Theranostic Approach Research Articles

Regulatory Non-Coding RNAs in Familial Hypercholesterolemia, Theranostic Applications.

Familial hypercholesterolemia (FH) is a common monogenic disease which is associated with high serum levels of low-density lipoprotein cholesterol (LDL-C) and leads to atherosclerosis and cardiovascular disease (CVD). Early diagnosis and effective treatment strategy can significantly improve prognosis. Recently, non-coding RNAs (ncRNAs) have emerged as novel biomarkers for the diagnosis and innovative targets for therapeutics. Non-coding RNAs have essential roles in the regulation of LDL-C homeostasis, suggesting that manipulation and regulating ncRNAs could be a promising theranostic approach to ameliorate clinical complications of FH, particularly cardiovascular disease. In this review, we briefly discussed the mechanisms and pathophysiology of FH and novel therapeutic strategies for the treatment of FH. Moreover, the theranostic effects of different non-coding RNAs for the treatment and diagnosis of FH were highlighted. Finally, the advantages and disadvantages of ncRNA-based therapies vs. conventional therapies were discussed.

Volbots: Volvox Microalgae‐Based Robots for Multimode Precision Imaging and Therapy

AbstractBiohybrid microrobotics are exploited as a delivery approach to actively transport therapeutic payload to tumors. However, the therapeutic utility of this approach can be diminished by tumor hypoxia. Moreover, current biohybrid microrobotics design is mainly focused on the living organisms’ motility and biocompatibility, yet the unique biological function of the natural organism is often overlooked. Here, an all‐in‐one self‐propelled volvox‐based multifunctional robot, that is, Volbot, with built‐in capabilities of fluid mixing, multimode imaging, and photosynthesis‐mediated in situ oxygen generation that can potentially relieve hypoxia is developed. Volbots can follow a pre‐specified route and directionality under the control of a magnetic field. Red‐light irradiation (λ = 650 nm) can enhance the Volbot's locomotive behavior, enhance the mixing of biofluids, and modulate the oxygen production to improve the efficacy of photodynamic therapy. Moreover, Volbots can absorb near‐infrared irradiation and produce localized hyperthermia to treat tumors. Subcutaneous tumor suppression can be achieved by this high‐yield oxygen‐producing biohybrid “microfactory” in a photodynamic/photothermal‐synergistic therapy strategy. Furthermore, Volbots also offer imaging capabilities and exhibit considerable promise as a multifunctional microrobotics‐based theranostic approach for a precision tumor therapy strategy.

Epigenetic Regulation in Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine neoplasms are a rare, diverse group of neuroendocrine tumors that form in the pancreatic and gastrointestinal tract, and often present with side effects due to hormone hypersecretion. The pathogenesis of these tumors is known to be linked to several genetic disorders, but sporadic tumors occur due to dysregulation of additional genes that regulate proliferation and metastasis, but also the epigenome. Epigenetic regulation in these tumors includes DNA methylation, chromatin remodeling and regulation by noncoding RNAs. Several large studies demonstrate the identification of epigenetic signatures that may serve as biomarkers, and others identify innovative, epigenetics-based targets that utilize both pharmacological and theranostic approaches towards the development of new treatment approaches.

GRPr Theranostics: Current Status of Imaging and Therapy using GRPr Targeting Radiopharmaceuticals.

Addressing molecular targets, that are overexpressed by various tumor entities, using radiolabeled molecules for a combined diagnostic and therapeutic (theranostic) approach is of increasing interest in oncology. The gastrin-releasing peptide receptor (GRPr), which is part of the bombesin family, has shown to be overexpressed in a variety of tumors, therefore, serving as a promising target for those theranostic applications. A large amount of differently radiolabeled bombesin derivatives addressing the GRPr have been evaluated in the preclinical as well as clinical setting showing fast blood clearance and urinary excretion with selective GRPr-binding. Most of the available studies on GRPr-targeted imaging and therapy have evaluated the theranostic approach in prostate and breast cancer applying bombesin derivatives tagged with the predominantly used theranostic pair of 68Ga/177Lu which is the focus of this review.

Theranostic pairing: ABY-025/251 targeting HER2 with 68Ga and 188Re—Minimized radioligands using Affibody peptide scaffold technology.

3093 Background: HER2 expressing tumors such as subsets of metastatic breast cancer and gastro-esophageal tumors can be targeted using specific antibodies or antibody-drug-conjugates (ADCs). However, some tumors remain refractory to treatment. External radiation therapy is unsuited to advanced metastatic disease. Targeted molecular radiation therapy has proven useful in other tumors such as neuroendocrine tumors or prostate cancer using 177Lu. 188Re is a beta emitting isotope that when chelated to the ABY-251 Affibody molecule has the potential to precisely target HER2 expressing tumors locally. The ABY-251 Affibody molecule is a very small, structured protein scaffold with a molecular weight of only 7 kDa targeting HER2 with high affinity (KD = 100pM). ABY-251 can be manufactured by chemical synthesis. A diagnostic analog molecule ABY-025 was also developed with chelation to 68Ga ideal for PET visualization. Methods: A pre-clinical study in mice was conducted to investigate tumor/tissue uptake, followed by a clinical diagnostic study for visualization in HER+ patients with metastatic breast cancer, to be followed by a theranostic study in humans. Results: Pre-clinical Study: A preclinical study in mice has previously demonstrated high contrast uptake in HER2 tumor tissue using the diagnostic analog ABY-025. Off target accumulation was seen in kidney tissue using the diagnostic ABY-025, which in the ABY-251 therapeutic molecule has been reduced by further engineering of the molecule. This molecule has now been proven to increase survival in mice bearing HER2+ tumors. Median survival in the treated animals was 68 days as compared to 29 and 27.5 days in animals treated with vehicle and non-labelled peptide respectively. Clinical diagnostic study ph1/2: ABY-025 was studied in HER2+ patients with metastatic breast cancer. In a study of 16 women with refractory metastatic breast cancer (>2 prior lines of therapy, 12 IHC positive and 4 IHC negative) 9 out of 10 patients showed high HER2 expression levels as measured with ABY-025 PET despite ongoing treatment with HER2 targeted therapy. Persistent high 68Ga-ABY-025 tumor uptake in patients despite treatment with standard HER2-targeted therapies is a sign of therapeutic drug resistance. These patients would be eligible for treatment with the therapeutic analog ABY-251 using 188Re generated beta radiation for tumor eradication. Clinical therapeutic study (planned): ABY-251 is in development to soon enter therapeutic clinical Ph1/2a trials in patients with refractory HER2+ tumors and positive tumor imaging using ABY-025 as a theranostic pair. Conclusions: A radiopharmaceutical theranostic approach diagnosing HER2+ patients with metastatic disease using 68Ga-ABY-025 for targetability and subsequent treatment using 188Re-ABY-251 seems feasible and is currently in clinical trials. Clinical trial information: NCT01858116.

Recent Advances in the Development of Tetrazine Ligation Tools for Pretargeted Nuclear Imaging.

Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios for radiopharmaceuticals based on nanomedicines, especially within early timeframes. This allows the use of radionuclides with short half-lives which are more suited for clinical applications. Pretargeting bears the potential to increase the therapeutic dose delivered to the target as well as reduce the respective dose to healthy tissue. Combined with the possibility to be applied for diagnostic imaging, pretargeting could be optimal for theranostic approaches. In this review, we highlight efforts that have been made to radiolabel tetrazines with an emphasis on imaging.

The significance of the fusion partner gene genomic neighborhood analysis in translocation‐defined tumors

IntroductionThis study presents a novel molecular parameter potentially co‐defining tumor biology—the total tumor suppressor gene (TSG) count at chromosomal loci harboring genes rearranged in fusion‐defined tumors. It belongs to the family of molecular parameters created using a black‐box approach.MethodIt is based on a public curated Texas TSG database. Its data are regrouped based on individual genes loci using another public database (Genecards). The total TSG count for NTRK (NTRK1; OMIM: 191315; NTRK2; OMIM: 600456; NTRK3; OMIM: 191316), NRG1 (OMIM: 142445), and RET (OMIM: 164761) rearranged tumors in patients treated with a theranostic approach is calculated using the results of recently published studies.ResultsAltogether 138 loci containing at least three TSGs are identified. These include 21 “extremely hot” spots, with 10 to 28 TSGs mapping to a given locus. However, the study falls short of finding a correlation between tumor regression or patient survival and the TSG count owing to a low number of cases meeting the study criteria.ConclusionThe total TSG count alone cannot predict the biology of translocation‐defined tumors. The addition of other parameters, including microsatellite instability (MSI), tumor mutation burden (TMB), homologous recombination repair deficiency (HRD), and copy number heterogeneity (CNH), might be helpful. Thus a multi‐modal data integration is advocated. We believe that large scale studies should evaluate the significance and value of the total TSG count.

Using Machine Learning to Detect Theranostic Biomarkers Predicting Respiratory Treatment Response.

Background: Theranostic approaches—the use of diagnostics for developing targeted therapies—are gaining popularity in the field of precision medicine. They are predominately used in cancer research, whereas there is little evidence of their use in respiratory medicine. This study aims to detect theranostic biomarkers associated with respiratory-treatment responses. This will advance theory and practice on the use of biomarkers in the diagnosis of respiratory diseases and contribute to developing targeted treatments. Methods: We performed a cross-sectional analysis on a sample of 13,102 adults from the UK household longitudinal study ‘Understanding Society’. We used recursive feature selection to identify 16 biomarkers associated with respiratory treatment responses. We then implemented several machine learning algorithms using the identified biomarkers as well as age, sex, body mass index, and lung function to predict treatment response. Results: Our analysis shows that subjects with increased levels of alkaline phosphatase, glycated haemoglobin, high-density lipoprotein cholesterol, c-reactive protein, triglycerides, hemoglobin, and Clauss fibrinogen are more likely to receive respiratory treatments, adjusting for age, sex, body mass index, and lung function. Conclusions: These findings offer a valuable blueprint on why and how the use of biomarkers as diagnostic tools can prove beneficial in guiding treatment management in respiratory diseases.

Ultrasound transmission tomography-guided heating with nanoparticles

Nanoparticles can be used in numerous therapeutic procedures, including controlled drug delivery and release, thermal therapy, and photo- and sonodynamic therapy. However, such approaches remain limited due to difficulties associated with accurately controlling their therapeutic efficiency and localized consequences. Thus, we propose the use of ultrasound transmission tomography (UTT) measurements following ultrasonic heating when using nanomaterials as mediators. We test various nanomaterials doped to agar tissue-mimicking phantoms to study how they affect the UTT imaging through improving the contrast. Simultaneously, we investigate the suitability of these mediators in relation to the process of ultrasonic heating under the guidance of UTT. The results show that UTT is sensitive to the presence of magnetic nanoparticle-based nanomaterials and induced temperature rises. The combination of an imaging modality based on generally safe and well-known ultrasound-based imaging and the use of nanomaterials as mediators represents our proposal for a new theranostic approach.

Encapsulation of Hydrophobic Porphyrins into Biocompatible Nanoparticles: An Easy Way to Benefit of Their Two-Photon Phototherapeutic Effect without Hydrophilic Functionalization.

Simple SummaryEfficient photosensitizers for photodyanmic therapy (PDT) need to be soluble in physiologic media. This requirement often complicates significantly the chemical access to such compounds, resulting in lower availability and higher production costs for the best representatives. Given that their screening and selection is often initially conducted in organic media from series of hydrophobic model compounds, the possibility to use directly such hydrophobic photosensitizers in real PDT studies was highly desirable to speed up their definitive identification but also to alleviate their cost. In this respect, PMLABe polymeric nanoparticles (NPs) were presently probed as nanocarriers to water-solubilize hydophobic star-shaped porphyrin-based which turned out to be promising oxygen photosensitizers for theranostic approaches. We show here that PDT conducted using such NPs loaded with these compounds is as efficient than when functional hydrosoluble analogues of these photosensitiers are tested alone and that tracking of the photosensitizer by fluorescence imaging is even easier.Star-shaped hydrophobic porphyrins, acting as powerful fluorescent two-photon photosensitizers for oxygen in organic solvents, can easily be loaded into PMLABe polymeric nanoparticles at various concentrations. In this contribution, the performance of these porphyrin-containing nanoparticles in terms of photodynamic therapy (PDT) is compared to those of the corresponding water-soluble porphyrin analogues when irradiated in MCF-7 cancer cells. While quite promising results are obtained for performing PDT with these nanoparticles, validating this approach as a mean for using more easily accessible and less expensive photosensitizers, from a synthetic perspective, we also show that their luminescence can still be used for bioimaging purposes in spite of their confinement in the nanoparticles, validating also the use of these nano-objects for theranostic purposes.

1064 nm activatable semiconducting polymer-based nanoplatform for NIR-II fluorescence/NIR-II photoacoustic imaging guided photothermal therapy of orthotopic osteosarcoma

As a promising anti-tumoral approach, photothermal therapy (PTT) with NIR-II (1000–1700 nm) absorption could penetrate deeper and generate more efficient hyperthermia in contrast to traditional PTT under 808 nm irradiation. As for optical tracking, NIR-II fluorescence imaging (FI) and NIR-II photoacoustic imaging (PAI) are the two emerging research hotspots. Unfortunately, each single modality has its intrinsic limitations and current research to integrate them in one-component system is still in infancy. Our development of all-in-one nanoplatforms aims to ultimately improve the efficacy of targeted hyperthermia, and incorporate the benefits of NIR-II FI and NIR-II PAI for tracking guidance. Herein, we designed a novel semiconducting polymer P2, and further encapsulated it with amphiphilic PEGylated phospholipid modified with a targeting peptide RGD to ultimately generate P2 based nanoparticles (P2NPs). As a single-component phototheranostic nanoplatform, P2NPs possessed intense NIR-II absorption, excellent NIR-II fluorescence, strong NIR-II PA signals, and high local hyperthermia capability simultaneously. Notably, due to the favorable binding capacity to osteosarcoma (OS) cells, in vitro studies revealed outstanding PTT efficacy of P2NPs against 143B cells under 1064 nm laser. Further work validated excellent dual-modal NIR-II FI/NIR-II PAI tracking and strong PTT tumor ablation in both subcutaneous and orthotopic OS mice models with negligible biotoxicity in vivo. Consequently, these findings warranted P2NPs as a promising 1064 nm activatable all-in-one nanoplatform to perform dual-modal NIR-II FI/NIR-II PAI-guided orthotopic tumoral treatment, providing a new approach for theranostics, therapeutic tracking, and the beyond in other diseases.

O-14 - Design and synthesis of a new bifunctional chelating agent for 18F-Al/177Lu radiolabelling: theranostic approach

O-14 - Design and synthesis of a new bifunctional chelating agent for 18F-Al/177Lu radiolabelling: theranostic approach

Development of an automated production process of [64 Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications.

Cyclotron‐produced copper‐64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [64Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo‐radiotherapy. Various production and radiosynthesis methods of [64Cu][Cu (ATSM)] exist in labs, but usually involved non‐standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [64Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End‐of‐synthesis (EOS) molar activity of [64Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM‐titration), and 3.0–4.4 Ci/μmol (ICP‐MS). Radiochemical purity was determined to be >99% based on radio‐HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [64Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.

Current and future strategies for radiation therapy in gastric cancer.

Gastric cancers are heterogeneous. There are important differences between gastric and junctional tumors and a focus on evidence based on true gastric cancers is important to guide treatment decision and the design of innovative strategies. We present key evidence shaping the current use of radiotherapy, discuss technical radiotherapy considerations that are important to consider in multidisciplinary decision-making, and highlight selected research strategies including radiotherapeutic advances, theranostic approaches and key ongoing clinical trials to watch that will shape the role of radiotherapy in gastric cancers for the future.

Magnetic mesoporous silica nanoparticles as a theranostic approach for breast cancer: Loading and release of the poorly soluble drug exemestane

Exemestane has a limited aqueous solubility that leads to a very high variability in absorption when administrated orally. It is crucial to develop strategies to increase the solubility and bioavailability of this drug. To overcome these issues, the aim of the present work was the development of magnetic silica mesoporous nanoparticles (IOMSNs) to carry and release exemestane. Furthermore, these nanoparticles could be also used as Magnetic Resonance Imaging (MRI) contrast agents for treatment monitorization and tumor detection. MRI analysis showed that IOMSNs present a concentration dependent contrast effect, revealing their potential for MRI applications. Also, IOMSNs present a very good polydispersity (0.224) and nanometric range size (137.2 nm). It was confirmed that the nucleus is composed by magnetite and the silica coating presents tubes with MCM-41-like hexagonal structure. Both iron oxide nanoparticles and iron oxide mesoporous silica nanoparticles were not toxic in cell culture for 24 h. Exemestane was successful released for 72 h following a typical sustained release pattern, achieving a very high loading capacity (37.7%) and in vitro release of 98.8%. Taking into account the results it is possible to conclude that IOMSNs have a high potential to be used as theranostic for intravenous breast cancer treatment with exemestane.

Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK2R Cancer Theranostic Agents: A Preclinical Study

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK2R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK2R-radioligands instead, we herein present three analogs of the nonpeptidic CCK2R-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCK2R cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCK2R cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCK2R and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCK2R-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCK2R, but not the CCK2R-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [111In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCK2R-targeted theranostics of human cancer.

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe.

The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety—alpha-fetoprotein receptor-binding peptide—enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.

Hyaluronan as "Agent Smith" in cancer extracellular matrix pathobiology: Regulatory roles in immune response, cancer progression and targeting.

Extracellular matrix (ECM) critically regulates cancer cell behavior by governing cell signaling and properties. Hyaluronan (HA) acts as a structural and functional ECM component that mediates critical properties of cancer cells in a molecular size-dependent manner. HA fragments secreted by cancer-associated fibroblasts (CAFs) reveal the correlation of HA to CAF-mediated matrix remodeling, a key step for the initiation of metastasis. The main goal of this article is to highlight the vital functions of HA in cancer cell initiation and progression as well as HA-mediated paracrine interactions among cancer and stromal cells. Furthermore, the HA implication in mediating immune responses to cancer progression is also discussed. Novel data on the role of HA in the formation of pre-metastatic niche may contribute towards the improvement of current theranostic approaches that benefit cancer management.

The 64Zn-based production route to 64Cu β ± emitter using accelerator-driven 14 MeV fusion neutrons

The development of personalized medicine is important to avoid unnecessary and expensive treatments. The theranostic approach is an established tool for specific molecular targeting, both for diagnostics and therapy. Radionuclides used for theranostic radiopharmaceuticals are typically produced in nuclear fission reactors or bio-medical cyclotrons. Here, an alternative route for producing an emerging theranostic radionuclide, namely 64Cu, is investigated by using 14 MeV fusion neutrons produced by the Frascati Neutron Generator (FNG) at the ENEA Frascati Research Centre. Samples of zinc (natural and 64Zn-enriched) were irradiated and characterized, in turn being measured at high-level metrological conditions, at the Radioactivity Laboratory of ENEA-INMRI located in Casaccia Research Centre. The results achieved in the experiments are presented and compared to those obtained by Monte Carlo simulations and previously published experimental data.

Radiolabeled Somatostatin Analogs-A Continuously Evolving Class of Radiopharmaceuticals.

Simple SummarySomatostatin receptors (SSTs) are of particular interest in oncology because these proteins are overexpressed on the cell membranes of different human malignancies, especially neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs). Radiolabeled short peptide analogs of the natural hormone somatostatin have been developed over the years to target SST-expressing tumors and are used for both imaging (diagnosis) and therapy. Today, this type of radiopharmaceutical plays a pivotal role in the management of NET and NEN patients. Despite their clinical success, new developments in recent years, in terms of peptide analogs and radionuclides, have shown certain advantages and hold promise for further improvement in both the diagnosis and therapy of SST-expressing tumors, even beyond NETs and NENs.Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST2) being the predominantly and most frequently expressed. PET/CT imaging with 68Ga-labeled SST agonists, e.g., 68Ga-DOTA-TOC (SomaKit TOC®) or 68Ga-DOTA-TATE (NETSPOT®), plays an important role in staging and restaging these tumors and can identify patients who qualify and would potentially benefit from peptide receptor radionuclide therapy (PRRT) with the therapeutic counterparts 177Lu-DOTA-TOC or 177Lu-DOTA-TATE (Lutathera®). This is an important feature of SST targeting, as it allows a personalized treatment approach (theranostic approach). Today, new developments hold promise for enhancing diagnostic accuracy and therapeutic efficacy. Among them, the use of SST2 antagonists, such as JR11 and LM3, has shown certain advantages in improving image sensitivity and tumor radiation dose, and there is evidence that they may find application in other oncological indications beyond NETs and NENs. In addition, PRRT performed with more cytotoxic α-emitters, such as 225Ac, or β- and Auger electrons, such as 161Tb, presents higher efficacy. It remains to be seen if any of these new developments will overpower the established radiolabeled SST analogs and PRRT with β--emitters.