Theranostic Approach Research Articles

Adaptive in vivo device for theranostics of inflammation: Real-time monitoring of interferon-γ and aspirin

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist among cytokines, inflammation, and the innate and adaptive immune responses in maintaining homeostasis, health, and well-being. On-demand, local delivery of anti-inflammatory drugs to target tissues provides an approach for more effective drug dosing while reducing the adverse effects of systemic drug delivery. This work demonstrates a proof-of-concept theranostic approach for inflammation based on analyte-kissing induced signaling, whereby a drug (in this report, aspirin) can be released upon the detection of a target level of a proinflammatory cytokine (i.e., interferon-γ (IFN-γ)) in real time. The structure-switching aptamer-based biosensor described here is capable of quantitatively and dynamically detecting IFN-γ both in vitro and in vivo with a sensitivity of 10 pg mL−1. Moreover, the released aspirin triggered by the immunoregulatory cytokine IFN-γ is able to inhibit inflammation in a rat model, and the release of aspirin can be quantitatively controlled. The data reported here provide a new and promising strategy for the in vivo detection of proinflammatory cytokines and the subsequent therapeutic delivery of anti-inflammatory molecules. This universal theranostic platform is expected to have great potential for patient-specific personalized medicine. Statement of SignificanceWe developed an adaptive in vivo sensing device whereby a drug, aspirin, can be released upon the detection of a proinflammatory cytokine, interferon-γ (IFN-γ), in real time with a sensitivity of 10 pg mL−1. Moreover, the aspirin triggered by IFN-γ depressed inflammation in the rat model and was delivered indirectly through blood and cerebrospinal fluid or directly to the inflammation tissue or organ without adverse gastrointestinal effects observed in the liver and kidney. We envision that, for the first time, patients with chronic inflammatory disease can receive the right intervention and treatment at the right time. Additionally, this technology may empower patients to monitor their personalized health and disease management program, allowing real-time diagnostics, disease monitoring, and precise and effective treatments.

In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3'-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy.

The role of theranostics in cancer management is growing so is the selection of vectors used to deliver these modalities to cancer cells. We describe biological evaluation of a novel theranostic agent targeted to microtubules. Methyl N-[5-(3'-[131 I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3'-[125 I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3'-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131 I-labeled β-particle emitting 1 were examined in vitro in human neuroblastoma and glioblastoma cells lines. The therapeutic potential of 1 was also examined in a subcutaneous mouse model of human glioblastoma U-87 MG. Compound 1 at the extracellular radioactive concentration of 0.35 MBq/mL, easily achievable in vivo, kills >90% of neuroblastoma cells and >60% glioblastoma cells as measured in a clonogenic assay. D10 doses established for 1 indicate that as few as 3,000 decays are sufficient to kill 90% of BE(2)-C cells. Even U-87 MG cells, the least sensitive of the tested cell lines, require <20,000 decays of intracellular 131 I to reduce number of clonogenic cells by 90%. Biodistribution studies of 2 delivered either intratumorally or intraperitoneally show a similar tissue distribution for both routes of the drug administration. The whole body clearance half-lives were on average 6 hr. Intratumor administration of 1 produces significant tumor growth delay. After a single dose of 8.4 ± 0.3 MBq of compound 1, the tumor doubling times were 3.2 ± 0.1 and 7.9 ± 0.6 days in control and treated mice, respectively. Methyl N-[5-(3'-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates have properties compatible with a theranostic approach to cancer management.

ES04.05 Advances in Radionuclide Treatment for Neuroendocrine Tumours

Lung carcinoids (LC) are rare tumours, however incidence is increasing due to improvement in diagnostic techniques. They account for approximately 2% of all lung malignancies and around 20-30% of all neuroendocrine tumours (NETs). They characteristically have an indolent clinical behaviour with longer survival intervals compared to poorly differentiated lung neuroendocrine malignancies. LC are divided into typical or atypical carcinoid tumours according to pathological characteristics, such as amount of mitosis and necrosis. A significant proportion of LC expresses somatostatin receptors by immunohistochemistry. Nuclear medicine imaging, such as somatostatin receptor scintigraphy, has been employed for staging of LC for years. Development of new nuclear medicine imaging techniques, including Positron Emission Tomography (PET) combined with CT has improved diagnosis, staging and treatment of patients diagnosed with LC. 68-Gallium(68Ga)-radiolabelled PET (68Ga-DOTA-PET) tracers for functional NET imaging have emerged as potentially useful tools for diagnosis and staging. For localised stages of LCs, surgery is the treatment of choice, performed with curative intent. Locally advanced inoperable or metastatic tumours are treated with palliative approaches based on somatostatin analogues (SSAs), temozolomide-based chemotherapy combination and targeted therapies (everolimus). Recently, the use of Peptide Receptor Radionuclide Therapy (PRRT) has revolutionised the treatment of extra-pulmonary neuroendocrine tumours. Based on the results of the NETTER-1 study, PRRT has been approved for the management of small bowel and pancreatic NETs and it is considered a standard of care after progression to SSA for patients with uptake in 68Ga-DOTA-PET (theranostic approach). This lecture will summarise the state of the art of LC with a focus behind the rationale of PRRT and its potential role in the management of LCs. Neuroendocrine, PRRT, carcinoid

974P - Prior tyrosine kinase inhibitors (TKI) and antibiotics (ATB) use are associated with distinct gut microbiota ‘guilds’ in renal cell carcinoma (RCC) patients

BackgroundEvidence suggests that ATB and gut microbiota composition are associated to anti-PD-1 outcomes in RCC patients. Network analysis of the gut microbiota represents a novel tool to determine “guilds” of bacterial communities. MethodsHere, we investigated guilds’ relationships with prior exposure to ATB, TKI [axitinib (axi), sunitinib (suni) or other] and clinical outcomes of RCC patients treated with nivolumab (nivo). ResultsConsidering prior exposure to ATB (n=11, 22%), axi (n=13, 19%), suni (n=49, 71%) or other TKI (n=20, 29%), n=36 (52%) patients were NR and 33 (48%) R to nivo. Cross-validation of overall fecal microbiota composition stratified RCC patients with different predictive power (ATB=84%; axi=81%; suni=69%; outcome=49%). Network analysis revealed six guilds (G1 to G6). G1-G2 behaved in an opposite way and topologically separated by negative correlations. G1-G2 were both related to NR, while G1 was dominated by species related to ATB. Conversely G2 was mainly represented by species related to no ATB (X2=8.98, P=0.0027) and more susceptible to prior TKI exposure (where axi and suni behaved in an opposite way) compared to the other guilds (X2=10.68, P=0.0011). G4 was mainly inhabited by species related to other TKI (no axi and no suni). Random forest analysis found definite bacterial species able to drive the stratification into guilds of the global RCC network, such as Akkermansia muciniphila for R and Dorea formicigenerans for no ATB. ConclusionsWe show that ATB and suni are the most powerful external features able to drive fecal microbiota compositional shifts in RCC patients treated with nivo. Analysis of the gut microbiota using bacterial communities guilds provides a novel theranostic approach to stratify RCC patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureL. Albiges: Honoraria (self): Novartis, BMS, Amgen, Ipsen, Roche, Pfizer, Astellas, Merck. K. Fizazi: Advisory / Consultancy: Participation to advisory boards/honorarium for: Astellas, AAA, Bayer, Clovis, Curevac, Incyte, Janssen, MSD, Orion, Sanofi. B. Escudier: Advisory / Consultancy: IPSEN, BMS, AZ, Novartis, Roche, Oncorena. L. Zitvogel: Advisory / Consultancy: BMS, AstraZeneca,; Research grant / Funding (self): Incyte, GSK, Transgene, Innovate Biopharma, Pilege; Advisory / Consultancy: Everimmune. All other authors have declared no conflicts of interest.

Theranostic radionuclides: recent advances in production methodologies

Various concepts involved in the quantification of radiation dose while following the theranostic approach in nuclear medicine are outlined. The availability of the relevant radionuclides is discussed. The production methodologies of many of the “matched-pair” of radionuclides were recently reviewed in detail. In this contribution, some additional information on a few positron emitters and therapeutic radionuclides is presented. In addition to generator production of 68Ga (T½ = 1.13 h), its direct production at a medical cyclotron is critically discussed. Besides conventional use of reactors and cyclotrons, there is a growing interest in utilizing fast neutrons from a d/Be source and high-energy photons from an electron linear accelerator to produce a few special therapeutic radionuclides. The related new developments are reviewed.

Nanobubble Liposome Complexes for Diagnostic Imaging and Ultrasound-Triggered Drug Delivery in Cancers: A Theranostic Approach.

The ability of ultrasound contrast agents to enhance the cell membrane permeability in response to an ultrasound pulse has unveiled avenues to facilitate the delivery of a higher intracellular payload at target sites. In light of the above, we report the development of submicron-sized (528.7 ± 31.7 nm) nanobubble-paclitaxel liposome (NB-PTXLp) complexes for ultrasound imaging and ultrasound responsive drug delivery in cancer cells. With a paclitaxel entrapment efficiency of 85.4 ± 4.39%, the 200 nm-sized liposomes tethered efficiently (conjugation efficiency ∼98.7 ± 0.14%) with the nanobubbles to form conjugates. Sonoporation of MiaPaCa-2 cells upon treatment with nanobubbles and ultrasound enhanced cellular permeability, resulting in 2.5-fold higher uptake of liposomes in comparison to only liposome treatment. This manifested into more than 300-fold higher anticancer activity of NB-PTXLps in the presence of ultrasound in MiaPaCa-2, Panc-1, MDA-MB-231, and AW-8507 cell lines, compared to commercial formulation ABRAXANE. Also, the NB-PTXLp conjugates were found to exhibit echogenicity comparable to the commercial ultrasound contrast agent SonoVue. In addition, the developed nanobubbles were found to exhibit more than 1 week echogenic stability as opposed to 6 h stability of the commercially available ultrasound contrast agent SonoVue. Hence, the NB-PTXLps developed herein could prove to be a promising and minimally invasive theranostic platform for cancer treatments in the future.

First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer.

Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [177Lu]Lu-PSMA-617 therapy. Thirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [68Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68years) were treated with [177Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline. Therapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1h. Mean absorbed organ doses were 1.08 ± 0.44Gy/GBq in the pancreas, 0.35 ± 0.14Gy/GBq in the kidneys, 0.05 ± 0.02Gy/GBq in the liver, 0.07 ± 0.02Gy/GBq in the gallbladder wall, 0.10 ± 0.06Gy/GBq in the spleen, and 0.02 ± 0.01Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00Gy/GBq. Application of GRPr antagonist [177Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.

Clinical Usefulness of 99mTc-HYNIC-TOC and 131I-MIBG Scintigraphy in the Evaluation of Adrenal Tumors

Abstract Disorders and morphological abnormalities affecting the adrenal gland, could lead to profound clinical consequences, owing to its biochemical structure-activity and morphological characteristics. The recent focus on theranostic approach has led to a need for tumors characterization and early diagnosis at the molecular level. Many radiotracers have been developed with specific imaging characteristics for the adrenal tumors, by exploiting different physiological mechanisms of uptake and metabolism. The aim of present study is to provide a prospective confirmation of 131I-MIBG and 99mTc-HYNIC-TOC scintigraphy, for the evaluation of patients with known or suspected tumors of the adrenal region. The research is designed as a cross-sectional observational study of the clinical correlates and diagnostic accuracy of radionuclide-based imaging methods in relation to in vitro analysis, clinical manifestations and morphological characteristics of these tumors. Furthermore, the present study also evaluates the usefulness and the clinical impact of each radiopharmaceutical for the detection and management of tumors, and functional imaging modality as well. Visual scintigraphic appearance of an increased focal tracer uptake in the suspected tumor site revealed that 99mTc-HYNIC-TOC is highly sensitive and reliable tumor-seeking radiotracer for adrenal tumors, but does not distinguish between adenoma and pheochromocytoma, and the existence of hormone secreting adrenocortical tumor cells. However, 131IMIBG scintigraphy is highly sensitive and specific method only in differentiating catecholamine-secreting adrenal tumors. Clinical significance of this research is in the accurate localization of adrenal tumors, and is of paramount importance for an algorithmic diagnostic approach and management, and provide the rationale to different therapeutic possibilities.

The Future of Nuclear Medicine as an Independent Specialty.

In this article, we provide an overview of established and emerging conventional nuclear medicine and PET imaging biomarkers, as the diagnostic nuclear medicine portfolio is rapidly expanding. Next, we review briefly nuclear theranostic approaches that have already entered or are about to enter clinical routine. Using some approximations and taking into account emerging applications, we also provide some simplified business forecasts for nuclear theranostics. We argue that an optimistic outlook by the nuclear medicine community is crucial to the growth of the specialty and emphasize the urgent need for training adaptations.

NIR- and thermo-responsive semi-interpenetrated polypyrrole nanogels for imaging guided combinational photothermal and chemotherapy

Versatile, multifunctional nanomaterials for theranostic approaches in cancer treatment are highly on demand in order to increase therapeutic outcomes. Here, we developed thermo-responsive nanogels equipped with the efficient near-infrared (NIR) transducing polymer polypyrrole (PPY) for combinational photothermal and chemotherapeutic therapy along with photoacoustic imaging ability. Long-term stability and water-dispersibility of PPY was achieved using semi-interpenetration method for in situ polymerization of PPY into hydrophilic thermo-responsive nanogels. The semi-interpenetrated nanogels of spherical shape and with hydrodynamic sizes of around 200 nm retained the temperature response behaviour and exhibit excellent photothermal transducing abilities in the NIR region. The PPY nanogels served as photoacoustic contrast agents, which allowed determination of biodistribution profiles ex vivo. In addition, we developed a new method for biodistribution determination based on the photothermal response of the nanogels with an accuracy down to 12.5 μg/mL. We examined the ability of the nanogels as photothermal agents and drug delivery systems in vitro and in vivo. We showed that they efficiently inhibit tumor growth with combinational effects of chemotherapeutics and photothermal treatment. Our work encourages further exploration of nanogels as functional stabilizing matrix for photothermal transducers and their application as drug delivery devices in combination with photothermal therapy and imaging.

Small Gold Quantum Probes for Drug‐Free Cancer Theranostics

AbstractGold quantum dots (QDs) have emerged as a distinct approach for cancer theranostics by using labeled and functionalized chemotherapeutic‐drug to realize its detection and chemotherapeutic functions. However, the toxicity induced by chemical‐based synthesis, their nonspecific accumulation in healthy tissues and organs hamper its translation to clinical applications. QDs are functionalized/labeled to reduce their toxicity and helps the QDs' cellular‐uptake. In addition, labeling increases the overall hydrodynamic size of QDs, which limits the dispersion, impedes efficient renal clearance and causes the accumulation of QDs in organs. Therefore, the unique properties that arise from quantum‐size (less than 5nm) are lost. Reports on the effect of real quantum‐size on cell‐interaction are, to date, limited. In this work, the concept of a small‐sized self‐functionalized pristine bright quantum gold probe (BQGP) for cancer‐theranostics. To the best of authors' knowledge, it is the first time cell‐interaction of BQGPs has been investigated and the results suggest that it can be used for label‐free/drug‐free cancer quantum‐theranostics. The pristine BQGPs demonstrate cancer‐selective cell‐uptake, enabling dosage‐dependent fluorescent detection/differentiation of cancerous‐cells and cancer‐selective cytotoxicity. The fabricated BQGPs demonstrate fluorophore‐free illuminance at a broad‐range of excitation wavelengths and drug‐free cancer‐specific treatment. Moreover, the drug‐free BQGPs may find advantages in fighting drug‐resistant cancers.

Porphyrinoid-based photosensitizers for diagnostic and therapeutic applications: An update

Porphyrin-based molecules are actively studied as dual function theranostics: fluorescence-based imaging for diagnostics and fluorescence-guided therapeutic treatment of cancers. The intrinsic fluorescent and photodynamic properties of the bimodal molecules allows for these theranostic approaches. Several porphyrinoids bearing both hydrophilic and/or hydrophobic units at their periphery have been developed for the aforementioned applications, but better tumor selectivity and high efficacy to destroy tumor cells is always a key setback for their use. Another issue related to their effective clinical use is that, most of these chromophores form aggregates under physiological conditions. Nanomaterials that are known to possess incredible properties that cannot be achieved from their bulk systems can serve as carriers for these chromophores. Porphyrinoids, when conjugated with nanomaterials, can be enabled to perform as multifunctional nanomedicine devices. The integrated properties of these porphyrinoid-nanomaterial conjugated systems make them useful for selective drug delivery, theranostic capabilities, and multimodal bioimaging. This review highlights the use of porphyrins, chlorins, bacteriochlorins, phthalocyanines and naphthalocyanines as well as their multifunctional nanodevices in various biomedical theranostic platforms.

European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma.

Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results. Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals. Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.

Clinical Results in Medullary Thyroid Carcinoma Suggest High Potential of Pretargeted Immuno-PET for Tumor Imaging and Theranostic Approaches.

Monoclonal antibody (mAb)-based therapies have experienced considerable growth in cancer management. When labeled with radionuclides, mAbs also represent promising probes for imaging or theranostic approaches. Initially, mAbs have been radiolabeled with single-photon emitters, such as 131I, 99mTc, or 111In, for diagnostic purposes or to improve radioimmunotherapy (RIT) using dosimetry estimations. Today, more accurate imaging is achieved using positron- emission tomography (PET). Thanks to the important technical advances in the production of PET emitters and their related radiolabeling methods, the last decade has witnessed the development of a broad range of new probes for specific PET imaging. Immuno-PET, which combines the high sensitivity and resolution of a PET camera with the specificity of a monoclonal antibody, is fully in line with this approach. As RIT, immuno-PET can be performed using directly radiolabeled mAbs or using pretargeting to improve imaging contrast. Pretargeted immuno-PET has been developed against different antigens, and promising results have been reported in tumor expressing carcinoembryonic antigen (CEA; CEACAM5) using a bispecific mAb (BsmAb) and a radiolabeled peptide. Medullary thyroid carcinoma (MTC) is an uncommon thyroid cancer subtype which accounts for <10% of all thyroid neoplasms. Characterized by an intense expression of CEA, MTC represents a relevant tumor model for immuno-PET. High sensitivity of pretargeted immunoscintigraphy using murine or chimeric anti-CEA BsMAb and pretargeted haptens-peptides labeled with 111In or 131I were reported in metastatic MTC patients 20 years ago. Recently, an innovative clinical study reported high tumor uptake and contrast using pretargeted anti-CEA immuno-PET in relapsed MTC patients. This review focuses on MTC as an example, but the same pretargeting technique has been applied with success for clinical PET imaging of other CEA-expressing tumors and other pretargeting systems. In particular, those exploiting bioorthogonal chemistry also appear interesting in preclinical animal models, suggesting the high potential of pretargeting for diagnostic and theranostic applications.

Pretherapeutic 68Ga-PSMA-617 PET May Indicate the Dosimetry of 177Lu-PSMA-617 and 177Lu-EB-PSMA-617 in Main Organs and Tumor Lesions.

Combined Ga-PSMA-617 PET imaging and Lu-PSMA-617 therapy is a precise targeted theranostic approach for patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of this study was to determine whether pretherapeutic standard uptake value (SUV) in Ga-PSMA-617 PET could indicate the effective dose in the main organs and absorbed dose in tumor lesions. After institutional review board approval and informed consent, 9 patients with mCRPC were recruited and underwent Ga-PSMA-617 PET/CT scans. Five patients received Lu-PSMA-617 (1.30-1.42 GBq, 35-38.4 mCi) and then underwent serial whole-body planar imaging and SPECT/CT imaging of both thoracic and abdominal regions at 0.5-, 2-, 24-, 48-, and 72-hour time points. The other 4 patients received Lu-EB-PSMA-617 (0.80-1.1 GBq, 21.5-30 mCi) and then underwent the same imaging procedures at 2-, 24-, 72-, 120-, and 168-hour time points. The effective dose in the main organs and the absorbed dose in tumor lesions were calculated. Detailed correlations between the pretherapeutic SUV in Ga-PSMA-617 PET and effective dose in the main organs as well as absorbed dose in the tumor lesions were analyzed. SUV of Ga-PSMA-617 PET was moderately correlated with effective dose in main organs (r = 0.610 for Lu-PSMA-617, r = 0.743 for Lu-EB-PSMA-617, both P < 0.001). SUV of tumor lesions in Ga-PSMA-617 PET had high correlation with those in Lu-PSMA-617 (r = 0.915, P < 0.001) and moderate correlation with those in Lu-EB-PSMA-617 (r = 0.611, P = 0.002). Pretherapeutic Ga-PSMA-617 PET may indicate the dosimetry of Lu-PSMA-617 and Lu-EB-PSMA-617. Both the effective dose in main organs and absorbed dose in tumor lesions correlate with SUV of Ga-PSMA-617 PET. This relationship may help select appropriate candidates for peptide receptor radionuclide therapy. Further investigations of larger cohorts are needed to confirm these initial findings.

Emerging Theranostic Silver and Gold Nanomaterials to Combat Prostate Cancer: A Systematic Review

Prostate cancer has emerged as the common malignancy in men and is considered as a global issue. Among different strategies to combat prostate cancer, nanobiotechnology appears as a novel approach for prostate cancer theranostics. The current systematic review discussing the recent development in the prostate anticancer activity of biologically synthesized silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) through laboratory investigations. The databases including Cochrane, Web of Science, PubMed, Scopus, Science Direct, ProQuest, and Embase were used to identify the records. It was found that most of the studies used herbal extracts for preparation of AgNPs and/or AuNPs. Majority of biosynthesized nanoparticles (NPs) were formed with spherical morphology. Besides, all studies reported the size of NPs less than 100 nm. Moreover, PC-3 prostate cancer cell was the predominant cell line that was evaluated for prostate anticancer activity of NPs. In the present study, we provided valuable information suggesting the significant prostate anticancer potential of biogenic AgNPs and/or AuNPs. However, further, in vivo investigations are required to provide stronger evidence of the efficacy of bio-mediated synthesized AgNPs and/or AuNPs to combat prostate cancer.

La radiothérapie interne vectorisée par les analogues de la somatostatine, en pratique, en 2019

Somatostatin receptors are overexpressed in differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET). Radiolabeled somatostatin analogs have been used for a few decades for imaging and more recently for peptide receptor radionuclide therapy (PRRT) in a theranostic approach. Medical access to PRRT has long been limited to a few European specialized medical centers despite promising results in large cohorts of patients. NETTER-1, a phase 3 randomized trial, has demonstrated a drastic improvement of midgut NET patients progression-free survival in PRRT arm as compared to somatostatin analogs, leading to marketing authorizations in USA and Europe. PRRT clinical availability is growing in France, with around 20 medical centers offering this innovative treatment for GEP-NET patients care in 2019. PPRT success-story should lead to improvements of radionuclide therapy developments, which will reshape our medical specialty to a more “clinically” practice. This review aims to detail PRRT in clinical practice in France in 2019, with emphasize on treatment indications, planning and practical aspects. Radioprotection aspects and future optimization perspectives will also be discussed.

(Invited) Biocompatible Doped Graphene Quantum Dots Enabling Visible/Near-Infrared Imaging, Drug Delivery and Cancer Detection

Despite significant advances of nanomedicine, the issues of biocompatibility, accumulation-derived toxicity and the lack of sensing and in vivo imaging capabilities hamper the translation of many nanocarriers into clinic. To address these needs we develop and test the feasibility of new nitrogen, sulfur or metal-doped graphene quantum dots (GQDs) as fully biocompatible multifunctional platforms enabling theranostic image-guided approaches both in vitro and in vivo. These GQDs scalably produced in one-step synthesis from a single biocompatible carbon-rich precursor form 3-5 nm few-layer structures functionalized with oxygen-containing groups, however, showing high crystallinity and lattice spacing indicative of a graphitic platform. They are water-soluble, show no cytotoxicity at high concentrations of 1 mg/mL, and demonstrate substantial degradation at 36h in biological environments as verified by TEM imaging. Due to their small sizes, GQDs exhibit efficient internalization maximized at 12 h followed by further degradation/excretion and enable active agent delivery. Their intrinsic fluorescence in blue/green with up to 62% quantum yield and near-infrared allows for multicolor in vitro imaging on its own or in combination with other fluorophores and offers the potential capabilities for in vivo near-IR fluorescence tracking. Additionally, several GQD types exhibit pH-dependent fluorescence response that is successfully utilized as a sensing mechanism for acidic extracellular environments of cancer cells. It allows for deterministic, ratiometric discrimination between cancerous (HeLa and MCF-7 cell) and healthy (HEK-293 cell) environments with substantial spectral peak intensity ratios of 1.6 to 8 in healthy versus cancer cells. Such spectral technique, less prone to quenching discrepancies, provides a useful tool for pH-sensing of microenvironments. These results suggest fully biocompatible doped GQDs as multifunctional candidates for in vitro delivery of active agents, multicolor visible/near-IR fluorescence imaging, and pH-sensing of cancerous environments.

Very high specific activity erbium 169Er production for potential receptor-targeted radiotherapy

Erbium 169Er is one of the most interesting radiolanthanides for new potential receptor-targeted β− therapy applications due to its low energy β− emissions, very low intensity ɣ rays and the possibility to use 68Ga or 44Sc as companion for diagnostic in a theranostics approach. Currently it can be produced in reactors through the neutron activation of highly enriched 168Er. The low specific activity of the produced carrier-added 169Er is limiting its use for receptor-targeted therapy. Nonetheless it is used for radiosynoviorthesis of small joints. The aim of this work is to develop a new large-scale production method for the supply of very high specific activity 169Er. Highly enriched 168Er target has been irradiated at ILL nuclear reactor and shipped to CERN-MEDICIS. There, the irradiated sample has been mass separated in order to isolate 169Er from the high amount of remaining stable 168Er. The proof of principle for a preclinical dose production has been demonstrated with a collection of ≈17 MBq. The specific activity obtained was ≈240 GBq/mg (≈200 times higher than the product obtained at End of Bombardment – EOB) and the overall separation efficiency was ≈0.2%. Several improvements for the future have been identified and are promising. One of them is the installation of the new laser laboratory at CERN-MEDICIS that will allow to improve the selective ionization of erbium atoms leading to an increase of the efficiency of the method. This method can provide the supply of high specific activity 168Er, first for preclinical studies, and opens also the potential for future large-scale supply.

Data Curation for Preclinical and Clinical Multimodal Imaging Studies

PurposeIn biomedical research, imaging modalities help discover pathological mechanisms to develop and evaluate novel diagnostic and theranostic approaches. However, while standards for data storage in the clinical medical imaging field exist, data curation standards for biomedical research are yet to be established. This work aimed at developing a free secure file format for multimodal imaging studies, supporting common in vivo imaging modalities up to five dimensions as a step towards establishing data curation standards for biomedical research.ProceduresImages are compressed using lossless compression algorithm. Cryptographic hashes are computed on the compressed image slices. The hashes and compressions are computed in parallel, speeding up computations depending on the number of available cores. Then, the hashed images with digitally signed timestamps are cryptographically written to file. Fields in the structure, compressed slices, hashes, and timestamps are serialized for writing and reading from files. The C++ implementation is tested on multimodal data from six imaging sites, well-documented, and integrated into a preclinical image analysis software.ResultsThe format has been tested with several imaging modalities including fluorescence molecular tomography/x-ray computed tomography (CT), positron emission tomography (PET)/CT, single-photon emission computed tomography/CT, and PET/magnetic resonance imaging. To assess performance, we measured the compression rate, ratio, and time spent in compression. Additionally, the time and rate of writing and reading on a network drive were measured. Our findings demonstrate that we achieve close to 50 % reduction in storage space for μCT data. The parallelization speeds up the hash computations by a factor of 4. We achieve a compression rate of 137 MB/s for file of size 354 MB.ConclusionsThe development of this file format is a step to abstract and curate common processes involved in preclinical and clinical multimodal imaging studies in a standardized way. This work also defines better interface between multimodal imaging modalities and analysis software.