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ABSTRACT: Radiopharmaceutical therapy has emerged as a promising approach for the treatment of various cancers. The exploration of novel targets such as tumor-specific antigens, overexpressed receptors, and intracellular biomolecules using antibodies, peptides, or small molecules has expanded the scope of radiopharmaceutical therapy, enabling precise and effective cancer treatment for an increasing number of tumor types. Alpha emitters, characterized by their high linear energy transfer and short path length, offer unique advantages in targeted therapy due to their potent cytotoxicity against cancer cells while sparing healthy tissues. This article reviews recent advancements in identifying novel targets for radiopharmaceutical therapy and applications in utilizing α-emitters for targeted treatment.

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Hemangioblastomas associated with von Hippel-Lindau (VHL) disease are frequently multiple and recur during prolonged follow-up. Currently, no systemic treatment is available for these tumors. Recent studies have shown the expression of somatostatin receptors in these types of hemangioblastomas. Notably, increased somatostatin receptor expression in a tumor, as determined by peptide-receptor radionuclide imaging, is a predictive factor of response to treatment with somatostatin analogs and peptide-receptor radionuclide therapy. The aim of this study was to describe the case of a patient with increased expression of somatostatin receptors in a suprasellar hemangioblastoma associated with VHL disease and conduct a literature review on somatostatin receptor expression in patients with VHL-associated hemangioblastomas. We describe herein the case of a 51-year-old man with VHL disease who had a suprasellar hemangioblastoma detected on magnetic resonance imaging. Peptide-receptor radionuclide imaging using gallium-68-DOTATOC (68Ga-DOTATOC) identified increased expression of somatostatin receptors in the suprasellar hemangioblastoma, along with multiple pancreatic neuroendocrine tumors and bilateral pheochromocytomas. The patient was treated for 1 year with lanreotide, a somatostatin analog. A repeat 68Ga-DOTATOC 1 year after starting lanreotide revealed decreased radiotracer uptake by the hemangioblastoma, consistent with a metabolic response. The presence of somatostatin receptors in hemangioblastomas associated with VHL disease is a novel finding. The decreased expression of these receptors after treatment with a somatostatin analog, as described in the present case, positions the somatostatin receptor as a new target for novel diagnostic, therapeutic, and follow-up opportunities in patients with VHL disease.

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Relative biological effectiveness is a radiobiological parameter relevant in radiotherapy planning and useful in evaluating the physiological impact of radiation in different tissues. Targeted radionuclide therapy allows the selective and specific deposition of higher radiation doses in a noninvasive way and without collateral effects through the administration of radiopharmaceuticals. Lu-DOTA-177(hydrazinylnicotinoyl-Lys-(Nal)-NH-CO-NH-Glu) also called Lu-iPSMA177 is a third generation radiopharmaceutical composed by a peptide that recognizes the prostate-specific membrane antigen (PSMA), a membrane protein overexpressed in several types of cancer and that mediates the radiopharmaceutical's recognition of cancer cells. The present study reports radiobiological parameters of Lu-iPSMA177 and demonstrates the superiority of targeted radiopharmaceuticals over external radiotherapy treatment options in terms of their relative biological effectiveness. The relative biological effectiveness value of 1.020±0.003 for the LINAC, estimated by fitting the linear-quadratic model equation to the resulting survival curves, was like those of 1.25±0.04,1.060±0.005and1.00±0.04 obtained by an alternative method in relation to the mean lethal doses at 90, 80 or 60 survival percent respectively. While the relative biological effectiveness values of 5.65±0.13,4.72±0.27and2.87±0.19 estimated for Lu-iPSMA177 were significantly higher than those for the LINAC. The results confirm that the biological effect produced by the deposition of a radiation absorbed dose delivered by the LINAC can be induced with a quarter of that dose using Lu-iPSMA177 due to the energy distribution, dose-rate and energy fluence.

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Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (177Lu-DOTA-PD-L1-i) and actinium-225 (225Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with 225Ac and 177Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of 177Lu-DOTA-PD-L1-i and 225Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. 225Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of 177Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of 225Ac and 177Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer.

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Nanotechnology has changed the world, with a great impact on industry and medicine. In this commentary, we discuss the importance of radiolabeled nanomaterials for the construction of theranostic, imaging and therapeutic agents in order to pave the future of medicine.

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Neuroendocrine neoplasms (NENs) comprise a beautifully complicated, exciting landscape of histologies and clinical behaviors. However, the nuanced complexity of low- and high-grade variants can easily overwhelm both patients and providers. In this chapter, we review the ever-expanding literature on both functioning and nonfunctioning small bowel and pancreatic NENs, touching on somatostatin analogs, hepatic-directed therapies, small molecules, radiopharmaceuticals, immunotherapy, cytotoxic chemotherapy, and new promising agents. Furthermore, we suggest some strategies to address the most challenging scenarios seen in clinical practice, including sequencing of agents, treatment of carcinoid syndrome, and options for well-differentiated high-grade disease.

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Positron emission tomography-computed tomography (PET-CT) is part of the new diagnostic and therapeutic algorithms for Hodgkin lymphoma. PET-CT is a valuable tool for the assessment of treatment response and prognosis, both by means of interim PET-CT with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) as well as end of treatment (EOT) PET-CT. Given the low specificity of [18F]FDG for the diffuse large B cell lymphoma (DLBCL), there is an emerging need for a more specific radiopharmaceutical agent. The recent approval of the radiotracer 3'-deoxy-[18F]-3'-flourothymidine ([18F]FLT), a phase-S mitosis cell proliferation marker, for clinical application in our country, shows as a promising radiopharmaceutical for diagnostic use with incremental value over [18F]FDG. In this study, non-human primates (Sapajus cay) were studied. PET-CT study was performed after the injection of [18F]FLT. Whole-body images were obtained to evaluate the biodistribution and to calculate the dosimetry of bone marrow, as this is a critic organ to this radiotracer. Time-activity curves were traced, normalized activity uptake of the organs of interest were calculated, and mean absorbed dose was also calculated using the established Medical Internal Radiation Dosimetry (MIRD) scheme. The mean dose obtained in the animal model per unit of activity administered was 8.7 uGy/MBq. This result was extrapolated to an adult human model resulting in 32 uGy/MBq, thereby suggesting that [18F]FLT is a secure diagnostic tool to be used on the tracing of patients with DLBCL.

En el linfoma Hodgkin, la tomografía por emisión de positrones (PET-TC) forma parte de los nuevos algoritmos diagnósticos y de valoración de respuesta al tratamiento como método eficaz para evaluar supervivencia y pronóstico de la enfermedad, ya sea a través del PET-TC interino con 2-[18F]fluoro-2-desoxi-D-glucosa, ([18F]FDG), como también del PET-TC al final de la terapéutica. Sin embargo, la [18F]FDG presenta una baja especificidad en linfoma no Hodgkin de grandes células B. Ante la aprobación en nuestro país del radiotrazador 3'-desoxi-3'-[18F]fluorotimidina, [18F]FLT, indicador de proliferación celular de fase S, éste resultaría un prometedor radiofármaco de uso diagnóstico frente a [18F]FDG. Por lo tanto, el objetivo de este estudio fue valorar la utilización de [18F]FLT mediante un modelo animal en primates no humanos Sapajus cay. Se obtuvieron imágenes de cuerpo entero para evaluar la biodistribución y realizar un cálculo dosimétrico en la médula ósea, dado que este es un órgano crítico por la permanencia del radiofármaco. Para órganos de interés, se trazaron curvas de actividad en función del tiempo y se calculó la actividad acumulada normalizada. La dosis media absorbida en la médula ósea se determinó aplicando el esquema conocido como Medical Internal Radiation Dosimetry (MIRD). La dosis media obtenida en el modelo animal por unidad de actividad administrada fue de 8.7 uGy/MBq. Este resultado se extrapoló a un modelo humano adulto resultando en 32 uGy/MBq, de lo que se desprende que PET-TC con [18F]FLT es una herramienta segura para uso diagnóstico y de seguimiento en pacientes con enfermedad oncológica linfoproliferativa u otros tumores sólidos.

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A 59-year-old woman with follicular thyroid carcinoma underwent total thyroidectomy followed by radioiodine treatment. Following treatment, the whole-body scan did not show any abnormal radioiodine uptake. However, during the follow-up, the serum thyroglobulin (Tg) value increased without detectable thyroglobulin-antibodies. We performed a Ga-68 DOTA-TATE PET/CT showing a sternal lesion and several lung nodules with high somatostatin receptor density. Also, on the next day, FDG PET/CT was performed, which confirmed the findings. Considering the high levels of somatostatin receptor expression in such metastases, we planned lu177 DOTA-TATE therapy. After two cycles of lu177 DOTA-TATE injection, serum thyroglobulin significantly dropped, and she claimed that her sternal pain and dyspnea were much better. This was the case of a patient suffering from iodine-refractory follicular thyroid carcinoma, with somatostatin-receptor expression, treated with 177Lu-DOTA-TATE, showing a significant response.

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Copper homeostasis is strictly regulated by protein transporters and chaperones, to allow its correct distribution and avoid uncontrolled redox reactions. Several studies address copper as involved in cancer development and spreading (epithelial to mesenchymal transition, angiogenesis). However, being endogenous and displaying a tremendous potential to generate free radicals, copper is a perfect candidate, once opportunely complexed, to be used as a drug in cancer therapy with low adverse effects. Copper ions can be modulated by the organic counterpart, after complexed to their metalcore, either in redox potential or geometry and consequently reactivity. During the last four decades, many copper complexes were studied regarding their reactivity toward cancer cells, and many of them could be a drug choice for phase II and III in cancer therapy. Also, there is promising evidence of using 64Cu in nanoparticles as radiopharmaceuticals for both positron emission tomography (PET) imaging and treatment of hypoxic tumors. However, few compounds have gone beyond testing in animal models, and none of them got the status of a drug for cancer chemotherapy. The main challenge is their solubility in physiological buffers and their different and non-predictable mechanism of action. Moreover, it is difficult to rationalize a structure-based activity for drug design and delivery. In this review, we describe the role of copper in cancer, the effects of copper-complexes on tumor cell death mechanisms, and point to the new copper complexes applicable as drugs, suggesting that they may represent at least one component of a multi-action combination in cancer therapy.

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