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The article titled "Editorial: Theranostics as a driving force in nuclear medicine" discusses the concept of theranostics in the field of nuclear medicine. Theranostics involves using diagnostic imaging to identify a target for therapy and then administering therapeutic molecules to that target. The article highlights the use of iodine-123 and iodine-131 as an archetype of theranostics and discusses recent advancements in theranostic approaches for neuroendocrine tumors and prostate cancer. The article also mentions several preclinical and clinical studies that explore the potential of theranostics in various cancer types. Overall, the article emphasizes the need for continued research and development in theranostics to improve patient care. [Extracted from the article]

How to boost the therapeutic efficiency is still the key to translation of anticancer nanomedicine from preclinical investigations to clinical practice. In this work, we proposed to integrate 211At-derived targeted-alpha therapy (TAT) and photothermal therapy (PTT) into nanoscale polydopamine (PDA), attempting to obtain a feasible solution to circumvent the barriers both in 211At-based endoradiotherapy and common nanomedicine. After radiolabeling with 211At and fibroblast activation protein inhibitor (FAPI) decoration of PDA nanoparticles, the obtained 211At-PDA-FAPI exhibits considerable photothermal conversion efficiency, high radioactive stability, excellent cancer affinity, and remarkable antitumor ability. The synergistic TAT-PTT therapeutic effect of 211At-PDA-FAPI in murine xenograft models of glioma has been well confirmed, with the tumor growth inhibition values of 80.82, 76.70, and 96.71% at 15 days postinjection for PTT, TAT, and TAT-PTT treatments, respectively. Meanwhile, the TAT-PTT regimen can prolong the median survival of tumor-bearing mice two times from 18 to 36 days, without detectable biotoxicity during the whole treatment. The outcome of this work provides important hints for the design of therapeutic nanomedicine and the development of traditional radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [123/131I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted. [ABSTRACT FROM AUTHOR]

Radiotheranostics is a field of rapid growth with some approved treatments including 131I for thyroid cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, and 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more. • The fundamentals of radiotheranostics, established therapies, and key clinical studies. • Future developments: new targets, new radionuclides, new platforms, and synergistic combination therapies. • Challenges: shortages in radionuclides and qualified professionals, efficient patient flow, and reimbursement. • Forthcoming considerations: dose limits, dosimetry-based therapy, new lines of therapy, complementary role with immunotherapy, and artificial intelligence. [ABSTRACT FROM AUTHOR]

Rationale: Despite recent advances in the targeted therapy of AML, the disease continues to have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains to be the curative therapy option for fit patients with high-risk disease. Especially patients with relapsed or refractory (r/r) AML continue to have poor outcomes. Myeloablative total body irradiation (TBI) based conditioning can be used in AML patients refractory to multiple lines of standard therapy, but the optimal conditioning regimen remains unclear for patients considered to be chemotherapy- refractory. Feasibility of C-X-C-motif chemokine receptor 4 (CXCR4)-directed endoradiotherapy (ERT) has previously been demonstrated in AML patients with CXCR4 expression on leukemic blasts. Methods: Here, we report on a small cohort of seven AML patients refractory to multiple lines (range 3-7) of therapy, who received CXCR4-directed ERT with [ 177 Lu]Pentixather in combination with TBI and chemotherapy prior to alloSCT. We report outcomes with a focus on toxicity, engraftment, the impact on the bone marrow (BM) niche and efficacy. Results: In this intensively pre-treated group of patients, promising response (6 out of 7 patients) and engraftment (6 out of 7 patients) rates were observed. Histopathological analysis showed that niche compartments are spared and allow for engraftment to occur despite the combined ERT and TBI conditioning. Conclusion: To the best of our knowledge, we report on the first seven patients who received CXCR4-directed ERT in sequential combination with TBI and chemotherapy, providing an effective, individualized conditioning regimen for intensively pre-treated r/r AML patients., Competing Interests: Competing Interests: WW reports Research Support from Siemens Healthineers, Blue Earth Diagnostics, ITM, Novartis, Pentixapharm, Ratio Therapeutics, Rayze Bio, Trimt, Roche. Employee/consultant/stock holder from Immu-Veo, ITM, Novartis, Rayze Bio, Roche. Honoraria from Siemens Healthineers and Scientific advisory board from Immune-Image, Immu-Veo. FB received honoraria from BMS and Janssen. ME reports fees from Blue Earth Diagnostics Ltd. (consultant, research funding), Novartis/AAA (consultant, speaker), Telix (consultant), Bayer (consultant, research funding), RayzeBio (consultant), Point Biopharma (consultant), Eckert-Ziegler (speaker), ABX GmbH (speaker) and Janssen Pharmaceuticals (consultant, speakers bureau), Parexel (image review) and Bioclinica (image review) outside the submitted work and a patent application for rhPSMA. He and other inventors are entitled to royalties on sales of POSLUMA®. PH reports personal fees and non-financial funding from Pentixapharm and personal fees from Immedica., (© The author(s).)

A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [68 Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [68 Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [177Lu]/[90Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies. [ABSTRACT FROM AUTHOR]

Background: CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods: Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [68Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUVmean) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUVmax), tumor volume (TV), and fractional tumor activity (FTA, defined as SUVmean x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results: Median SUVmean in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUVmax in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions: In patients with solid tumors imaged with [68Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) binding tracers are promising agents for the targeting of prostate tumors. To further optimize the clinically established radiopharmaceutical PSMA-617, novel PSMA ligands for prostate cancer endoradiotherapy were developed. A series of PSMA binding tracers that comprise a benzyl group at the chelator moiety were obtained by solid-phase synthesis. The compounds were labeled with 68Ga or 177Lu. Competitive cell-binding assays and internalization assays were performed using the cell line C4-2, a subline of the PSMA positive cell line LNCaP (human lymph node carcinoma of the prostate). Positron emission tomography (PET) imaging and biodistribution studies were conducted in a C4-2 tumor bearing BALB/c nu/nu mouse model. All 68Ga-labeled ligands were stable in human serum over 2 h; 177Lu-CA030 was stable over 72 h. The PSMA ligands revealed inhibition potencies [Ki] (equilibrium inhibition constants) between 4.8 and 33.8 nM. The percentage of internalization of the injected activity/106 cells of 68Ga-CA028, 68Ga-CA029, and 68Ga-CA030 was 41.2 ± 2.7, 44.3 ± 3.9, and 53.8 ± 5.4, respectively; for the comparator 68Ga-PSMA-617, 15.5 ± 3.1 was determined. Small animal PET imaging of the compounds showed a high tumor-to-background contrast. Organ distribution studies revealed high specific uptake in the tumor, that is, approximately 34.4 ± 9.8% of injected dose per gram (%ID/g) at 1 h post injection for 68Ga-CA028. At 1 h p.i., 68Ga-CA028 and 68Ga-CA030 demonstrated lower kidney uptake than 68Ga-PSMA-617, but at later time points, kidney time–activity curves converge. In line with the preclinical data, first diagnostic PET imaging using 68Ga-CA028 and 68Ga-CA030 revealed high-contrast detection of bone and lymph node lesions in patients with metastatic prostate cancer. The novel PSMA ligands, in particular CA028 and CA030, are promising agents for targeting PSMA-positive tumor lesions as shown in the preclinical evaluation and in a first patient, respectively. Thus, clinical translation of 68Ga-CA028 and 68Ga/177Lu-CA030 for diagnostics and endoradiotherapy of prostate cancer in larger cohorts of patients is warranted.

Holmium-loaded AcAc nanoparticles are potential agents for radionuclides endoradiotherapy because of their low density, biodegradability and favorable radiation characteristics. In this study, production, quality control and biodistribution studies of 166Ho-AcAc nanoparticles have been presented. Firstly, the stable 165Ho acetylacetonate (AcAc) spheres were prepared by the solvent evaporation technique. The 165Ho-AcAc nanoparticles were converted to the 166Ho-AcAc by irradiation in the Tehran Research Reactor. The morphology, stability, and structural parameters of the complex were investigated by SEM, ITLC, IR and XRD, respectively. The complex solutions (100 μCi/100 μl) were injected intra-tail into rat followed by scarification studies post- injection. The results indicated that the 166Ho-AcAc nanoparticles were prepared successfully with an optimal mean particle size of 70-100 nm and displayed a smooth surface with a high radiochemical purity of more than 97%. The complex was stable at 4ºC, human serum, PBS buffer, and room temperature. The most upper %ID/g of the 166Ho-AcAc nanoparticles was observed in the liver. Our data showed that the AcAc nanoparticles could be made in the optimal size range for the laser irradiation, and their ability to retain 166Ho makes them attractive agents for endoradiotherapy.

Castration-resistant prostate cancer (CRPC) treatment is an evolving challenge. Prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) with small-molecule, urea-based agents labeled with the β-particle–emitting radionuclide lutetium-177 (177Lu) is a promising new approach. In this systematic review and meta-analysis, we evaluated the efficacy and toxicity of PRLT. A systematic search was performed in PubMed/Medline (last updated February 18, 2019). A total of 250 studies were reviewed, and 24 studies with 1192 patients were included in the analysis. Proportions of patients with ≥50% serum prostate-specific antigen (PSA) decrease, any PSA decrease, and any PSA increase were extracted. Proportions of patients showing any grade toxicity and those with grade 3/4 toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) grading were extracted from manuscripts. Overall survival and progression-free survival were evaluated. A meta-analysis of single proportions was carried out. Furthermore, we compared the two most common PRLT agents, 177Lu-PSMA with 177Lu-PSMA-I&T, for effectiveness and toxicity. Among the 24 included studies, 20 included data on 177Lu-PSMA-617, three included data on 177Lu-PSMA-I&T, and one study had aggregated data for 177Lu-PSMA-617 and 177Lu-PSMA-I&T. The estimated proportion of 177Lu-PSMA-617–treated patients who showed a serum PSA decrease of ≥50% with at least an 8-wk interval between therapy and PSA measurement was 0.44 (0.39; 0.50). Therapy with 177Lu-PSMA-I&T demonstrated an estimated proportion of patients with ≥50% PSA reduction to be 0.36 (0.26; 0.47). The aggregate results for men treated with more than one cycle of any kind of PRLT showed an estimated proportion of 0.46 (0.41; 0.51) for PSA response ≥50%. Regarding aggregate data from all of the PRLT agents, we found that grade 3 and 4 toxicities were uncommon, with estimated proportions from 0.01 (0.00;0.04) for nausea, fatigue, diarrhea, and elevated aspartate transaminase up to 0.08 (0.05; 0.12) for anemia. There was considerable heterogeneity among the studies in the "any-grade toxicity" groups. Meta-regression showed that more than one cycle of PRLT is associated with a greater proportion of patients with ≥50% PSA reduction. Overall survival according to pooled hazard ratios (HRs) for any PSA decline was 0.29 (0.18; 0.46), and for >50% PSA reduction was 0.67 (0.43; 1.07). Progression-free survival according to a pooled HR of >50% PSA reduction was 0.53 (0.32; 0.86). The relatively high number of PSA responders alongside the low rate of severe toxicity reflects the potentially promising role of PRLT in treating CRPC. The ultimate utility of this treatment modality will become clearer as multiple prospective studies continue to accrue. In the interim, this systematic review and meta-analysis can serve as a compendium of effectiveness and adverse events associated with PRLT for treating clinicians. Prostate-specific membrane antigen–targeted endoradiotherapy/radioligand therapy (PRLT) is associated with ≥50% reduction in prostate-specific antigen level in a large number of patients and a low rate of toxicity, reflecting its potential in treating castration-resistant prostate cancer. This systematic review and meta-analysis presents as a compendium of the effectiveness and adverse events related to PRLT for treating clinicians. Prostate-specific membrane antigen–targeted endoradiotherapy/radioligand therapy appears to provide effective treatment with low toxicity rates in patients with castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer is the commonest non-cutaneous cancer in males and frequently metastasizes to nodal and skeletal tissues. Metastases to soft tissue viscera such as lung and liver are associated with decreased overall survival compared to nodal and skeletal metastases despite androgen deprivation and chemotherapy with palliative intent.We present a case with complete resolution of lung metastases after 225Ac-PSMA targeted alpha endoradiotherapy in a treatment naïve patient with metastatic prostate cancer. Our case gives preliminary clinical support for the efficacy of 225Ac-PSMA therapy in lung metastases.

Abstract Background Several radiolabeled prostate-specific membrane antigen (PSMA) inhibitors based on the lysine-urea-glutamate (KuE) motif as the pharmacophore proved to be suitable tools for PET/SPECT imaging of the PSMA expression in prostate cancer patients. PSMA I&T, a theranostic tracer developed in our group, was optimized through alteration of the peptidic structure in order to increase the affinity to PSMA and internalization in PSMA-expressing tumor cells. However, further structural modifications held promise to improve the pharmacokinetic profile. Results Among the investigated compounds 1–9, the PSMA inhibitors 5 and 6 showed the highest PSMA affinity (lowest IC 50 values) after the introduction of a naphthylalanine modification. The affinity was up to three times higher compared to the reference PSMA I&T. Extended aromatic systems such as the biphenylalanine residue in 4 impaired the interaction with the lipophilic binding pocket of PSMA, resulting in a tenfold lower affinity. The IC 50 of DOTAGA-conjugated 10 was slightly increased compared to the acetylated analog; however, efficient PSMA-mediated internalization and 80% plasma protein binding of 68Ga-10 resulted in effective tumor targeting and low uptake in non-target tissues of LNCaP tumor-bearing CD-1 nu/nu mice at 1 h p.i., as determined by small-animal PET imaging and biodistribution studies. For prolonged tumor retention, the plasma protein binding was increased by insertion of 4-iodo-d-phenylalanine resulting in 97% plasma protein binding and 16.1 ± 2.5% ID/g tumor uptake of 177Lu-11 at 24 h p.i. Conclusions Higher lipophilicity of the novel PSMA ligands 10 and 11 proved to be beneficial in terms of affinity and internalization and resulted in higher tumor uptake compared to the parent compound. Additional combination with para-iodo-phenylalanine in the spacer of ligand 11 elevated the plasma protein binding and enabled sustained tumor accumulation over 24 h, increasing the tumor uptake almost fourfold compared to 177Lu-PSMA I&T. However, high renal uptake remains a drawback and further studies are necessary to elucidate the responsible mechanism behind it.

The application of 225Ac (half-life T1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to 90Y, 177Lu or 188Re while maintaining the therapeutic outcome. Additionally, the range of alpha particles of 225Ac and its daughter nuclides in tissue is much lower (47–85 μm for alpha energies Eα = 5.8–8.4 MeV), which results in a very precise dose deposition within the tumor. DOTA-conjugated commercially available peptides used for endoradiotherapy, which can readily be labeled with 177Lu or 90Y, can also accommodate 225Ac. The benefits are lower doses in normal tissue for the patient, dose reduction of the employees and environment and less shielding material. The low availability of 225Ac activity is preventing its application in clinical practice. Overcoming this barrier would open a broad field of 225Ac therapy. Independent which production pathway of 225Ac proves the most feasible, the use of automated synthesis and feasible and reproducible patient doses are needed. The Modular-Lab EAZY is one example of a GMP-compliant system, and the cassettes used for synthesis are small. Therefore, also the waste after the synthesis can be minimized. In this work, two different automated setups with different purification systems are presented. In its final configuration, three masterbatches were performed on the ML EAZY for DOTA-TATE and PSMA-I&T, respectively, fulfilling all quality criteria with final radiochemical yields of 80–90% for the 225Ac-labeled peptides.

Purpose: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has impacted the management of patients with prostate cancer (PCa) in many parts of the world. PSMA-targeted endoradiotherapies are also being increasingly utilized and for these applications, the radiopharmaceutical distribution in normal organs is particularly important because it may limit the dose that can be delivered to tumors. In this study, we measured both interpatient and intrapatient variability of [18F]DCFPyL uptake in the most relevant normal organs.Procedures: Baseline and 6-month follow-up PSMA-targeted [18F]DCFPyL PET/computed tomography (CT) scans from 39 patients with PCa were reviewed. Volumes of interest were manually drawn using the best visual approximation of the organ edge for both lacrimal glands, all four major salivary glands, the liver, the spleen, and both kidneys for all patients. The average SUVmean, the COVs, and intraclass correlation coefficients (ICCs) across scans were calculated. Bland-Altman analyses were performed for all organs to derive repeatability coefficients (RCs).Results: The liver demonstrated the lowest interpatient variability (13.0 and 16.6 % at baseline and follow-up, respectively), while the spleen demonstrated the largest interpatient variability (44.6 and 51.0 % at baseline and follow-up, respectively). The lowest intrapatient variability was found in the spleen (ICC 0.86) while the highest intrapatient variability was in the kidneys (ICCs 0.40-0.50). Bland-Altman analyses showed 95 % repeatability coefficients for mean uptake > 40 % for multiple organs and were highest for the lacrimal glands, kidneys, and spleen.Conclusions: Normal organs demonstrate significant variability in uptake of the PSMA-targeted radiotracer [18F]DCFPyL. Depending on the organ, different contributions of interpatient and intrapatient factors affect the intrinsic variability. The RCs also vary significantly among the different organs were highest for the lacrimal glands, kidneys, and spleen. These findings may have important implications for the design of clinical protocols and personalized dosimetry for PSMA-targeted endoradiotherapies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Medical radiolanthanides are efficiently produced via neutron irradiation. • Pure radiolanthanides are needed for radiotherapy and theranostics. • Target material is chemically processed after irradiation. • Long-lived impurities are removed from carrier added radiolanthanides. • Non-carrier added radiolanthanides are isolated from irradiated target material. Abstract Several radiolanthanides find their application in nuclear medicine because of their favorable decay properties, the most important ones being 143Pr, 149Pm, 153Sm, 165Dy, 161Tb, 166Ho, 169Er, 170Tm and 177Lu. These radiolanthanides can be efficiently produced via neutron irradiation in a high-flux nuclear research reactor. Radiochemical processing of the irradiated target is required to obtain the required purity or to remove redundant target material. Long-lived impurities can be removed to extend the expiration time of carrier added radiolanthanides, whereas non-carrier added radiolanthanides with high radionuclidic purity and high specific activities can be obtained for targeted radiotherapy. Transport and distribution criteria might become more flexible, helping to safeguard the supply of radiolanthanides for medical purposes. Valuable and expensive target material can be regenerated after separation of the medical radiolanthanide. Different radiochemical separation processes are discussed which are able to separate two adjacent lanthanides, with a focus on those techniques making use of the underlying coordination chemistry. [ABSTRACT FROM AUTHOR]

The combination of low molecular weight, reversible human serum albumin (HSA) binders with targeted radiopharmaceuticals in dual-targeted radioconjugates holds great promise, in particular for endoradiotherapy. Attachment of HSA-binders to radiopharmaceuticals extends their blood circulation time and results in an enhanced tumour uptake as well as often in an improved pharmacokinetic profile. In this mini-review, an overview of currently pursued approaches of this novel strategy is provided. [ABSTRACT FROM AUTHOR]

[Display omitted] Recently, endoradiotherapy based on actinium-225 (225Ac) has attracted increasing attention, which is due to its α particles can generate maximal damage to cancer cells while minimizing unnecessary radiation effects on healthy tissues. Herein, 111In/225Ac-radiolabeled conjugated polymer nanoparticles (CPNs) coated with amphiphilic polymer DSPE-PEG-DOTA have been developed as a new injectable nano-radiopharmaceuticals for cancer endoradiotherapy under the guidance of nuclear imaging. Single photon emission computed tomography/computed tomography (SPECT/CT) using 111In-DOTA-PEG-CPNs as nano probe indicates a prolonged retention of radiolabeled nanocarriers, which was consistent with the in vivo biodistribution examined by direct radiometry analysis. Significant inhibition of tumor growth has been observed in murine 4T1 models treated with 225Ac-DOTA-PEG-CPNs when compared to mice treated with PBS or DOTA-PEG-CPNs. The 225Ac-DOTA-PEG-CPNs group experienced no single death within 24 days with the median survival considerably extended to 35 days, while all the mice treated with PBS or DOTA-PEG-CPNs died at 20 days post injection. Additionally, the histopathology studies demonstrated no obvious side effects on healthy tissues after treatment with 225Ac-DOTA-PEG-CPNs. All these results reveal that the new 225Ac-labeled DOTA-PEG-CPNs is promising as paradigm for endoradiotherapy. [ABSTRACT FROM AUTHOR]

Due to its 4 carbonic acid groups being available for bioconjugation, the cyclen tetraphosphinate chelator DOTPI, 1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)], represents an ideal scaffold for synthesis of tetrameric bioconjugates for labeling with radiolanthanides, to be applied as endoradiotherapeuticals. We optimized a protocol for bio-orthogonal DOTPI conjugation via Cu(I)-catalyzed Huisgen-cycloaddition of terminal azides and alkynes (CuAAC), based on the building block DOTPI(azide)4. A detailed investigation of kinetic properties of Cu(II)-DOTPI complexes aimed at optimization of removal of DOTPI-bound copper by transchelation. Protonation and equilibrium properties of Ca(II)-, Zn(II), and Cu(II)-complexes of DOTPI and its tetra-cyclohexylamide DOTPI(Chx)4 (a model for DOTPI conjugates) as well as kinetic inertness (transchelation challenge in the presence of 20 to 40-fold excess of EDTA) were investigated by pH-potentiometry and spectrophotometry. Similar stability constants of CaII-, ZnII, and CuII-complexes of DOTPI (logK(CaL) = 8.65, logK(ZnL = 15.40, logK(CuL) = 20.30) and DOTPI(Chx)4 (logK(CaL) = 8.99, logK(ZnL) = 15.13, logK(CuL) = 20.42) were found. Transchelation of Cu(II)-complexes occurs via proton-assisted dissociation, whereafter released Cu(II) is scavenged by EDTA. The corresponding dissociation rates [kd = 25 × 10−7 and 5 × 10−7 s−1 for Cu(DOTPI) and Cu(DOTPI(Chx)4), respectively, at pH 4 and 298 K] indicate that conjugation increases the kinetic inertness by a factor of 5. However, demetallation is completed within 4.5 and 7.2 h at pH 2 and 25°C, respectively, indicating that Cu(II) removal after formation of CuAAC can be achieved in an uncomplicated manner by addition of excess H4EDTA. For proof-of-principle, tetrameric DOTPI conjugates of the prostate-specific membrane antigen (PSMA) targeting motif Lys-urea-Glu (KuE) were synthesized via CuAAC as well as dibenzo-azacyclooctine (DBCO) based, strain-promoted click chemistry (SPAAC), which were labeled with Lu-177 and subsequently evaluated in vitro and in SCID mice bearing subcutaneous LNCaP tumor (PSMA+ human prostate carcinoma) xenografts. High affinities (3.4 and 1.4 nM, respectively) and persistent tumor uptakes (approx. 3.5% 24 h after injection) confirm suitability of DOTPI-based tetramers for application in targeted radionuclide therapy.

The discovery and clinical development of radiolabeled small-molecule ligands targeting prostate-specific membrane antigen (PSMA) has had a profound influence on the field of nuclear medicine. Such agents have been successfully deployed for both imaging and therapeutic applications. In particular, PSMA radioligand therapy (PRLT) has been shown to be a life-prolonging therapy for men with metastatic, castration-resistant prostate cancer and has also brought nuclear medicine physicians and nuclear radiologists into the forefront of direct patient care. In this review, we will discuss the clinical study data regarding the efficacy and toxicities related to PRLT, outline the key personnel that any center offering PRLT should have, offer salient clinical examples, and provide an overview of future directions for PRLT. As PRLT continues to evolve as a treatment modality, it is paramount that nuclear medicine physicians and nuclear radiologists understand the clinical context, management implications, and practical aspects so as to best deliver high-value care to patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Case studies of 32, 62 and 75 years patients are presented with relapsed refractory multiple myeloma, diffuse large B cell lymphoma, and acute lymphoblastic leukaemia. C-X-C-motif chemokine receptor 4 (CXCR4)-directed treatment was offered on a compassionate use basis prior to stem cell transplantation; and initial CXCR4-expression was confirmed in all patients using Pentixafor positron emission tomography/computed tomography and immunohistochemical analysis.

The neurotensin receptors are overexpressed in various tumor types, especially in highly progressive pancreatic tumors. As this cancer has a poor 5‐year survival prognosis, there is an urgent need to improve early diagnosis and treatment strategies. This review article provides an overview of the latest developments in radiopharmaceuticals for neurotensin receptor‐positive tumors, including peptidic and non‐peptidic radiopharmaceuticals, not only for SPECT and PET but also for endoradiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Prostate-specific membrane antigen (PSMA)-targeting radioligand therapy (RLT) was introduced in 2011. The first report described the antitumor and side effects of a single dose. The aim of this analysis was to evaluate toxicity and antitumor activity after single and repetitive therapies. Methods: Thirty-four men with metastatic castration-resistant prostate cancer received PSMA-RLT with I-MIP-1095. Twenty-three patients received a second, and three patients a third dose, timed at PSA progression after an initial response to the preceding therapy. The applied doses were separated in three groups: <3.5, 3.5-5.0 and >5.0 GBq. Antitumor and side-effects were analyzed by blood samples and other clinical data. Follow-up was conducted for up to 5 years. Results: The best therapeutic effect was achieved by the first therapy. A PSA decline of ≥50% was achieved in 70.6% of the patients. The second and third therapies were significantly less effective. There was neither an association between the applied activity and PSA response or the time-to-progression. Hematologic toxicities were less prevalent but presented in a higher percentage of patients with increasing number of therapies. After hematologic toxicities, xerostomia was the second most frequent side effect and presented more often and with higher intensity after the second or third therapy. Conclusion: The first dose of RLT with I-MIP-1095 presented with low side effects and could significantly reduce the tumor burden in a majority of patients. The second and third therapies were less effective and presented with more frequent and more intense side effects, especially hematologic toxicities and xerostomia. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed. We demonstrate the clinical potential of C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging and endoradiotherapy in DSRCT. Methods: Eight male patients underwent dual-tracer imaging with [ 18 F]FDG and CXCR4-directed [ 68 Ga]pentixafor PET/CT. A visual comparison of both tracers, along with uptake quantification in active DSRCT lesions, was performed. [ 68 Ga]pentixafor uptake was correlated with immunohistochemical CXCR4 expression on tumor cells. Four patients with end-stage progressive disease underwent CXCR4-based endoradiotherapy. We report the safety, response by RECIST 1.1, and survival after endoradiotherapy. Results: Uptake of [ 68 Ga]pentixafor in tumor lesions was demonstrated in all patients with DSRCT, providing diagnostic power comparable to [ 18 F]FDG PET. Corresponding CXCR4 expression was confirmed by immunohistochemistry in all DSRCT biopsies. Finally, 4 patients were treated with CXCR4-directed [ 90 Y]endoradiotherapy, 3 in a myeloablative dose range with subsequent autologous stem cell transplantation. All 3 required transfusions, and febrile neutropenia occurred in 2 patients (resulting in 1 death). Notably, severe nonhematologic adverse events were absent. We observed signs of response in all 3 patients, translating into disease stabilization in 2 patients for 143 and 176 d, respectively. In the third patient, postmortem autopsy confirmed a partial pathologic response. Conclusion: We validated CXCR4 as a diagnostic biomarker and a promising target for endoradiotherapy in DSRCT, demonstrated its feasibility, and provided the first evidence of its clinical efficacy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Irradiation of salivary glands remains the main dose-limiting side effect of therapeutic PSMA-inhibitors, especially when using alpha emitters. Thus, further advances in radiopharmaceutical design and therapy strategies are needed to reduce salivary gland uptake, thereby allowing the administration of higher doses and potentially resulting in improved response rates and better tumor control. As the uptake mechanism remains unknown, this work investigates the salivary gland uptake of [177Lu]Lu-PSMA-617 by autoradiography studies on pig salivary gland tissue and on PSMA-overexpressing LNCaP cell membrane pellets. Displacement studies were performed with non-labeled PSMA-617 and 2-PMPA, respectively. The uptake of [177Lu]Lu-PSMA-617 in glandular areas was determined to be partly PSMA-specific, with a high non-specific uptake fraction. The study emphasizes that [177Lu]Lu-PSMA-617 accumulation in pig salivary glands can be attributed to a combination of both specific and non-specific uptake mechanisms. The observation is of high impact for future design of novel radiopharmaceuticals addressing the dose-limiting salivary gland irradiation of current alpha endoradiotherapy in prostate cancer.

Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [177Lu]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy β− emitting therapeutic radiolanthanide 177Lu. For routine chemical application, an automated synthesis of this radiopharmaceutical and a Kit-type labeling procedure appears to be a basic requirement for its good manufacturing practice (GMP) based production. A Kit formulation combining BPAMD, acetate buffer, and ethanol resulted in almost quantitative labeling yields. The use of ethanol and ascorbic acid as quenchers prevented radiolysis over 48 hours. An automated synthesis unit was designed for the production of therapeutic doses of [177Lu]BPAMD up to 5 GBq. The procedure was successfully applied for patient treatments. [ABSTRACT FROM AUTHOR]

C-X-C-motif chemokine receptor 4 (CXCR4) is a novel predictive biomarker for metastasis and poor prognosis in individuals with malignancies. CXCL12 is the only cognate ligand of CXCR4. CXCL12/CXCR4 signaling pathways are involved in the cross-talk among cancer cells, T cells, stromal cells, and their microenvironments, including the regulation and direction of T cell migration (chemotaxis), proliferation, and differentiation of immature progenitor stem cells. As CXCR4 overexpression is related to tumor prognosis, it is essential to quantitatively evaluate CXCR4 expression levels in vivo . 68 Ga-Pentixafor, as a radiolabeled tracer, shows high specificity and affinity for CXCR4 in tumors. Thus, CXCR4-directed imaging with 68 Ga-Pentixafor has been investigated to evaluate CXCR4 expression in patients non-invasively. In recent years, many small cohorts, including those of individuals with hematologic malignancies, solid tumors, and cardiovascular and infectious diseases, have been reported. So far, 68 Ga-Pentixafor has been used successfully in individuals with hematologic malignancies. In addition, Lutetium-177 ( 177 Lu) or Yttrium-90 ( 90 Y)-labeled Pentixather (an analog of Pentixafor) suggested high potential applicability in tumor endoradiotherapy (ERT) with CXCR4 overexpression. Patients with advanced-stage multiple myeloma, refractory acute leukemia, and diffuse large B-cell lymphoma received a certain amount of 177 Lu-Pentixather or 90 Y-Pentixather. This review aimed to overview the current CXCR4-directed positron emission computed tomography (PET) molecular imaging based on Pentixafor in several diseases and ERT., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The objective of the study was to conjugate the DNA binding ligand para-[125I]-iodoHoechst to octreotate, and to explore the tumour targeting potential of this conjugate in the octreotate-somatostatin receptor system. Methods: We synthesized a Hoechst analogue containing a tri-butylstannyl group in the para position of phenyl ring, conjugated it to the N-terminal amino group of octreotate and prepared 125I-labelled conjugate by iododestannylation. We used the somatostatin receptor (SSTR2) over-expressing cell line A427-7 derived from its parent A427 human non-small cell lung carcinoma cell line to investigate SSTR2 affinity and receptor-mediated internalisation of the conjugate, and the mouse A427-7 tumour xenograft model for in vivo biodistribution studies of the radiolabelled conjugate. Results: A method was developed for convenient preparation of high specific activity radioiodinated conjugate which retains affinity for somatostatin receptors and is internalised into A427-7 SSTR2 over-expressing cells via a receptor-mediated mechanism. The conjugate accumulates in mouse A427-7 tumour xenografts following intravenous administration. Conclusions: A dual targeting strategy for Auger endoradiotherapy, in which a DNA ligand is used to target the Auger decay to DNA, in conjunction with receptor-mediated targeting to specific receptors, using a labelled DNA ligand/peptide conjugate, has been demonstrated for the octreotate-somatostatin receptor system. [ABSTRACT FROM AUTHOR]

Abstract: Peptides, proteins and antibodies are promising candidates as carriers for radionuclides in endoradiotherapy. This novel class of pharmaceuticals offers a great potential for the targeted therapy of cancer. The fact that some receptors are overexpressed in several tumor types and can be targeted by small peptides, proteins or antibodies conjugated to radionuclides has been used in the past for the development of peptide endoradiotherapeutic agents such as 90Y-DOTATOC or radioimmunotherapy of lymphomas with Zevalin. These procedures have been shown to be powerful options for the treatment of cancer patients. Design of new peptide libraries and scaffolds combined with biopanning techniques like phage and ribosome display may lead to the discovery of new specific ligands for target structures overexpressed in malignant tumors. Display methods are high throughput systems which select for high affinity binders. These methods allow the screening of a vast amount of potential binding motifs which may be exposed to either cells overexpressing the target structures or in a cell-free system to the protein itself. Labelling these binders with radionuclides creates new potential tracers for application in diagnosis and endoradiotherapy. This review highlights the advantages and problems of phage and ribosome display for the identification and evaluation of new tumor specific peptides. [Copyright &y& Elsevier]

Abstract: Increased cellular proliferation is an integral part of the cancer phenotype. Hence, the sustained and continued demand on supply of DNA building blocks during the DNA replication presents a potential target for therapeutic intervention. For this propose, the α and Auger electron emitting nucleotides analogs are attractive for targeted endoradiotherapy, given that DNA of malignant cells is selectively addressed. This review summarizes development and preclinical and clinical studies of endoradiotherapeutic acting nucleoside analogs with a special focus on thymidine analogs. [Copyright &y& Elsevier]

Abstract: Endoradiotherapy represents an alternative therapeutic method in cancer treatment with advantageous features compared to chemotherapy and radiation therapy. Intelligent dose delivery concepts using small drugs, peptides or antibodies as radionuclide carriers enable the verification of a selective accumulation in the tumour lesion and to reduce radiation toxicity for the peripheral organs. The development of endoradiotherapeutic agents, especially chelator-conjugated biomolecules, for example ibritumomab tiuxetan or DOTATOC, gains importance due to the stable complexation of versatile radiometals, such as 90Y or 177Lu. The rational design of novel target binding sides and their grafting into a drug scaffold is a highly promising strategy, which may promote further implication in endoradiotherapy. This review highlights the basic concepts of endoradiotherapy and discusses the potential of targeted therapy and the properties of energy-rich particles emitted by radionuclides for tumour therapy. [Copyright &y& Elsevier]

The chemokine receptor 4 (CXCR4), which is overexpressed in many solid and hematologic malignancies, can be targeted for radiopeptide therapy via the antagonist pentixather. The biokinetics and dosimetry of 177 Lu-pentixather and 90 Y-pentixather were analyzed in this study. Methods: This retrospective study was a standardized reevaluation of data collected for treatment planning. Nineteen patients with complete sets of planar whole-body scans over at least 4 d and a single SPECT/CT scan after administration of 200 MBq of 177 Lu-pentixather were included. Kinetics were measured in the whole body, in tissues with activity retention, and in 10 individuals in the blood. Time-integrated activity coefficients and tissue-absorbed doses were derived. Results: Increased uptake of pentixather was observed in the kidneys, liver, spleen, and bone marrow, inducing respective median absorbed doses of 0.91 Gy (range, 0.38-3.47 Gy), 0.71 Gy (range, 0.39-1.17 Gy), 0.58 Gy (range, 0.34-2.26 Gy), and 0.47 Gy (range, 0.14-2.33 Gy) per GBq of 177 Lu-pentixather and 3.75 Gy (range, 1.48-12.2 Gy), 1.61 Gy (range, 1.14-2.97 Gy), 1.66 Gy (range, 0.97-6.69 Gy), and 1.06 Gy (range, 0.27-4.45 Gy) per GBq of 90 Y-pentixather. In most tissues, activity increased during the first day after the administration of 177 Lu-pentixather and afterward decayed with mean effective half-lives of 41 ± 10 h (range, 24-64 h) in the kidneys and median half-lives of 109, 86, and 92 h in the liver, spleen, and bone marrow, respectively. Maximum uptake per kidney was 2.2% ± 1.0% (range, 0.6%-5.1%). In organs showing no specific uptake, absorbed doses exceeding 0.3 Gy/GBq of 90 Y-pentixather were estimated for the urinary bladder and for tissues adjacent to accumulating organs such as the adrenal glands, bone surface, and gallbladder. Dose estimates for tumors and extramedullary lesions ranged from 1.5 to 18.2 Gy/GBq of 90 Y-pentixather. Conclusion: In patients with hematologic neoplasms, absorbed doses calculated for bone marrow and extramedullary lesions are sufficient to be effective as an adjunct to high-dose chemotherapies before stem cell transplantation., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: An updated systematic review and meta-analysis of relevant studies to evaluate the effectiveness of prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) in castration resistant prostate cancer (CRPC)., Methods: A systematic search was performed in July 2020 using PubMed/Medline database to update our prior systematic review. The search was limited to papers published from 2019 to June 2020. A total of 472 papers were reviewed. The studied parameters included pooled proportion of patients showing any or ≥50% prostate-specific antigen (PSA) decline after PRLT. Survival effects of PRLT were assessed based on pooled hazard ratios (HRs) of the overall survival (OS) according to any PSA as well as ≥50% PSA decline after PRLT. Response to therapy based on ≥50% PSA decrease after PRLT versus controls was evaluated using Mantel-Haenszel random effect meta-analysis. All p values < 0.05 were considered as statistically significant., Results: A total of 45 publications were added to the prior 24 studies. 69 papers with total of 4157 patients were included for meta-analysis. Meta-analysis of the two recent randomized controlled trials showed that patients treated with 177 Lu-PSMA 617 had a significantly higher response to therapy compared to controls based on ≥50% PSA decrease. Meta-analysis of the HRs of OS according to any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT., Conclusions: PRLT results in higher proportion of patients responding to therapy based on ≥50% PSA decline compared to controls. Any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT., Advances in Knowledge: This is the first meta-analysis to aggregate the recent randomized controlled trials of PRLT which shows CRPC patients had a higher response to therapy after PRLT compared to controls., (© 2022 The Authors. The Prostate Published by Wiley Periodicals LLC.)

Sm, a radiolanthanide of half life 46.27 h, has a gamma emission of 0.103 MeV which is well suited to imaging, it is also a moderate energy beta emitter and tumour localization of various Sm chelates was evaluated in B16 murine melanoma to assess their endoradiotherapeutic potential. Sm was prepared from enriched Sm in the Australian Nuclear Science and Technology Organization reactor. Sm chelates were prepared from Smchloride and their chromatographic behaviour characterized. Tumour and organ uptake of Sm-chloride, Sm-citrate and the Sm chelates, DTPA, HEDTA, HIDA, BZ, PBH, PIH and NTA were measured at 1, 6, 24 and 48 h after intravenous administration to C57 black mice bearing either melanotic or amelanotic B16 melanoma of mean size 0.75 cm. Histopathological examination of the tumours at each passaging assured comparability of the degree of melanogenesis and the absence of necrosis. Sm-chloride was immobile on chromatography and the rapid hepatic accumulation of both Sm-chloride and Sm-citrate was attributed to in vivo formation of a colloid. In contrast, Sm-DTPA, moving at the solvent front on chromatography, showed no reticuloendothelial accumulation in vivo and was rapidly excreted by the kidneys without tumour uptake. The other Sm chelates were of intermediate stability and all localized in both melanotic and amelanotic tumours, although to a significantly lesser degree than Ga-citrate. The relatively high Sm-HIDA activity in liver and Sm-NTA activity in bone impaired tumour definition, but on imaging of all the Sm chelates only Sm-DTPA failed to demonstrate the B16 melanoma and the best tumour delineation was obtained using Sm-HEDTA. [ABSTRACT FROM AUTHOR]

The microscopic distribution of the potential endoradiotherapeutic drug, 6-[At]-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt) in normal tissues of the mouse has been studied by α-particle track autoradiography. The uptake into critical radiosensitive tissues, especially bone marrow, colon and lung, was low. [ABSTRACT FROM AUTHOR]

Lu-177-based, targeted radiotherapeutics/endoradiotherapies are an emerging clinical tool for the management of various cancers. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remains the workhorse for such applications but can limit apparent molar activity or efficient charge modulation, which can impact target binding and, as a consequence, target efficacy. Previously, our lab had developed the small, rare earth selective bifunctional chelator, picaga, as an efficient bifunctional chelator for scandium and lutetium isotopes. Here, we assess the performance of these constructs for therapy in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts. To assess the viability of picaga conjugates in conjunction with long in vivo circulation, a picaga conjugate functionalized with a serum albumin binding moiety, 177 Lu-picaga-Alb53-PSMA, was also synthesized. A directly comparative, low, single 3.7 MBq dose treatment study with Lu-PSMA-617 was conducted. Treatment with 177 Lu-picaga-Alb53-PSMA resulted in tumor regression and lengthened median survival (54 days) when compared with the vehicle (16 days), 47 Sc-picaga-DUPA-, 177 Lu-picaga-DUPA-, and 177 Lu-PSMA-617-treated cohorts (21, 23, and 21 days, respectively).

The application of 225Ac (half-life T1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to 90Y, 177Lu or 188Re while maintaining the therapeutic outcome. Additionally, the range of alpha particles of 225Ac and its daughter nuclides in tissue is much lower (47–85 μm for alpha energies Eα = 5.8–8.4 MeV), which results in a very precise dose deposition within the tumor. DOTA-conjugated commercially available peptides used for endoradiotherapy, which can readily be labeled with 177Lu or 90Y, can also accommodate 225Ac. The benefits are lower doses in normal tissue for the patient, dose reduction of the employees and environment and less shielding material. The low availability of 225Ac activity is preventing its application in clinical practice. Overcoming this barrier would open a broad field of 225Ac therapy. Independent which production pathway of 225Ac proves the most feasible, the use of automated synthesis and feasible and reproducible patient doses are needed. The Modular-Lab EAZY is one example of a GMP-compliant system, and the cassettes used for synthesis are small. Therefore, also the waste after the synthesis can be minimized. In this work, two different automated setups with different purification systems are presented. In its final configuration, three masterbatches were performed on the ML EAZY for DOTA-TATE and PSMA-I&T, respectively, fulfilling all quality criteria with final radiochemical yields of 80–90% for the 225Ac-labeled peptides. [ABSTRACT FROM AUTHOR]