used to monitor inflammatory
response after stroke and provide a useful method for evaluating the
efficacy of anti-inflammation treatment.
stroke; AMD3100; translocator protein (TSPO); DPA-714; PET
19F MRI and optical imaging are two powerful non-invasive molecular imaging modalities in biomedical applications. 19F MRI has great potential for high resolution in vivo imaging, while fluorescent probes enable ultracontrast cellular/tissue imaging with high accuracy and sensitivity. We, thus, developed a bimodal nanoprobe integrating the merits of 19F MRI and fluorescence imaging into a single synthetic molecule, which was further engineered into nanoprobe, by addressing shortcomings of conventional contrast agents to explore the quantitative 19F MRI and fluorescence imaging and cell tracking. Results showed that this bimodal imaging nanoprobe presented high correlation of 19F MR signal and NIR fluorescence intensity in vitro and in vivo. Additionally, this nanoprobe enabled quantitative 19F MR analysis, confirmed by complementary fluorescence analysis. This unique feature can hardly be obtained by traditional 19F MRI contrast agents. We envision that this nanoprobe would hold great potential for quantitative and sensitive multi-modal molecular imaging.
19F MRI; fluorescence imaging; nanoparticles; stem cells; biodegradable polymer
To determine the relationship between the subventricular zone (SVZ) and astrocytoma based on magnetic resonance imaging (MRI) and whether SVZ involvement can be used to distinguish solitary cerebral metastases (SCMs) from astrocytomas.
This retrospective study involved 154 patients with solitary low-grade astrocytoma (LGA), high-grade astrocytoma (HGA), and SCM, who underwent T1-weighted imaging (T1WI), Gd-DTPA–enhanced T1WI, and T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) T2WI. The spatial relationship between the tumor and SVZ was classified as “involvement” or “segregation” on contrast-enhanced T1WI for enhanced tumors and T2WI/FLAIR T2WI for non-enhanced tumors. Patient-based SVZ-contact rates were compared between the LGA, HGA, and SCM groups. The frequencies of involvement of various lateral ventricle regions by astrocytoma were compared. The correlation between SVZ involvement and tumor necrosis was analyzed.
Patient-based SVZ-contact rates in SCM, LGA, and HGA were 24.1%, 68.8%, and 85.4%, respectively. Univariate analysis showed that the SVZ-contact rate was significantly different between SCM and astrocytoma (24.1% vs. 75.2% P < 0.001), also between LGA and HGA (68.1% vs. 85.4% P=0.037). After the tumor volume was adjusted as a covariate, SVZ-contact rates still differed between SCMs and astrocytomas (Odds ratio [OR]: 4.58, 95% Confidence interval [CI]: 1.65 to 12.8, P=0.004). Tumor volume differed between LGA and HGA (P< 0.001), and influenced the association between SVZ involvement and astrocytoma grade (P = 0.05). Among the lateral ventricle regions, the frontal horn was the most frequently involved by astrocytomas. SVZ-contact rates were higher in necrosis group compared with non-necrosis groups (83.9% vs. 50.0%, P < 0.001) among astrocytoma patients. Necrosis positively correlated with SVZ involvement in astrocytomas (rs = 0.342, P < 0.001), but did not correlate with SVZ involvement in SCMs (P = 0.193).
Compared to SCMs, solitary cerebral astrocytomas exhibited spatial proximity to the SVZ, which might distinguish the supratentorial astrocytomas from SCMs.
Using positron emission tomography (PET) imaging to monitor and quantitatively analyze the delivery and localization of Au nanomaterials (NMs), a widely used photothermal agent, is essential to optimize therapeutic protocols to achieve individualized medicine and avoid side effects. Coupling radiometals to Au NMs via a chelator faces the challenges of possible detachment of the radiometals as well as surface property changes of the NMs. In this study, we reported a simple and general chelator-free 64Cu radiolabeling method by chemically reducing 64Cu on the surface of polyethylene glycol (PEG)-stabilized Au NMs regardless of their shape and size. Our 64Cu-integrated NMs are proved to be radiochemically stable and can provide an accurate and sensitive localization of NMs through noninvasive PET imaging. We further integrated 64Cu onto arginine-glycine-aspartic acid (RGD) peptide modified Au nanorods (NRs) for tumor theranostic application. These NRs showed high tumor targeting ability in a U87MG glioblastoma xenograft model and were successfully used for PET image-guided photothermal therapy.
64Cu labeling; chelator free; PET; image-guided photothermal therapy
Inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial to its pathologic process. In order to follow the microglia activation and neuroinflammation after TBI, herein, we performed PET imaging in a rat TBI model using 18F-labeled DPA-714, a ligand of 18 KDa translocator protein (TSPO).
TBI was induced in male SD rats by controlled cortical impact (CCI). The success of the TBI model was confirmed by magnetic resonance imaging (MRI). Automated synthesis of [18F]DPA-714 was carried out using a slightly modified TRACERLab FX-FN module. In vivo PET imaging was performed at different time points after surgery by an Inveon small animal PET scanner. The specificity of [18F]DPA-714 was confirmed by displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results.
Both in vivo T2-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham group, [18F]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal brain ratio of [18F]DPA-714 in TBI rats was observed at day 2 after surgery, peaked around day 6 (2.65 ± 0.36) and then decreased gradually to nearly normal level at day 28. Displacement study using PK11195 confirmed the specific binding of [18F]DPA-714 to TSPO. Ex vivo autoradiography was consistent with in vivo PET results. The immunofluorescence staining showed a time course of TSPO expression after TBI and the temporal and spatial distribution of microglia in damaged brain area.
TSPO targeted PET using [18F]DPA-714 as the imaging probe can be used to dynamically monitor inflammatory response after TBI in a non-invasive manner. This method will not only facilitate a better understanding of inflammation process after traumatic brain injury, but also provide a useful in vivo monitoring strategy for anti-inflammation therapy of TBI.
Traumatic brain injury (TBI); Translocator protein (TSPO); [18F]DPA-714; PET; molecular imaging
Tumor-associated macrophages (TAMs) have been found to be associated with the progression and metastasis of breast cancer. To clarify the mechanisms underlying the crosstalk between TAMs and cancer stem cells (CSCs) in breast cancer recurrence and metastasis, we used a co-culture model of macrophages and apoptotic human breast cancer cell line MCF-7 cells to investigate the effects of TAMs on MCF-7 in vitro and in vivo. Macrophages co-cultured with apoptotic MCF-7 had increased tumor growth and metastatic ability in a nude mouse transplantation assay. The macrophages exposed to apoptotic cells also induce an increase in the proportion of CD44+/CD24− cancer stem-like cells, as well as their proliferative ability accompanied with an increase in mucin1 (MUC1) expression. During this process, macrophages secreted increased amounts of interleukin 6 (IL-6) leading to increased phosphorylation of signal transducers and activators of transcription 3 (STAT3), which likely explains the increased transcription of STAT3 target genes such as TGF-β1 and HIF-1α. Our results indicate that when cancer cells endure chemotherapy induced apoptosis, macrophages in their microenvironment can then activate cancer stem cells to promote cancer growth and metastasis by secreting IL-6, which activates STAT3 phosphorylation to regulate the transcription of its downstream target genes.
cancer stem cells; apoptosis; TAMs; metastasis; IL-6; STAT3
and quantitative detection of cancer biomarkers
is an unmet challenge because of their ultralow concentrations in
clinical samples. Although gold nanoparticle (AuNP)-based immunoassays
offer high sensitivity, they were unable to quantitatively detect
targets of interest most likely due to their very narrow linear ranges.
This article describes a quantitative colorimetric immunoassay based
on glucose oxidase (GOx)-catalyzed growth of 5 nm AuNPs that can detect
cancer biomarkers from attomolar to picomolar levels. In addition,
the limit of detection (LOD) of prostate-specific antigen (PSA) of
this approach (93 aM) exceeds that of commercial enzyme-linked immunosorbent
assay (ELISA) (6.3 pM) by more than 4 orders of magnitude. The emergence
of red or purple color based on enzyme-catalyzed growth of 5 nm AuNPs
in the presence of target antigen is particularly suitable for point-of-care
(POC) diagnostics in both resource-rich and resource-limited settings.
present a novel gold bellflower (GBF) platform with multiple-branched
petals, prepared by a liquid–liquid–gas triphase interface
system, for photoacoustic imaging (PAI)-guided photothermal therapy
(PTT). Upon near-infrared (NIR) laser irradiation, the GBFs, with
strong NIR absorption, showed very strong PA response and an ultrahigh
photothermal conversion efficiency (η, ∼74%) among the
reported photothermal conversion agents. The excellent performance
in PAI and PTT is mainly attributed to the unique features of the
GBFs: (i) multiple-branched petals with an enhanced local electromagnetic
field, (ii) long narrow gaps between adjacent petals that induce a
strong plasmonic coupling effect, and (iii) a bell-shaped nanostructure
that can effectively amplify the acoustic signals during the acoustic
propagation. Besides the notable PTT and an excellent PAI effect,
the NIR-absorbing GBFs may also find applications in NIR light-triggered
drug delivery, catalysis, surface enhanced Raman scattering, stealth,
antireflection, IR sensors, telecommunications, and the like.
Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors’ origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as “smart” carriers that site-specifically deliver 1O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.
photodynamic therapy; EPR; ferritin; nanoparticles; drug delivery; integrin αvβ3
As a part of an ongoing assessment of its mechanism of action, we evaluated the in vivo pharmacokinetics, tissue distribution, toxicity and antitumor efficacy of VEGF121/rGel, a novel fusion protein. Pharmacokinetic studies showed that VEGF121/rGel cleared from the circulation in a biphasic manner with calculated half-lives of 0.3 and 6 hours for the alpha and beta phases, respectively. Pharmacokinetic evaluation of 64Cu-DOTA-VEGF121/rGel showed relatively high blood retention 30 min after injection (26.6 ± 1.73 %ID/g), dropping to 11.8 ± 2.83 % and 0.82 ± 0.11 % ID/g at 60 and 240 minutes post injection, respectively. Tissue uptake studies showed that kidneys, liver and tumor had the highest drug concentrations 48 hrs after administration. The maximum tolerated dose (MTD), based on a QOD X5 i.v. administration schedule, was found to be 18 mg/kg with an LD50 of 25 mg/kg. Treatment of BALB/c mice with VEGF121/rGel at doses up to the MTD caused no alterations in hematologic parameters. However, AST and ALT parameters increased in a dose-related manner. The no-observable-adverse-effect-level (NOAEL) was determined to be 20% of the MTD (3.6 mg/kg). VEGF121/rGel treatment of mice bearing orthotopically-placed MDA-MB-231 breast tumors caused increased vascular permeability of tumor tissue by 53% compared to saline-treated controls. Immunohistochemical analysis showed significant tumor hypoxia and necrosis as a consequence of vascular damage. In summary, VEGF121/rGel appears to be an effective therapeutic agent causing focused damage to tumor vasculature with minimal toxic effects to normal organs. This agent appears to be an excellent candidate for further clinical development.
Graphical Abstract (for review)
Angiogenesis; Necrosis; Pharmacokinetics; Toxicology; VEGF; Vascular permeability
a novel prosthetic agent that is thiol-specific, was synthesized using
a one-pot two-step strategy: (1) 18F incorporation by a
nucleophilic displacement of trimethylammonium substrate under mild
conditions; (2) amidation of the resulting 6-[18F]fluoronicotinic
acid 2,3,5,6-tetrafluorophenyl ester with N-(2-aminoethyl)maleimide
trifluoroacetate salt. The radiosynthesis of the maleimide tracer
was completed in 75 min from [18F]fluoride with 26 ±
5% decay uncorrected radiochemical yield, and specific activity of
19–88 GBq/μmol (decay uncorrected). The in vitro cell uptake, in vivo biodistribution, and positron
emission tomography (PET) imaging properties of its conjugation product
with [Cys40]-exendin-4 were described. [18F]FNEM-Cys40-exendin-4 showed specific targeting of glucagon-like peptide
1 receptor (GLP-1R) positive insulinomas and comparable imaging results
to our recently reported [18F]FPenM-Cys40-exendin-4.
fluorine-18; thiol reactive prosthetic group; insulinoma imaging
Stem-cell-based therapies have attracted considerable interest in regenerative medicine and oncological research. However, a major limitation of systemic delivery of stem cells is the low homing efficiency to the target site. Here, we report a serendipitous finding that various iron-based magnetic nanoparticles (MNPs) actively augment chemokine receptor CXCR4 expression of bone-marrow-derived mesenchymal stem cells (MSCs). On the basis of this observation, we designed an iron-based nanocluster that can effectively label MSCs, improve cell homing efficiency, and track the fate of the cells in vivo. Using this nanocluster, the labeled MSCs were accurately monitored by magnetic resonance imaging and improved the homing to both traumatic brain injury and glioblastoma models as compared to unlabeled MSCs. Our findings provide a simple and safe method for imaging and targeted delivery of stem cells and extend the potential applications of iron-based MNPs in regenerative medicine and oncology.
mesenchymal stem cell; homing; iron oxide nanoparticle; magnetic resonance imaging; CXCR4/SDF-1α
Resistance to chemotherapy is the primary cause of treatment failure in over 90% of cancer patients in the clinic. Research in nanotechnology-based therapeutic alternatives has helped provide innovative and promising strategies to overcome multidrug resistance (MDR). By targeting CD44-overexpressing MDR cancer cells, we have developed in a single-step a self-assembled, self-targetable, therapeutic semiconducting single-walled carbon nanotube (sSWCNT) drug delivery system that can deliver chemotherapeutic agents to both drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells. The novel nanoformula with a cholanic acid-derivatized hyaluronic acid (CAHA) biopolymer wrapped around a sSWCNT and loaded with doxorubicin (DOX), CAHA-sSWCNT-DOX, is much more effective in killing drug-resistant cancer cells compared to the free DOX and phospholipid PEG (PL-PEG)-modified sSWCNT formula, PEG-sSWCNT-DOX. The CAHA-sSWCNT-DOX affects the viscoelastic property more than free DOX and PL-PEG-sSWCNT-DOX, which in turn allows more drug molecules to be internalized. Intravenous injection of CAHA-sSWCNT-DOX (12 mg/kg DOX equivalent) followed by 808 nm laser irradiation (1 W/cm2, 90 s) led to complete tumor eradication in a subcutaneous OVCAR8/ADR drug-resistant xenograft model, while free DOX alone failed to delay tumor growth. Our newly developed CAHA-sSWCNT-DOX nanoformula, which delivers therapeutics and acts as a sensitizer to influence drug uptake and induce apoptosis with minimal resistance factor, provides a novel effective means of counteracting the phenomenon of multidrug resistance.
semiconducting carbon nanotube; hyaluronic acid; doxorubicin; multidrug resistance; viscoelasticity; live cell imaging; quartz-crystal microbalance with dissipation (QCM-D)
Glucokinase (GCK) is the rate-limiting enzyme of liver glucose metabolism. Through protein-protein interactions, glucokinase regulatory protein (GCKR) post-transcriptionally regulates GCK function in the liver, and causes its nuclear localization. However the role of GCK in regulating GCKR localization is unknown. In the present study, using in vitro and in vivo models, we examined the levels of GCK and GCKR, and their subcellular localization. We found that total cellular levels of GCKR did not vary in the in vivo models, but its subcellular localization did. In animals with normal levels of GCK, GCKR is mainly localized to the nuclei of hepatocytes. In seven-day old rats and liver-specific Gck gene knockout mice (animals that lack or have reduced levels of GCK protein), GCKR was found primarily in the cytoplasm. The interaction of GCK with GCKR was further examined using in vitro models where we varied the levels of GCK and GCKR. Varying the level of GCK protein had no effect on total cellular GCKR protein levels. Taken together, our results indicate that GCK is important for the localization of GCKR to the nucleus and raises the possibility that GCKR may have functions in addition to those regulating GCK activity in the cytoplasm.
protein–protein interaction; glucokinase regulatory protein; glucokinase; sub-cellular localization; glucose metabolism
Due to the important roles of matrix metalloproteinases (MMPs) play in tumor invasion and metastasis, various activatable optical probes have been developed to visualize MMP activities in vitro and in vivo. Our recently developed MMP-13 activatable probe, L-MMP-P12, has been successfully applied to image the expression and inhibition of MMPs in a xenografted tumor model (Zhu L et al., Theranostics. 2011;1:18–27). In this study, to further optimize the in vivo behavior of the proteinase activatable probe, we tracked and profiled the metabolites by a high resolution LC/MS system. Two major metabolites that contributed to the fluorescence recovery were identified: One was specifically cleaved between Glycine (G4) and Valine (V5) by MMP, while the other one was generated by non-specific cleavage between Glycine (G7) and Lysine (K8). In order to visualize the MMP activity more accurately and specifically, a new probe D-MMP-P12 was designed by replacing the L-lysine with D-lysine in the MMP substrate sequence. The metabolic profile of the new probe, D-MMP-P12, was further characterized by in vitro enzymatic assay and no non-specific metabolite was found by LC/MS. Our in vivo optical imaging also demonstrated that D-MMP-12 had significantly higher tumor-to-background ratio (TBR, 5.55 ± 0.75) compared with L-MMP-P12 (3.73 ± 0.31) at 2 h post-injection. The improved MMP activatable probe may have the potential for drug screening, tumor diagnosis and therapy response monitoring. Moreover, our research strategy can be further extended to study other protease activatable probes.
Liquid chromatography–mass spectrometry (LC-MS); activatable probe; matrix metalloproteinases (MMPs); metabolite; near-infrared fluorescence imaging
of self-illuminating semiconducting nanocrystals, also called quantum
dots (QDs), has attracted much attention recently due to their potential
as highly sensitive optical probes for biological imaging applications.
Here we prepared a self-illuminating QD system by doping positron-emitting
radionuclide 64Cu into CdSe/ZnS core/shell QDs via a cation-exchange
reaction. The 64Cu-doped CdSe/ZnS QDs exhibit efficient
Cerenkov resonance energy transfer (CRET). The signal of 64Cu can accurately reflect the biodistribution of the QDs during circulation
with no dissociation of 64Cu from the nanoparticles. We
also explored this system for in vivo tumor imaging. This nanoprobe
showed high tumor-targeting ability in a U87MG glioblastoma xenograft
model (12.7% ID/g at 17 h time point) and feasibility for in vivo
luminescence imaging of tumor in the absence of excitation light.
The availability of these self-illuminating integrated QDs provides
an accurate and convenient tool for in vivo tumor imaging and detection.
In many cases cancer is caused by gene deficiency that is being passed along from generation to generation. Soluble carbon nanotubes (CNTs) have shown promising applications in the diagnosis and therapy of cancer, however, the potential relationship between cancer-prone individuals and response to CNT exposure as a prerequisite for development of personalized nanomedicine, is still poorly understood. Here we report that intravenous injections of multi-walled carbon nanotubes into p53 (a well-known cancer susceptible gene) heterozygous pregnant mice can induce p53- dependent responses in fetal development. Larger sized multi-walled carbon nanotubes moved across the blood-placenta barrier (BPB), restricted the development of fetuses, and induced brain deformity, whereas single-walled and smaller sized multi-walled carbon nanotubes showed no or less fetotoxicity. A molecular mechanism study found that multi-walled carbon nanotubes directly triggered p53-dependent apoptosis and cell cycle arrest in response to DNA damage. Based on the molecular mechanism, we also incorporated N-acetylcysteine (NAC), a FDA approved antioxidant, to prevent CNTs induced nuclear DNA damage and reduce brain development abnormalities. Our findings suggest that CNTs might have genetic background-dependent toxic effect on the normal development of the embryo, and provide new insights into protection against nanoparticle-induced toxicity in potential clinical applications.
Carbon nanotubes; nanotoxicity; genetic background; blood-placenta barrier; fetal development
A Site-specifically PEGylated exendin-4 (denoted as PEG-Ex4) is an exendin-4 (denoted as Ex4) analog we developed by site-specific PEGylation of exendin-4 with a high molecular weight trimeric poly(ethylene glycol) (tPEG). It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified exendin-4 by our previous work. This study is sought to test whether PEG-Ex4 is suitable for treating myocardial infarction (MI). In the MI model, PEG-Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily. Animal survival rate, heart function, remodeling and neoangiogenesis were evaluated and compared. Tube formation was examined in endothelial cells. In addition, Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved. PEG-Ex4 and Ex4 showed comparable binding affinity to GLP-1 receptor. In MI mice, PEG-Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily, while Ex4 given at 3 days interval failed to produce protection. PEG-Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI. PEG-Ex4 increased Akt activity and VEGF production in a GLP-1R dependent manner in endothelial cells and antagonism of GLP-1R, Akt or VEGF abolished the protection of PEG-Ex4 in the MI model. PEG-Ex4 is a potent long-acting GLP-1 receptor agonist for the treatment of chronic heart disease. Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and VEGF.
Exendin-4; PEGylation; cardioprotection; Angiogenesis; myocardial infarction.
In view of the importance of sentinel lymph nodes (SLNs) in tumor staging and patient management, sensitive and accurate imaging of SLNs has been intensively explored. Along with the advance of the imaging technology, various contrast agents have been developed for lymphatic imaging. In this review, the lymph node imaging agents were summarized into three groups: tumor targeting agents, lymphatic targeting agents and lymphatic mapping agents. Tumor targeting agents are used to detect metastatic tumor tissue within LNs, lymphatic targeting agents aim to visualize lymphatic vessels and lymphangionesis, while lymphatic mapping agents are mainly for SLN detection during surgery after local administration. Coupled with various signal emitters, these imaging agents work with single or multiple imaging modalities to provide a valuable way to evaluate the location and metastatic status of SLNs.
Sentinel lymph node; contrast agent; PET; MRI; fluorescence; imaging.
Purpose: The chemokine receptor CXCR4 is overexpressed in various types of human cancers. As a specific imaging agent of CXCR4, 68Ga-NOTA-NFB was investigated in this study to assess its safety, biodistribution and dosimetry properties in healthy volunteers, and to preliminarily evaluate its application in glioma patients.
Methods: Six healthy volunteers underwent whole-body PET scans at 0, 0.5, 1, 2 and 3 h after 68Ga-NOTA-NFB injection (mean dose, 182.4 ± 3.7 MBq (4.93 ± 0.10 mCi)). For time-activity curve calculations, 1 mL blood samples were obtained at 1, 3, 5, 10, 30, 60, 90, 120, 150 and 180 min after the injection. The estimated radiation doses were calculated by OLINDA/EXM software. Eight patients with glioma were enrolled and underwent both 68Ga-NOTA-NFB and 18F-FDG PET/CT scans before surgery. The expression of CXCR4 on the resected brain tumor tissues was determined by immunohistochemical staining.
68Ga-NOTA-NFB was safe and well tolerated by all subjects. A rapid activity clearance from the blood circulation was observed. The organs with the highest absorbed doses were spleen (193.8 ± 32.5 μSv/MBq) and liver (119.3 ± 25.0 μSv/MBq). The mean effective dose was 25.4 ± 6.1 μSv/MBq. The maximum standardized uptake values (SUVmax) and the maximum target to non-target ratios (T/NTmax) of 68Ga-NOTA-NFB PET/CT in glioma tissues were 4.11 ± 2.90 (range, 0.45-8.21) and 9.21 ± 8.75 (range, 3.66-24.88), respectively, while those of 18F-FDG PET/CT were 7.34 ± 2.90 (range, 3.50-12.27) and 0.86 ± 0.41 (range, 0.35-1.59). The histopathological staining confirmed that CXCR4 was overexpressed on resected tumor tissues with prominent 68Ga-NOTA-NFB uptake.
Conclusion: With a favorable radiation dosimetry profile, 68Ga-NOTA-NFB is safe for clinical imaging. Compared to 18F-FDG PET/CT, 68Ga-NOTA-NFB PET/CT is more sensitive in detecting glioma and could have potential in diagnosing and treatment planning for CXCR4 positive patients.
68Ga-NOTA-NFB; internal dosimetry; CXCR4; glioma; PET/CT
This pilot prospective evaluation study is to verify the efficiency of 18F-Alfatide II, a specific PET imaging agent for integrin αvβ3, in detecting bone metastasis in human, with comparison to 18F-FDG PET. Thirty recruited patients underwent 18F-FDG and 18F-alfatide II PET/CT successively within days. The final diagnosis of bone lesions was established based on the comprehensive assessment of all available data and clinical follow-up, which fall into four groups: osteolytic, osteoblastic, mixed and bone marrow. Visual analysis and quantification of SUVmax were performed to compare the detection sensitivity of 18F-Alfatide II and 18F-FDG PET. Eleven patients were found to have a total of 126 bone metastasis lesions. 18F-Alfatide II PET can detect the bone metastatic lesions with good contrast and higher sensitivity (positive rate of 92%) than 18F-FDG PET (77%). Especially, 18F-Alfatide II PET showed superiority to 18F-FDG PET in detecting osteoblastic (70% vs. 53%) and bone marrow metastatic lesions (98% vs. 77%). In conclusion, 18F-Alfatide II PET/CT can be used to detect skeletal and bone marrow metastases, with nearly 100% sensitivity in osteolytic, mixed and bone marrow lesions. The sensitivity of 18F-Alfatide II PET/CT in osteoblastic metastases is relatively low but still significantly higher than that of 18F-FDG PET/CT. This pilot clinical study warrants the further application of 18F-Alfatide II PET/CT in metastatic lesion detection, patient management and drug therapy response monitoring.
RGD peptide; Alfatide II; FDG; PET/CT; bone metastasis