Clinical aspects of radiolabeled aptamers in diagnostic nuclear medicine: A new class of targeted radiopharmaceuticals

Targeted radiopharmaceuticals offer the possibility of improved imaging with reduced side effects. Up to now, a variety of biological receptors such as aptamers have been successfully radiolabeled and applied to diagnostic imaging of cancers. The concept of using radio-labeled aptamers for binding to their targets has stimulated an immense body of research in diagnostic nuclear medicine. These biological recognition elements are single-stranded oligonucleotides that interact with their target molecules with high affinity and specificity in unique three-dimensional structures. Because of their high affinity and specificity, the receptor-binding aptamers labeled with gamma emitters such as ^99mTc, ⁶⁴Cu, ¹¹¹In, ¹⁸F and ⁶⁷Ga can facilitate the visualization of receptor-expressing tissues noninvasively. Compared to the antibody-based radiopharmaceuticals, the radiolabeled aptamers provide a number of advantages for clinical diagnostics including high stability, low cost, and ease of production and modification, low immunogenicity and, especially, superior tissue penetration because of their smaller size. In this review, we present recent progresses and challenges in aptamer-based diagnostic radiopharmaceuticals and highlight some representative applications of aptamers in nuclear medicine.     

Anti-melanoma efficacy of internal radionuclide therapy in relation to melanin target distribution

Targeted internal radionuclide therapy (TRT) could be an efficient, specific way to treat disseminated melanoma. Based on a previous pharmacomodulation study, we selected a quinoxaline-derived molecule (ICF01012) for its melanin specificity and kinetic properties suitable for TRT. Here, we determined the efficacy of [¹³¹I]ICF01012 radiotherapy in vitro and in vivo in relation to melanogenesis using human melanoma models. [¹²⁵I]ICF01012 uptake was first assessed in relation to melanin content. We found that melanin distribution in different models was representative of pathology seen in human tumours: melanin content was high in the extracellular space of SKMel3 tumours, and accumulated primarily in melanophages in M4Beu tumours. Targeted [¹³¹I]ICF01012 radiotherapy had a strong anti-tumoural efficacy in pigmented versus unpigmented tumours, regardless of target distribution and content. This study supports the use of melanin targeting with ¹³¹I-labelled iodoquinoxaline for effective treatment of melanoma.     

Reducing the renal retention of low- to moderate-molecular-weight radiopharmaceuticals

The field of nuclear imaging and therapy is rapidly progressing with the development of targeted radiopharmaceuticals that show rapid targeting and rapid clearance with minimal background. Unfortunately, they are often reabsorbed in the kidneys, leading to possible nephrotoxicity, limiting the therapeutic dose, and/or reducing imaging quality. The blocking of endocytic receptors has been extensively used as a strategy to reduce kidney radiation. Alternatively, the physicochemical properties of radiotracers can be modulated to either prevent their reuptake or promote the excretion of radiometabolites. Other interesting strategies focus on the insertion of a cleavable linker between the radiolabel and the targeting moiety or pretargeting approaches in which the targeting moiety and radiolabel are administered separately. In the context of this review, we will discuss the latest advances and insights on strategies used to reduce renal retention of low- to moderate-molecular-weight radiopharmaceuticals.     

Assessment of radionuclide impurities in [18F]fluoromethylcholine ([18F]FMCH)

Purpose[¹⁸F]Fluoromethylcholine ([¹⁸F]FMCH) is a radiopharmaceutical used in positron emission tomography (PET) imaging for the study of prostate, breast, and brain tumors. It is usually synthesized in cyclotron facilities where ¹⁸F is produced by proton irradiation of [¹⁸O]H₂O through ¹⁸O(p,n)¹⁸F reaction. Due to the activation of target materials, the bombardment causes unwanted radionuclidic impurities in [¹⁸O]H₂O, that need to be removed during the radiopharmaceutical synthesis. Thus, the aim of this study is to quantify the radionuclide impurities in the ¹⁸F production process and in the synthesized [¹⁸F]FMCH, demonstrating the radionuclidic purity of this radiopharmaceutical.MethodsLong-lived radionuclide impurities were experimentally assessed using high-resolution gamma and liquid scintillation spectrometries, while short-lived impurities were monitored analyzing the decay curve of the irradiated [¹⁸O]H₂O with an activity calibrator. As spectrometric radionuclide library, a Geant4 Monte Carlo simulation of the ¹⁸F-target assembly was previously performed.Results³H, ^52,54Mn, ^56,57,58Co, ^95m,96Tc, ¹⁰⁹Cd, and ¹⁸⁴Re were found in the irradiated [¹⁸O]H₂O, but no radionuclide was found in the non-irradiated [¹⁸O]H₂O neither in the final [¹⁸F]FMCH solution with an activity concentration greater than the minimum detectable activity concentration. A total impurity activity <6.2 kBq was measured in the irradiated [¹⁸O]H₂O, whereas a [¹⁸F]FMCH radionuclide purity >99.9999998% was estimated. Finally, the decay curve of the irradiated [¹⁸O]H₂O revealed a very low maximum of ¹³N activity (<0.03% of ¹⁸F) even immediately after the end of bombardment.ConclusionsThis study demonstrated the radionuclidic purity of [¹⁸F]FMCH according to the EU Pharmacopeia.     

Construction of human naïve fab library and characterization of anti-met fab fragment generated from the library

Inappropriate expression of the receptor tyrosine kinase Met and its ligand hepatocyte growth factor (HGF)/scatter factor (SF) is usually associated with an aggressive solid tumor phenotype (angiogenesis, invasiveness, and metastasis) and poor clinical prognosis. We report here the design and construction of a large, human naïve antigen-binding fragment (Fab) phage-display library with a diversity of 2.0×10⁹, which allows rapid isolation of antigen-specific human antibody fragments. A Fab fragment specifically against Met (designated hFab-Met-1) was successively selected from this library by using biopanning on Met-transfected cell line S114. The specificity of hFab-Met-1 was characterized by immunoprecipitation, Western blotting, and flow cytometry. The results demonstrate that hFab-Met-1 reacts with the extracellular domain of Met in its native conformation. Moreover, functional analysis by Madine-Darby canine kidney cell scattering and urokinase-type plasminogen activator assays demonstrated that hFab-Met-1 is not an agonist to HGF/Met signaling compared with a murine intact monoclonal antibody (MAb) Met5. To confirm that hFab-Met-1 interacts with Met-expressing tumors in vivo, I-125-labeled hFab-Met-1 was nuclear-imaged in a mouse xenograft of Met- and HGF/SF-expressing human leiomyosarcoma. Total body scintigrams were obtained between 1 and 48 h postinjection (PI). Tumor-associated activity was imaged as early as 1 h PI, and remained visible in some animals as late as 24 h PI. As expected, activity was highest in the kidneys in early images, whereas thyroid activity became predominant in later images. In conclusion, hFab-Met-1 interacts with Met both in vitro and in vivo, and is a promising candidate for clinical diagnosis and therapeutics.     

Updated Review of Nuclear Molecular Imaging of Thyroid Cancers

ObjectivesWe initiate this comprehensive review to update the advances in this field by objectively elucidating the efficacies of promising radiopharmaceuticals.MethodsWe performed a comprehensive PUBMED search using the combined terms of “thyroid cancer” and “radiopharmaceuticals” or “nuclear medicine”, yielding 3273 and 11026 articles prior to December 31, 2020, respectively.ResultsBased on the mechanism of molecular metabolism, the evaluation of differentiated thyroid cancer and dedifferentiated thyroid cancer is largely centered around radioiodine and fluorine 18 (¹⁸F)-fludeoxyglucose, respectively. Further, ¹⁸F-L-dihydroxyphenylalanine and gallium 68 DOTATATE are the preferred tracers for medullary thyroid cancer. In dedifferentiated medullary thyroid cancer and anaplastic thyroid cancer, ¹⁸F-fludeoxyglucose is superior.ConclusionsThe future lies in advances in molecular biology, novel radiopharmaceuticals and imaging devices, paving ways to the development of personalized medication for thyroid cancer patients.