Search Results (14)

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from β-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to β-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols. Full article

The high energy of α emitters, and the strong linear energy transfer that goes along with it, lead to very efficient cell killing through DNA damage. Moreover, the degree of oxygenation and the cell cycle state have no impact on these effects. Therefore, α radioisotopes can offer a treatment choice to individuals who are not responding to β− or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves ²²⁵Ac and its daughter nuclide ²¹³Bi. Additionally, the ²²⁵Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying ²²⁵Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates. To boost the availability of ²²⁵Ac, along with its clinical and potential theranostic applications, this review attempts to highlight the fundamental physical properties of this α-particle-emitting isotope, as well as its existing and possible production methods. Full article

This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate. Thirteen surrogates for TAT are explored: ¹³³La, ¹³²La, ¹³⁴Ce/¹³⁴La, and ²²⁶Ac for ²²⁵Ac TAT; ²⁰³Pb for ²¹²Pb TAT; ¹³¹Ba for ²²³Ra and ²²⁴Ra TAT; ¹²³I, ¹²⁴I, ¹³¹I and ²⁰⁹At for ²¹¹At TAT; ¹³⁴Ce/¹³⁴La for ²²⁷Th TAT; and ¹⁵⁵Tb and ¹⁵²Tb for ¹⁴⁹Tb TAT. Full article

The actinium-225 (²²⁵Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the ²²⁵Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the ²²⁵Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on ²²⁵Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on ²²⁵Ac is discussed. Quality control measures in the preparation of ²²⁵Ac-conjugates are also highlighted. Full article

Targeted alpha therapy (TAT) has garnered significant interest as an innovative cancer therapy. Owing to their high energy and short range, achieving selective α-particle accumulation in target tumor cells is crucial for obtaining high potency without adverse effects. To meet this demand, we fabricated an innovative radiolabeled antibody, specifically designed to selectively deliver ²¹¹At (α-particle emitter) to the nuclei of cancer cells. The developed ²¹¹At-labeled antibody exhibited a superior effect compared to its conventional counterparts. This study paves the way for organelle-selective drug delivery. Full article

Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides ¹⁷⁷Lu and ²²⁵Ac. This was improved with the dimer DOTAGA.(SA.FAPi)₂, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)₂ and DOTAGA.Glu.(FAPi)₂. were synthesized and quantitatively radiolabeled with ⁶⁸Ga, ⁹⁰Y, ¹⁷⁷Lu and ²²⁵Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [²²⁵Ac]Ac-DOTAGA.Glu.(FAPi)₂ in PBS. In vitro affinity studies resulted in subnanomolar IC₅₀ values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [^natLu]Lu-DOTAGA.Glu.(FAPi)₂. In a first proof-of-principle patient study (medullary thyroid cancer), [¹⁷⁷Lu]Lu-DOTAGA.Glu.(FAPi)₂ was compared to [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂. High uptake and long tumor retention was observed in both cases, but [¹⁷⁷Lu]Lu-DOTAGA.Glu.(FAPi)₂ significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)₂ showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)₂. [¹⁷⁷Lu]Lu-DOTAGA.Glu.(FAPi)₂ and [²²⁵Ac]Ac-DOTAGA.Glu.(FAPi)₂ appear promising for translational application in patients. Full article

Alpha-particle radiotherapy has gained considerable attention owing to its potent anti-cancer effect. ²¹¹At, with a relatively short half-life of 7.2 h, emits an alpha particle within a few cell diameters with high kinetic energy, which damages cancer cells with high biological effectiveness. In this study, we investigated the intravenous injection of ²¹¹At-labeled gold nanoparticles (AuNPs) for targeted alpha-particle therapy (TAT). Different kinds of surface-modified gold nanoparticles can be labeled with ²¹¹At in high radiochemical yield in 5 min, and no purification is necessary. The in vivo biodistribution results showed the accumulation of 5 nm ²¹¹At-AuNPs@mPEG at 2.25% injection dose per gram (% ID/g) in tumors within 3 h via the enhanced permeability and retention (EPR) effect. Additionally, we observed a long retention time in tumor tissues within 24 h. This is the first study to demonstrate the anti-tumor efficacy of 5 nm ²¹¹At-AuNPs@mPEG that can significantly suppress tumor growth in a pancreatic cancer model via intravenous administration. AuNPs are satisfactory carriers for ²¹¹At delivery, due to simple and efficient synthesis processes and high stability. The intravenous administration of 5 nm ²¹¹At-AuNPs@mPEG has a significant anti-tumor effect. This study provides a new framework for designing nanoparticles suitable for targeted alpha-particle therapy via intravenous injection. Full article

Neuroblastoma (NB) represents the most common extracranial tumor of childhood. Prognosis is quite variable, ranging from spontaneous regression to aggressive behavior with wide metastatization, high mortality, and limited therapeutic options. Radiotheranostics combines a radiopharmaceutical pair in a unique approach, suitable both for diagnosis and therapy. For many years, metaiodobenzylguanidine (MIBG), labeled with ¹²³I for imaging or ¹³¹I for therapy, has represented the main theranostic agent in NB, since up to 90% of NB incorporates the aforementioned radiopharmaceutical. In recent years, novel theranostic agents hold promise in moving the field of NB radiotheranostics forward. In particular, SarTATE, consisting of octreotate targeting somatostatin receptors, has been applied with encouraging results, with ⁶⁴Cu-SARTATE being used for disease detection and with ⁶⁷Cu-SARTATE being used for therapy. Furthermore, recent evidence has highlighted the potential of targeted alpha therapy (TAT) for treating cancer by virtue of alpha particles’ high ionizing density and high probability of killing cells along their track. On this path, ²¹¹At-astatobenzylguanidine (MABG) has been developed as a potential agent for TAT and is actually under evaluation in preclinical NB models. In this review, we performed a web-based and desktop literature research concerning radiotheranostic approaches in NB, covering both the radiopharmaceuticals already implemented in clinical practice (i.e.,¹²³/¹³¹1-MIBG) and those still in a preliminary or preclinical phase. Full article

The rationale for application of nanotechnology in targeted alpha therapy (TAT) is sound. However, the translational strategy requires attention. Formulation of TAT in nanoparticulate drug delivery systems has the potential to resolve many of the issues currently experienced. As α-particle emitters are more cytotoxic compared to beta-minus-emitting agents, the results of poor biodistribution are more dangerous. Formulation in nanotechnology is also suggested to be the ideal solution for containing the recoil daughters emitted by actinium-225, radium-223, and thorium-227. Nanoparticle-based TAT is likely to increase stability, enhance radiation dosimetry profiles, and increase therapeutic efficacy. Unfortunately, nanoparticles have their own unique barriers towards clinical translation. A major obstacle is accumulation in critical organs such as the spleen, liver, and lungs. Furthermore, inflammation, necrosis, reactive oxidative species, and apoptosis are key mechanisms through which nanoparticle-mediated toxicity takes place. It is important at this stage of the technology’s readiness level that focus is shifted to clinical translation. The relative scarcity of α-particle emitters also contributes to slow-moving research in the field of TAT nanotechnology. This review describes approaches and solutions which may overcome obstacles impeding nanoparticle-based TAT and enhance clinical translation. In addition, an in-depth discussion of relevant issues and a view on technical and regulatory barriers are presented. Full article

The application of nanotechnology in nuclear medicine offers attractive therapeutic opportunities for the treatment of various diseases, including cancer. Indeed, nanoparticles-conjugated targeted alpha-particle therapy (TAT) would be ideal for localized cell killing due to high linear energy transfer and short ranges of alpha emitters. New approaches in radiolabeling are necessary because chemical radiolabeling techniques are rendered sub-optimal due to the presence of recoil energy generated by alpha decay, which causes chemical bonds to break. This review attempts to cover, in a concise fashion, various aspects of physics, radiobiology, and production of alpha emitters, as well as highlight the main problems they present, with possible new approaches to mitigate those problems. Special emphasis is placed on the strategies proposed for managing recoil energy. We will also provide an account of the recent studies in vitro and in vivo preclinical investigations of α-particle therapy delivered by various nanosystems from different materials, including inorganic nanoparticles, liposomes, and polymersomes, and some carbon-based systems are also summarized. Full article

PD-L1 (programmed death-ligand 1, B7-H1, CD274), the ligand for PD-1 inhibitory receptor, is expressed on various tumors, and its expression is correlated with a poor prognosis in melanoma. Anti-PD-L1 mAbs have been developed along with anti-CTLA-4 and anti-PD-1 antibodies for immune checkpoint inhibitor (ICI) therapy, and anti-PD-1 mAbs are now used as first line treatment in melanoma. However, many patients do not respond to ICI therapies, and therefore new treatment alternatives should be developed. Because of its expression on the tumor cells and on immunosuppressive cells within the tumor microenvironment, PD-L1 represents an interesting target for targeted alpha-particle therapy (TAT). We developed a TAT approach in a human melanoma xenograft model that stably expresses PD-L1 using a ²¹³Bi-anti-human-PD-L1 mAb. Unlike treatment with unlabeled anti-human-PD-L1 mAb, TAT targeting PD-L1 significantly delayed melanoma tumor growth and improved animal survival. A slight decrease in platelets was observed, but no toxicity on red blood cells, bone marrow, liver or kidney was induced. Anti-tumor efficacy was associated with specific tumor targeting since no therapeutic effect was observed in animals bearing PD-L1 negative melanoma tumors. This study demonstrates that anti-PD-L1 antibodies may be used efficiently for TAT treatment in melanoma. Full article

This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including ²²⁵Ac, ²¹³Bi, ²²⁴Ra, ²¹²Pb, ²²⁷Th, ²²³Ra, ²¹¹At, and ¹⁴⁹Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT. Full article

The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [²²⁵Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [²²⁵Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [²²⁵Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [²²⁵Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [¹¹¹In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [²²⁵Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model. Full article

Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date. Full article