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PurposeApoptosis is a key factor in unstable plaques. The aim of this study is to evaluate the utility of visualizing atherosclerotic plaques with radiolabeled duramycin and Annexin V.ProceduresApoE−/− mice were fed with a high-fat diet to develop atherosclerosis, C57 mice as a control. Using a routine conjugation protocol, highly pure [99mTc]duramycin and [99mTc]Annexin V were obtained, which were applied for in vitro cell assays of apoptosis and in vivo imaging of atherosclerotic plaques in the animal model. Oil Red O staining, TUNEL, hematoxylin-eosin (HE), and CD68 immunostaining were used to evaluate the deposition of lipids and presence of apoptotic macrophages in the lesions where focal intensity positively correlated with the uptake of both tracers.Results[99mTc]duramycin and [99mTc]Annexin V with a high radiochemical purity (97.13 ± 1.52 and 94.94 ± 0.65 %, respectively) and a well stability at room temperature were used. Apoptotic cells binding activity to [99mTc]duramycin (Kd, 6.92 nM and Bmax, 56.04 mol/1019 cells) was significantly greater than [99mTc]Annexin V (Kd, 12.63 nM and Bmax, 31.55 mol/1019 cells). Compared with [99mTc]Annexin V, [99mTc]duramycin bound avidly to atherosclerotic lesions with a higher plaque-to-background ratio (P/B was 8.23 ± 0.91 and 5.45 ± 0.48 at 20 weeks, 15.02 ± 0.23 and 12.14 ± 0.22 at 30 weeks). No plaques were found in C57 control mice. Furthermore, Oil Red O staining showed lipid deposition areas were significantly increased in ApoE−/− mice at 20 and 30 weeks, and TUNEL and CD68 staining confirmed that the focal uptake of both tracers contained abundant apoptotic macrophages.ConclusionsThis stable, fast clearing, and highly specific [99mTc]duramycin, therefore, can be useful for the quantification of vulnerable atherosclerotic plaques.

BackgroundThe human tumor microenvironment (TME) is a complex and dynamic milieu of diverse acellular and cellular components, creating an immunosuppressive environment, which contributes to tumor progression. We have previously shown that phosphatidylserine (PS) expressed on the surface of exosomes isolated from human TMEs is causally linked to T-cell immunosuppression, representing a potential immunotherapeutic target. In this study, we investigated the effect of ExoBlock, a novel PS-binding molecule, on T-cell responses in the TME.MethodsWe designed and synthesized a new compound, (ZnDPA)6-DP-15K, a multivalent PS binder named ExoBlock. The PS-binding avidity of ExoBlock was tested using an in vitro competition assay. The ability of this molecule to reverse exosome-mediated immunosuppression in vitro was tested using human T-cell activation assays. The in vivo therapeutic efficacy of ExoBlock was then tested in two different human tumor xenograft models, the melanoma-based xenomimetic (X-)mouse model, and the ovarian tumor-based omental tumor xenograft (OTX) model.ResultsExoBlock was able to bind PS with high avidity and was found to consistently and significantly block the immunosuppressive activity of human ovarian tumor and melanoma-associated exosomes in vitro. ExoBlock was also able to significantly enhance T cell-mediated tumor suppression in vivo in both the X-mouse and the OTX model. In the X-mouse model, ExoBlock suppressed tumor recurrence in a T cell-dependent manner. In the OTX model, ExoBlock treatment resulted in an increase in the number as well as function of CD4 and CD8 T cells in the TME, which was associated with a reduction in tumor burden and metastasis, as well as in the number of circulating PS+ exosomes in tumor-bearing mice.ConclusionOur results establish that targeting exosomal PS in TMEs with ExoBlock represents a promising strategy to enhance antitumor T-cell responses.

Glioblastoma multiforme (GBM), the most common type of brain cancer, is extremely aggressive and has a dreadful prognosis. GBM comprises 60% of adult brain tumors and the 5 year survival rate of GBM patients is only 4.3%. Standard-of-care treatment includes maximal surgical removal of the tumor in combination with radiation and temozolomide (TMZ) chemotherapy. TMZ is the “gold-standard” chemotherapy for patients suffering from GBM. However, the median survival is only about 12 to 18 months with this protocol. Consequently, there is a critical need to develop new therapeutic options for treatment of GBM. Nanomaterials have unique properties as multifunctional platforms for brain tumor therapy and diagnosis. As one of the nanomaterials, lipid-based nanocarriers are capable of delivering chemotherapeutics and imaging agents to tumor sites by enhancing the permeability of the compound through the blood–brain barrier, which makes them ideal for GBM therapy and imaging. Nanocarriers also can be used for delivery of radiosensitizers to the tumor to enhance the efficacy of the radiation therapy. Previously, high-atomic-number element-containing particles such as gold nanoparticles and liposomes have been used as radiosensitizers. SapC–DOPS, a protein-based liposomal drug comprising the lipid, dioleoylphosphatidylserine (DOPS), and the protein, saposin C (SapC), has been shown to be effective for treatment of a variety of cancers in small animals, including GBM. SapC–DOPS also has the unique ability to be used as a carrier for delivery of radiotheranostic agents for nuclear imaging and radiotherapeutic purposes. These unique properties make tumor-targeting proteo-liposome nanocarriers novel therapeutic and diagnostic alternatives to traditional chemotherapeutics and imaging agents. This article reviews various treatment modalities including nanolipid-based delivery and therapeutic systems used in preclinical and clinical trial settings for GBM treatment and detection.

Glioblastoma multiforme (GBM), a common type of brain cancer, has a very poor prognosis. In general, viable GBM cells exhibit elevated phosphatidylserine (PS) on their membrane surface compared to healthy cells. We have developed a drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), that selectively targets cancer cells by honing in on this surface PS. To examine whether SapC-DOPS, a stable, blood–brain barrier-penetrable nanovesicle, could be an effective delivery system for precise targeted therapy of radiation, we iodinated several carbocyanine-based fluorescent reporters with either stable iodine (127I) or radioactive isotopes (125I and 131I). While all of the compounds, when incorporated into the SapC-DOPS delivery system, were taken up by human GBM cell lines, we chose the two that best accumulated in the cells (DiI (22,3) and DiD (16,16)). Pharmacokinetics were conducted with 125I-labeled compounds and indicated that DiI (22,3)-SapC-DOPS had a time to peak in the blood of 0.66 h and an elimination half-life of 8.4 h. These values were 4 h and 11.5 h, respectively, for DiD (16,16)-SapC-DOPS. Adult nude mice with GBM cells implanted in their brains were treated with 131I-DID (16,16)-SapC-DOPS. Mice receiving the radionuclide survived nearly 50% longer than the control groups. These data suggest a potential novel, personalized treatment for a devastating brain disease.

Purpose Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo . A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging. Methods Bacterial infection and sterile inflammation were induced in separate groups ( n  = 5) of mice. PS was targeted with a NIR fluorophore, PSVue ® 794 (2.7 pmol). Imaging was performed (ex = 730 nm, em = 830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity. Results Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post-injection, the lesion to background intensity ratios in the foci of infection (6.6 ± 0.2) were greater than those in inflammation (3.2 ± 0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS. Conclusions Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7–14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection.

Introduction Development of non-invasive molecular imaging techniques that are based on cellular changes in inflammation has been of active interest for arthritis diagnosis. This technology will allow real-time detection of tissue damage and facilitate earlier treatment of the disease, thus representing an improvement over X-rays, which detect bone damage at the advanced stage. Tracing apoptosis, an event occurring in inflammation, has been a strategy used. PSVue 794 is a low-molecular-weight, near-infrared (NIR)-emitting complex of bis(zinc 2+ -dipicolylamine) (Zn-DPA) that binds to phosphatidylserine (PS), a plasma membrane anionic phospholipid that becomes flipped externally upon cell death by apoptosis. In this study, we evaluated the capacity of PSVue 794 to act as an in vivo probe for non-invasive molecular imaging assessment of rheumatoid arthritis (RA) via metabolic function in murine collagen-induced arthritis, a widely adopted animal model for RA. Methods Male DBA/1 strain mice were treated twice with chicken collagen type II in Freund’s adjuvant. Their arthritis development was determined by measuring footpad thickness and confirmed with X-ray analysis and histology. In vivo imaging was performed with the NIR dye and the LI-COR Odyssey Image System. The level of emission was compared among mice with different disease severity, non-arthritic mice and arthritic mice injected with a control dye without the Zn-DPA targeting moiety. Results Fluorescent emission correlated reliably with the degree of footpad swelling and the manifestation of arthritis. Ex vivo examination showed emission was from the joint. Specificity of binding was confirmed by the lack of emission when arthritic mice were given the control dye. Furthermore, the PS-binding protein annexin V displaced the NIR dye from binding, and the difference in emission was numerically measurable on a scale. Conclusions This report introduces an economical alternative method for assessing arthritis non-invasively in murine models. Inflammation in feet and ankles can be measured longitudinally using the PSVue 794 probe for cell death and with a commonly available multipurpose imager. This technique provides metabolic and functional information that anatomical measurement of footpad swelling or visual determination of arthritic index cannot. It also may decrease the number of animals required per experiment because tissue damage will not necessarily require evaluation by harvesting joints for histology.

Objectives Molecular imaging of apoptosis is frequently discussed for monitoring cancer therapies. Here, we compare the low molecular weight phosphatidylserine-targeting ligand zinc 2+ -dipicolylamine (Zn 2+ -DPA) with the established but reasonably larger protein annexin V. Methods Molecular apoptosis imaging with the fluorescently labelled probes annexin V (750 nm, 36 kDa) and Zn 2+ -DPA (794 nm, 1.84 kDa) was performed in tumour-bearing mice (A431). Three animal groups were investigated: untreated controls and treated tumours after 1 or 4 days of anti-angiogenic therapy (SU11248). Additionally, μPET with 18  F-FDG was performed. Imaging data were displayed as tumour-to-muscle ratio (TMR) and validated by quantitative immunohistochemistry. Results Compared with untreated control tumours, TUNEL staining indicated significant apoptosis after 1 day ( P  < 0.05) and 4 days ( P  < 0.01) of treatment. Concordantly, Zn 2+ -DPA uptake increased significantly after 1 day ( P  < 0.05) and 4 days ( P  < 0.01). Surprisingly, annexin V failed to detect significant differences between control and treated animals. Contrary to the increasing uptake of Zn 2+ -DPA, 18  F-FDG tumour uptake decreased significantly at days 1 ( P  < 0.05) and 4 ( P  < 0.01). Conclusions Increase in apoptosis during anti-angiogenic therapy was detected significantly better with the low molecular weight probe Zn 2+ -DPA than with the annexin V-based probe. Additionally, significant treatment effects were detectable as early using Zn 2+ -DPA as with measurements of the glucose metabolism using 18  F-FDG. Key points • The detection of apoptosis by non - invasive imaging is important in oncology . • A new low molecular weight probe Zn 2 + - DPA shows promise in depicting anti - angiogenic effects . • The small Zn 2 + - DPA ligand appears well suited for monitoring therapy . • Treatment effects are detectable just as early with Zn 2 + - DPA as with 18   F - FDG .

We report the preclinical evaluation of potent long-acting [225Ac]Ac-EBTATE against SSTR2-positive small cell lung cancer (SCLC) and pancreatic neuroendocrine tumors (pan-NETs).PURPOSEWe report the preclinical evaluation of potent long-acting [225Ac]Ac-EBTATE against SSTR2-positive small cell lung cancer (SCLC) and pancreatic neuroendocrine tumors (pan-NETs).The pharmacokinetic, biodistribution, and safety studies were evaluated in healthy female and/or male BALB/c mice after intravenous injections of [225Ac]Ac-EBTATE. Further biodistribution and radioligand therapy were investigated in female athymic BALB/c nude mice bearing high or low SSTR2-expressing subcutaneous SCLC models NCI-H524 or NCI-H727, respectively, and in a pan-NET model QGP1.SSTR2.METHODSThe pharmacokinetic, biodistribution, and safety studies were evaluated in healthy female and/or male BALB/c mice after intravenous injections of [225Ac]Ac-EBTATE. Further biodistribution and radioligand therapy were investigated in female athymic BALB/c nude mice bearing high or low SSTR2-expressing subcutaneous SCLC models NCI-H524 or NCI-H727, respectively, and in a pan-NET model QGP1.SSTR2.Pharmacokinetics confirmed a prolonged clearance half-life (40.27 ± 9.23 h) while biodistribution in healthy male and female BALB/c mice was similar, with prolonged blood circulation that peaked at 6 h. Biodistribution in subcutaneous xenograft models of NCI-H524 and NCI-H727 showed consistent tumor-uptake with SSTR2-overexpression while the projected human effective doses for males and females were 61.7 and 83.7 millisievert/megabecquerel, respectively. 2 × 34 kBq of [225Ac]Ac-EBTATE administered 10 days (d) apart, was generally tolerated for 28 days in healthy BALB/c mice as revealed by blood biochemistry, complete blood count, and histopathological examination of H&E-stained organs. Targeted alpha therapy at 2 × 30 kBq of [225Ac]Ac-EBTATE, injected 10 days apart, resulted in 100% survivals and 80% and 20% complete remissions for NCI-H524 and QGP1.SSTR2 models, respectively. Additionally, [225Ac]Ac-EBTATE had a dose-dependent response in the NCI-H727 model, with median survivals for 2 × 30 kBq and 2 × 15 kBq groups being 63 d (p < 0.0007), and 47 d (p = 0.0148), respectively.RESULTSPharmacokinetics confirmed a prolonged clearance half-life (40.27 ± 9.23 h) while biodistribution in healthy male and female BALB/c mice was similar, with prolonged blood circulation that peaked at 6 h. Biodistribution in subcutaneous xenograft models of NCI-H524 and NCI-H727 showed consistent tumor-uptake with SSTR2-overexpression while the projected human effective doses for males and females were 61.7 and 83.7 millisievert/megabecquerel, respectively. 2 × 34 kBq of [225Ac]Ac-EBTATE administered 10 days (d) apart, was generally tolerated for 28 days in healthy BALB/c mice as revealed by blood biochemistry, complete blood count, and histopathological examination of H&E-stained organs. Targeted alpha therapy at 2 × 30 kBq of [225Ac]Ac-EBTATE, injected 10 days apart, resulted in 100% survivals and 80% and 20% complete remissions for NCI-H524 and QGP1.SSTR2 models, respectively. Additionally, [225Ac]Ac-EBTATE had a dose-dependent response in the NCI-H727 model, with median survivals for 2 × 30 kBq and 2 × 15 kBq groups being 63 d (p < 0.0007), and 47 d (p = 0.0148), respectively.[225Ac]Ac-EBTATE is safe and effective against SCLC and pan-NET and therefore warrants clinical investigation.CONCLUSIONS[225Ac]Ac-EBTATE is safe and effective against SCLC and pan-NET and therefore warrants clinical investigation.

Molecular imaging of apoptosis is frequently discussed for monitoring cancer therapies. Here, we compare the low molecular weight phosphatidylserine-targeting ligand zinc^sup 2+^-dipicolylamine (Zn^sup 2+^-DPA) with the established but reasonably larger protein annexin V. Molecular apoptosis imaging with the fluorescently labelled probes annexin V (750 nm, 36 kDa) and Zn^sup 2+^-DPA (794 nm, 1.84 kDa) was performed in tumour-bearing mice (A431). Three animal groups were investigated: untreated controls and treated tumours after 1 or 4 days of anti-angiogenic therapy (SU11248). Additionally, [mu]PET with ^sup 18^F-FDG was performed. Imaging data were displayed as tumour-to-muscle ratio (TMR) and validated by quantitative immunohistochemistry. Compared with untreated control tumours, TUNEL staining indicated significant apoptosis after 1 day (P<0.05) and 4 days (P<0.01) of treatment. Concordantly, Zn^sup 2+^-DPA uptake increased significantly after 1 day (P<0.05) and 4 days (P<0.01). Surprisingly, annexin V failed to detect significant differences between control and treated animals. Contrary to the increasing uptake of Zn^sup 2+^-DPA, ^sup 18^F-FDG tumour uptake decreased significantly at days 1 (P<0.05) and 4 (P<0.01). Increase in apoptosis during anti-angiogenic therapy was detected significantly better with the low molecular weight probe Zn^sup 2+^-DPA than with the annexin V-based probe. Additionally, significant treatment effects were detectable as early using Zn^sup 2+^-DPA as with measurements of the glucose metabolism using ^sup 18^F-FDG. * The detection of apoptosis by non-invasive imaging is important in oncology. * A new low molecular weight probe Zn ^sup 2+^-DPA shows promise in depicting anti-angiogenic effects. * The small Zn ^sup 2+^-DPA ligand appears well suited for monitoring therapy. * Treatment effects are detectable just as early with Zn ^sup 2+^-DPA as with ^sup 18^ F-FDG.[PUBLICATION ABSTRACT]