IL-1RAP, a Key Therapeutic Target in Cancer.

Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG. METHODS: Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. RESULTS: We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. CONCLUSION: [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.

Superparamagnetic Nanoparticle Delivery to the Cochlea Through Round Window by External Magnetic Field: Feasibility and Toxicity.

Introduction. The objective of this study was to evaluate the feasibility and toxicity of superparamagnetic iron oxide nanoparticles (SPIONs) administered into the cochlea through the round window (RW) by an external magnetic field. Materials and Methods. In 5 Wistar rats, the left RW was punctured. SPIONs suspended in hyaluronic gel (5 mg/mL) were applied in the RW niche and covered by a muscle graft. The nanoparticles were mobilized using a rare earth magnet (0.54 T) held in 4 consecutive positions around the head. The right ear served as control. Hearing function was monitored by auditory brainstem responses (4-32 kHz tone bursts). Results. The auditory thresholds remained unchanged 1 month after the administration. The histological study of the cochleae showed that SPIONs were driven into the scala tympani in the basal turn, the second turn, and the apex. Conclusion. Superparamagnetic nanoparticles can be driven inside the cochlea toward the apex with a preserved hearing up to 1 month in rats.

Site-Specific Dual Labeling of Proteins on Cysteine Residues with Chlorotetrazines.

Dual-labeled biomolecules constitute a new generation of bioconjugates with promising applications in therapy and diagnosis. Unfortunately, the development of these new families of biologics is hampered by the technical difficulties associated with their construction. In particular, the site specificity of the conjugation is critical as the number and position of payloads can have a dramatic impact on the pharmacokinetics of the bioconjugate. Herein, we introduce dichlorotetrazine as a trivalent platform for the selective double modification of proteins on cysteine residues. This strategy is applied to the dual labeling of albumin with a macrocyclic chelator for nuclear imaging and a fluorescent probe for fluorescence imaging.

Near-Infrared-Emitting BODIPY-trisDOTA(111) In as a Monomolecular Multifunctional Imaging Probe: From Synthesis to In Vivo Investigations.

A new generation of monomolecular imaging probes (MOMIP) based on a distyryl-BODIPY (BODIPY=boron-dipyrromethene) coupled with three DOTA macrocycles has been prepared (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The MOMIP presents good fluorescence properties and is very stable in serum. The bimodal probe was conjugated to trastuzumab, and an optical in vivo study showed high accumulation of the imaging agent at the tumor site. (111) In radiometallation of the bioconjugate was performed in high radiochemical yield, highlighting the potential of this new BODIPY-chelators derivative as a bimodal imaging probe.

BODIPY: A Highly Versatile Platform for the Design of Bimodal Imaging Probes.

In molecular imaging, multimodal imaging agents can provide complementary information, for improving the accuracy of disease diagnosis or enhancing patient management. In particular, optical/nuclear imaging may find important preclinical and clinical applications. To simplify the preparation of dual-labeled imaging agents, we prepared versatile monomolecular multimodal imaging probe (MOMIP) platforms containing both a fluorescent dye (BODIPY) and a metal chelator (polyazamacrocycle). One of the MOMIP was conjugated to a cyclopeptide (i.e., octreotide) and radiolabeled with (111) In. In vitro and in vivo studies of the resulting bioconjugate were conducted, highlighting the potential of these BODIPY-based bimodal probes. This work also confirmed that the biovector and/or the bimodal probes must be chosen carefully, due to the impact of the MOMIP on the overall properties of the resulting imaging agent.

Identification of the Proteins Determining the Blood Circulation Time of Nanoparticles.

The therapeutic efficacy and adverse impacts of nanoparticles (NPs) are strongly dependent on their systemic circulation time. The corona proteins adsorbed on the NPs determine their plasma half-lives, and hence, it is crucial to identify the proteins shortening or extending their circulation time. In this work, the in vivo circulation time and corona composition of superparamagnetic iron oxide nanoparticles (SPIONs) with different surface charges/chemistries were analyzed over time. SPIONs with neutral and positive charges showed the longest and shortest circulation times, respectively. The most striking observation was that corona-coated NPs with similar opsonin/dysopsonin content showed different circulation times, implying these biomolecules are not the only contributing factors. Long-circulating NPs adsorb higher concentrations of osteopontin, lipoprotein lipase, coagulation factor VII, matrix Gla protein, secreted phosphoprotein 24, alpha-2-HS-glycoprotein, and apolipoprotein C-I, while short-circulating NPs adsorb higher amounts of hemoglobin. Therefore, these proteins may be considered to be determining factors governing the NP systemic circulation time.

Iodixanol as a New Contrast Agent for Cyanoacrylate Embolization: A Preliminary In Vivo Swine Study.

N-butyl cyanoacrylate (NBCA) is a lipophilic, permanent embolic glue that must be opacified for fluoroscopic guidance. Empirically, lipophilic Lipiodol Ultra Fluid® (LUF) has been added to produce a single-phase physically stable mixture. Varying the dilution ratio allows control of glue polymerization kinetics. LUF is far more costly than water-soluble iodinated contrast agents (ICAs). Our purpose was to evaluate whether a water-soluble nonionic iso-osmolar ICA could be used instead. We embolized both renal arteries of six swine using 1:3 NBCA-LUF or NBCA-iodixanol in 1:1, 1:3, and 1:7 ratios. We used both micro-computed tomography to assess the distality of glue penetration and indexed cast ratio and histology to assess distality, arterial obliteration, vessel-wall damage, and renal-parenchyma necrosis. Glue-LUF produced significantly greater indexed cast ratio and renal-artery ROI values and a significantly shorter cast-to-capsule distance. The injected volume was significantly greater with 1:7 iodixanol than with the other mixtures. No significant differences were found for histological evidence of artery obliteration, vessel-wall damage, or renal-parenchyma necrosis. This is the first study dealing with ICA alone as a contrast agent for cyanoacrylate embolization, compared to LUF. More research is needed to determine whether water-soluble nonionic iodinated agents can be used for human NBCA embolization given the good safety profile, availability, and low cost of ICA.

A new experimental rat model of erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: the testosterone-supplemented spontaneously hypertensive rat.

UNLABELLED: What's known on the subject? and What does the study add? Lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common problems in the aging male population. Moreover, several recent studies have shown that ED is closely associated with the presence and severity of LUTS independently of co-morbidities. However, the pathophysiological mechanisms linking LUTS/BPH and ED remain largely unexplored. The major difficulty in studying such relationships between ED and LUTS/BPH, and of exploring the impact of new therapeutic approaches for both LUTS/BPH and ED, is the lack of experimental model combining ED, prostate enlargement and bladder dysfunction all at once. The present study describes a new model of BPH, the SHR supplemented with testosterone which is the first animal model which displays all at once the key features of BPH: prostate enlargement and an increased sympathetic tone of bladder outlet mimicking the static and the dynamic components of voiding symptoms of BPH, a significant impairment of bladder function which reflects the storage symptoms of BPH and finally, ED. This model could be very relevant to better characterize the close relationship that exists between BPH/LUTS and ED, and to evaluate new therapeutic strategies for BPH together with their side effect profile on sexual function on the same animal, thus allowing a reduction of the number of animals to be used in such studies. Study Type - Aetiology (case control) Level of Evidence 3b. OBJECTIVE: • To design a new experimental model combining erectile dysfunction, prostate enlargement and urodynamic impairment characteristic of lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). MATERIALS AND METHODS: • Three groups of animals (12-week-old; n= 7/group) were considered: Wistar Kyoto (control) rats (WKY), untreated spontaneously hypertensive rats (SHR) and SHR treated with testosterone (SHR-T, 3 mg/kg/day) for 3 weeks. • Cystometry experiments and evaluation of erectile function were performed. Prostate enlargement was evaluated. RESULTS: • SHR displayed a significant decrease in the intercontraction interval (ICI) and in the voided volume (VV) whereas non-voiding contractions (NVC) were increased. SHR-T exhibited a further decreased ICI and VV and an increased frequency of NVC. • Erectile responses to electrical stimulation of the cavernous nerve were significantly impaired in both SHR (-66%) and SHR-T (-58%). • The prostate weight was similar in WKY and SHR, but significantly increased in SHR-T. CONCLUSIONS: • The testosterone-supplemented SHR represents an experimental model for urodynamic impairment combining both static and dynamic components of voiding symptoms with erectile dysfunction and prostate enlargement. • This model is suitable for the assessment of sexual side effects of LUTS/BPH treatments and efficacy of new therapeutic agents in LUTS/BPH and associated erectile dysfunction.

Superparamagnetic Iron Oxide Nanoparticles for Immunotherapy of Cancers through Macrophages and Magnetic Hyperthermia.

Cancer immunotherapy has tremendous promise, but it has yet to be clinically applied in a wider variety of tumor situations. Many therapeutic combinations are envisaged to improve their effectiveness. In this way, strategies capable of inducing immunogenic cell death (e.g., doxorubicin, radiotherapy, hyperthermia) and the reprogramming of the immunosuppressive tumor microenvironment (TME) (e.g., M2-to-M1-like macrophages repolarization of tumor-associated macrophages (TAMs)) are particularly appealing to enhance the efficacy of approved immunotherapies (e.g., immune checkpoint inhibitors, ICIs). Due to their modular construction and versatility, iron oxide-based nanomedicines such as superparamagnetic iron oxide nanoparticles (SPIONs) can combine these different approaches in a single agent. SPIONs have already shown their safety and biocompatibility and possess both drug-delivery (e.g., chemotherapy, ICIs) and magnetic capabilities (e.g., magnetic hyperthermia (MHT), magnetic resonance imaging). In this review, we will discuss the multiple applications of SPIONs in cancer immunotherapy, focusing on their theranostic properties to target TAMs and to generate MHT. The first section of this review will briefly describe immune targets for NPs. The following sections will deal with the overall properties of SPIONs (including MHT). The last section is dedicated to the SPION-induced immune response through its effects on TAMs and MHT.

X-ray Microtomography to Assess Determinants of In Vivo N-Butyl Cyanoacrylate Glubran®2 Polymerization: A Rabbit-Model Study.

Although introduced decades ago, few cyanoacrylate glues have been approved for endovascular use, despite evidence of their usefulness, notably for complex procedures suchas hemostatic embolization. Indications include massive bleeding requiring emergent hemostasis and prevention of severe bleeding during scheduled surgery to remove a hypervascular tumor. Adding radiopaque Lipiodol Ultra Fluid® (LUF) modulates glue polymerization and allows fluoroscopic guidance, but few comparative in vivo studies have assessed the impact of the resulting change in glue concentration or of other factors such as target-vessel blood flow. In a rabbit model, we used ex vivo X-ray microtomography to assess the results of in vivo renal-artery embolization by various mixtures of N-butyl cyanoacrylate (NBCA), metacryloxysulfolane, and LUF. Overall, penetration to the superficial interlobular arteries was achieved in about two-thirds of cases and into the capillaries in nearly half the cases, while cast fragmentation was seen in slightly more than half the cases. Greater NBCA dilution and the blocked-blood-flow technique were independently associated with greater distality of penetration. Blocked-blood-flow injection was independently associated with absence of fragmentation, capillary penetration, a shorter cast-to-capsule distance, and higher cast attenuation. A larger mixture volume was independently associated with higher indexed cast ratio and deeper penetration. Finally, microtomography is an adapted tool to assess ex vivo distribution of glue cast.

[123I]MIBG is a better early marker of anthracycline cardiotoxicity than [18F]FDG: a preclinical SPECT/CT and simultaneous PET/MR study.

BACKGROUND: During anthracycline treatment of cancer, there is a lack for biomarkers of cardiotoxicity besides the cardiac dysfunction. The objective of the present study was to compare [18F]FDG and [123I]MIBG (metaiodobenzylguanidine) in a longitudinal study in a doxorubicin-induced cardiotoxicity rat model. METHODS: Male Wistar Han rats were intravenously administered 3 times at 10 days' interval with saline or doxorubicin (5 mg/kg). [123I]MIBG SPECT/CT (single photon emission computed tomography-computed tomography) and simultaneous [18F]FDG PET (positron emission tomography)/7 Tesla cardiac MR (magnetic resonance) imaging acquisitions were performed at 24 h interval before first doxorubicin / saline injection and every 2 weeks during 6 weeks. At 6 weeks, the heart tissue was collected for histomorphometry measurements. RESULTS: At week 4, left ventricle (LV) end-diastolic volume was significantly reduced in the doxorubicin group. At week 6, the decreased LV end-diastolic volume was maintained, and LV end-systolic volume was increased resulting in a significant reduction of LV ejection fraction (47 ± 6% vs. 70 ± 3%). At weeks 4 and 6, but not at week 2, myocardial [18F]FDG uptake was decreased compared with the control group (respectively, 4.2 ± 0.5%ID/g and 9.2 ± 0.8%ID/g at week 6). Moreover, [18F]FDG cardiac uptake correlated with cardiac function impairment. In contrast, from week 2, a significant decrease of myocardial [123I]MIBG heart to mediastinum ratio was detected in the doxorubicin group and was maintained at weeks 4 and 6 with a 45.6% decrease at week 6. CONCLUSION: This longitudinal study precises that after doxorubicin treatment, cardiac [123I]MIBG uptake is significantly reduced as early as 2 weeks followed by the decrease of the LV end-diastolic volume and [18F]FDG uptake at 4 weeks and finally by the increase of LV end-systolic volume and decrease of LV ejection fraction at 6 weeks. Cardiac innervation imaging should thus be considered as an early key feature of anthracycline cardiac toxicity.

How does chronic sildenafil prevent vascular oxidative stress in insulin-resistant rats?

INTRODUCTION: Insulin resistance features both endothelial dysfunction and increased oxidative stress. Both disorders are targeted by a chronic treatment with sildenafil. However, the mechanism of action by which chronic sildenafil exerts its effects on reactive oxygen species sources is still largely unknown. AIM: We therefore investigated how chronic sildenafil administration could impact vascular endothelial NO and superoxide release in a rat model of insulin resistance induced by fructose overload. METHODS: Adult male Wistar rats were fed a fructose-enriched diet (fructose-fed rats [FFR]) for 9 weeks. From weeks 6-8, sildenafil was administered subcutaneously twice daily (20 mg/kg), followed by a 1-week washout. MAIN OUTCOME MEASURES: Vascular endothelial NO and superoxide release were monitored in vitro in thoracic aortic segments using oxidative fluorescence. Specific inhibitors were used to distinguish the respective role of the main superoxide-producing systems within the vascular wall (i.e., mitochondrial respiratory chain and NADPH oxidases). The levels of expression of eNOS, Akt, and NADPH oxidase subunits were determined in the abdominal aorta. RESULTS: Chronic sildenafil administration corrected hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in FFR. Moreover, after 9 weeks of diet, while global unstimulated aortic endothelial NO and superoxide release were unchanged in FFR, the relative contribution of the mitochondrial respiratory chain and NADPH oxidases was modified. Chronic sildenafil treatment, even after the 1-week washout period, was able to increase endothelial NO release independently of Akt-dependent phosphorylation by up-regulating eNOS expression, and restored the relative contribution of each superoxide-producing system examined, yielding endothelial superoxide release. Finally, in vitro incubation of aortic segments with sildenafil markedly decreased the endothelial aortic superoxide release. CONCLUSIONS: The present study showed that chronic sildenafil produced sustained vascular antioxidant effects in insulin-resistant rats by increasing NO release and regulating vascular superoxide release, supporting therefore further investigations using chronic sildenafil administration in preventing cardiovascular alterations associated with oxidative stress.

Titanate Nanotubes Engineered with Gold Nanoparticles and Docetaxel to Enhance Radiotherapy on Xenografted Prostate Tumors.

Nanohybrids based on titanate nanotubes (TiONts) were developed to fight prostate cancer by intratumoral (IT) injection, and particular attention was paid to their step-by-step synthesis. TiONts were synthesized by a hydrothermal process. To develop the customengineered nanohybrids, the surface of TiONts was coated beforehand with a siloxane (APTES), and coupled with both dithiolated diethylenetriaminepentaacetic acidmodified gold nanoparticles (Au@DTDTPA NPs) and a heterobifunctional polymer (PEG3000) to significantly improve suspension stability and biocompatibility of TiONts for targeted biomedical applications. The prefunctionalized surface of this scaffold had reactive sites to graft therapeutic agents, such as docetaxel (DTX). This novel combination, aimed at retaining the AuNPs inside the tumor via TiONts, was able to enhance the radiation effect. Nanohybrids have been extensively characterized and were detectable by SPECT/CT imaging through grafted Au@DTDTPA NPs, radiolabeled with 111In. In vitro results showed that TiONtsAuNPsPEG3000DTX had a substantial cytotoxic activity on human PC3 prostate adenocarcinoma cells, unlike initial nanohybrids without DTX (Au@DTDTPA NPs and TiONtsAuNPsPEG3000). Biodistribution studies demonstrated that these novel nanocarriers, consisting of AuNP- and DTXgrafted TiONts, were retained within the tumor for at least 20 days on mice PC3 xenografted tumors after IT injection, delaying tumor growth upon irradiation.

Innovative Magnetic Nanoparticles for PET/MRI Bimodal Imaging.

Superparamagnetic iron oxide nanoparticles were developed as positron emission tomography (PET) and magnetic resonance imaging (MRI) bimodal imaging agents. These nanoparticles (NPs), with a specific nanoflower morphology, were first synthesized and simultaneously functionalized with 3,4-dihydroxy-l-phenylalanine (LDOPA) under continuous hydrothermal conditions. The resulting NPs exhibited a low hydrodynamic size of 90 ± 2 nm. The functional groups of LDOPA (-NH2 and -COOH) were successfully used for the grafting of molecules of interest in a second step. The nanostructures were modified by poly(ethylene glycol) (PEG) and a new macrocyclic chelator MANOTA for further 64Cu radiolabeling for PET imaging. The functionalized NPs showed promising bimodal (PET and MRI) imaging capability with high r 2 and r 2* (T 2 and T 2* relaxivities) values and good stability. They were mainly uptaken from liver and kidneys. No cytotoxicity effect was observed. These NPs appear as a good candidate for bimodal tracers in PET/MRI.

Cleaved Caspase-3 Transcriptionally Regulates Angiogenesis-Promoting Chemotherapy Resistance.

Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3-proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer. SIGNIFICANCE: These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcriptionally regulate the VEGFR pathway.

Abnormalities of mitochondrial functioning can partly explain the metabolic disorders encountered in sarcopenic gastrocnemius.

Aging triggers several abnormalities in muscle glycolytic fibers including increased proteolysis, reactive oxygen species (ROS) production and apoptosis. Since the mitochondria are the main site of substrate oxidation, ROS production and programmed cell death, we tried to know whether the cellular disorders encountered in sarcopenia are due to abnormal mitochondrial functioning. Gastrocnemius mitochondria were extracted from adult (6 months) and aged (21 months) male Wistar rats. Respiration parameters, opening of the permeability transition pore and ROS production, with either glutamate (amino acid metabolism) or pyruvate (glucose metabolism) as a respiration substrate, were evaluated at different matrix calcium concentrations. Pyruvate dehydrogenase and respiratory complex activities as well as their contents measured by Western blotting analysis were determined. Furthermore, the fatty acid profile of mitochondrial phospholipids was also measured. At physiological calcium concentration, state III respiration rate was lowered by aging in pyruvate conditions (-22%), but not with glutamate. The reduction of pyruvate oxidation resulted from a calcium-dependent inactivation of the pyruvate dehydrogenase system and could provide for the well-known proteolysis encountered during sarcopenia. Matrix calcium loading and aging increased ROS production. They also reduced the oxidative phosphorylation. This was associated with lower calcium retention capacities, suggesting that sarcopenic fibers are more prone to programmed cell death. Aging was also associated with a reduced mitochondrial superoxide dismutase activity, which does not intervene in toxic ROS overproduction but could explain the lower calcium retention capacities. Despite a lower content, cytochrome c oxidase displayed an increased activity associated with an increased n-6/n-3 polyunsaturated fatty acid ratio of mitochondrial phospholipids. In conclusion, we propose that mitochondria obtained from aged muscle fibers display several functional abnormalities explaining the increased proteolysis, ROS overproduction and vulnerability to apoptosis exhibited by sarcopenic muscle. These changes appear to be related to modifications of the fatty acid profile of mitochondrial lipids.

Nuclear Imaging Study of the Pharmacodynamic Effects of Debio 1143, an Antagonist of Multiple Inhibitor of Apoptosis Proteins (IAPs), in a Triple-Negative Breast Cancer Model.

Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model. Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99mTc-HYNIC-Annexin V, and a cell proliferation assay. 99mTc-HYNIC-Annexin V SPECT and [18F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells. Results: Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [18F]-FDG uptake when measured during treatment. Conclusions: This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.

Functionalization of Gadolinium Chelates Silica Nanoparticle through Silane Chemistry for Simultaneous MRI/64Cu PET Imaging.

Multimodal nanoprobes are highly demanded for biomedical imaging applications to enhance the reliability of the diagnostic results. Among different types of nano-objects, ultrasmall silica gadolinium nanoparticle (SiGdNP) appears as a safe, effective, and versatile platform for this purpose. In this study, a new method to functionalize SiGdNP based on silane chemistry has been reported. Two types of chelating silanes (APTES-DOTAGA and APTES-NODAGA) have been synthesized and grafted on SiGdNP by a simple one-step protocol. This functionalization strategy requires no other reactants or catalyzers and does not compromise the ultrasmall size of the particles. NODAGA-functionalized particle has been labeled with 64Cu isotope and injected intravenously to mice bearing TS/A carcinoma tumor for biodistribution study to demonstrate its potential as a bimodal MRI/PET imaging agent. A fully integrated MRI/PET system was used to simultaneously monitor the distribution of the particle. The results showed that the functionalized particle maintained properties of a renal clearable NP which could rapidly escape through kidneys and had low retention in other organs, especially liver, even though its accumulation in the tumor was modest.

Automatic deformable PET/MRI registration for preclinical studies based on B-splines and non-linear intensity transformation.

PET images deliver functional data, whereas MRI images provide anatomical information. Merging the complementary information from these two modalities is helpful in oncology. Alignment of PET/MRI images requires the use of multi-modal registration methods. Most of existing PET/MRI registration methods have been developed for humans and few works have been performed for small animal images. We proposed an automatic tool allowing PET/MRI registration for pre-clinical study based on a two-level hierarchical approach. First, we applied a non-linear intensity transformation to the PET volume to enhance. The global deformation is modeled by an affine transformation initialized by a principal component analysis. A free-form deformation based on B-splines is then used to describe local deformations. Normalized mutual information is used as voxel-based similarity measure. To validate our method, CT images acquired simultaneously with the PET on tumor-bearing mice were used. Results showed that the proposed algorithm outperformed affine and deformable registration techniques without PET intensity transformation with an average error of 0.72 ± 0.44 mm. The optimization time was reduced by 23% due to the introduction of robust initialization. In this paper, an automatic deformable PET-MRI registration algorithm for small animals is detailed and validated. Graphical abstract ᅟ.