Inspired by novel radiopharmaceuticals:Rush hour of nuclear medicine

Nuclear medicine plays an irreplaceable role in the diagnosis and treatment of tumors.Radiopharmaceuticals are important components of nuclear medicine.Among the radiopharmaceuticals approved by the Food and Drug Administration(FDA),radio-tracers targeting prostate-specific membrane antigen(PSMA)and somatostatin receptor(SSTR)have held essential positions in the diagnosis and treatment of prostate cancers and neuroendocrine neoplasms,respectively.In recent years,FDA-approved serials of immune-therapy and targeted therapy drugs targeting programmed death 1(PD-1)/programmed death ligand 1(PD-L1),human epidermal growth factor receptor 2(HER2),and nectin cell adhesion molecule 4(Nectin 4).How to screen patients suitable for these treatments and monitor the therapy?Nuclear medicine with specific radiopharmaceuticals can visualize the expression level of those targets in systemic lesions and evaluate the efficacy of treatment.In addition to radiopharmaceuticals,imaging equipment is also a key step for nuclear medicine.Advanced equipment including total-body positron emission tomography/computed tomography(PET/CT)and positron emission tomography/magnetic resonance imaging(PET/MRI)has been developed,which contribute to the diagnosis and treatment of tumors,as well as the development of new radiopharmaceuticals.Here,we conclude most recently advances of radiopharmaceuticals in nuclear medicine,and they substantially increase the“arsenal”of clinicians for tumor therapy.

PREPARATION OF BONE TUMOR THERAPEUTIC RADIOPHARMACEUTICALS ^(153)Sm-EDTMP

Samarium-153- EDTMP (ethylene diamine tetramethylene phosphonate), for its promising biological properties, has been proved as a palliating therapeutic agent for bone tumor in human beings. 153Sin with high radionuclear purity and specific activity of 5.18 GBq (140 mCi)/mg Sm2O3 was prepared by irradiating naturalSm2O3(152Sm, 26.7%) sample, replacing costly enriched samarium oxide target, at a flux of 4x 1013n.cm-2.s-1 for 110 h. The yield of 153Sm complexing with EDTMP is greater than 98% at PH 8￣10 in boiling water bath for 30 min, and not significantly decreases within one week after 153Sm-EDTMP complex formation.

Potential synergistic implications for stromal-targeted radiopharmaceuticals in bone-metastatic prostate cancer

Genetic heterogeneity and chemotherapy-resistant ＇stem cells＇ represent two of the most pressing issues in devising new strategies for the treatment of advanced prostate cancer. Though curative strategies have long been present for men with localized disease, metastatic prostate cancer is currently incurable. Though substantial improvements in outcomes are now possible through the utilization of newly approved therapies, novel combinations are clearly needed. Herein we describe potentially synergistic interactions between bone stromal-targeted radiopharmaceuticals and other therapies for treatment of bone-metastatic prostate cancer. Radiation has long been known to synergize with cytotoxic chemotherapies and recent data also suggest the possibility of synergy when combining radiation and immune-based strategies. Combination therapies will be required to substantially improve survival for men with castrate-resistant metastatic prostate cancer and we hypothesize that bone-targeted radiopharmaceuticals will play an important role in this Drocess.

Advancement in treatment and diagnosis of pancreatic cancer with radiopharmaceuticals

Pancreatic cancer(PC) is a major health problem. Conventional imaging modalities show limited accuracy for reliable assessment of the tumor. Recent researches suggest that molecular imaging techniques with tracers provide more biologically relevant information and are benefit for the diagnosis of the cancer. In addition,radiopharmaceuticals also play more important roles in treatment of the disease. This review summaries the advancement of the radiolabeled compounds in the theranostics of PC.

Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters

Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer.Different radionuclides that emitβ-rays such as 153Samarium and 89Strontium and achieve palliation are commercially available.In contrast toβ-emitters,223Radium as a a-emitter has a short path-length.The advantage of the a-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms.Due to the limited range of the a-particles the bone surface to red bone marrow dose ratio is also lower for 223Radium which is expressed in a lower myelotoxicity.The a emitter 223Radium dichloride is the first radiopharmaceutical that significantly prolongslife in castrate resistant prostate cancer patients with wide-spread bone metastatic disease.In a phaseⅢ,randomized,double-blind,placebo-controlled study 921patients with castration-resistant prostate cancer and bone metastases were randomly assigned.The analysis confirmed the 223Radium survival benefit compared to the placebo(median,14.9 mo vs 11.3 mo;P<0.001).In addition,the treatment results in pain palliation and thus,improved quality of life and a delay of skeletal related events.At the same time the toxicity profile of223Radium was favourable.Since May 2013,223Radium dichloride(Xofigo?)is approved by the US Food and Drug Administration.

Natural product-based radiopharmaceuticals:Focus on curcumin and its analogs,flavonoids,and marine peptides

Natural products provide a bountiful supply of pharmacologically relevant precursors for the development of various drug-related molecules,including radiopharmaceuticals.However,current knowledge regarding the importance of natural products in developing new radiopharmaceuticals remains limited.To date,several radionuclides,including gallium-68,technetium-99m,fluorine-18,iodine-131,and iodine-125,have been extensively studied for the synthesis of diagnostic and therapeutic radiopharmaceuticals.The availability of various radiolabeling methods allows the incorporation of these radionuclides into bioactive molecules in a practical and efficient manner.Of the radiolabeling methods,direct radioiodination,radiometal complexation,and halogenation are generally suitable for natural products owing to their simplicity and robustness.This review highlights the pharmacological benefits of curcumin and its analogs,flavonoids,and marine peptides in treating human pathologies and provides a perspective on the potential use of these bioactive compounds as molecular templates for the design and development of new radiopharmaceuticals.Additionally,this review provides insights into the current strategies for labeling natural products with various radionuclides using either direct or indirect methods.

Multifunctional Nanostructured Materials Applied in Controlled Radiopharmaceuticals Release

The metaiodobenzylguanidine (MIBG) radiopharmaceutical, an analogue of norepinephrine, has been used to diagnose certain diseases in the cardiovascular system when radiolabeled with 123I. This radiopharmaceutical can also be used to treat tumors, such as neuroblastomas and pheochromocytomas, when radiolabeled with 131I. Its clinical use is often accompanied by a slow intravenous administration, where a significant dose of radiation can directly affect workers in nuclear medicine services. To overcome this problem, the incorporation and controlled release of radiopharmaceuticals from the matrix of mesoporous systems based on silica, such as SBA-15 and hybrid [SBA-15/P(N-iPAAm)], can lead to a significant reduction in radiation doses received by workers. In the present study, silica matrices SBA-15 and hybrid [SBA-15/P(N-iPAAm)] containing the radiopharmaceutical MIBG were prepared and physicochemically characterized through FTIR, SEM, and small angle X-ray diffraction techniques. The release profiles of MIBG from SBA-15 and [SBA-15/P(N-iPAAm)] were studied in a simulated body fluid (SBF) to evaluate their potential application as vehicles for controlled releases. Furthermore, in vitro studies were performed to assess the cytotoxicity of matrices as compared to human lung fibroblast cells (MRC-5). The results revealed that the amount of MIBG incorporated within the studied matrices was indeed quite different, showing that only the hybrid [SBA-15/P(N-iPAAm)] system allowed for a more adequate release profile of MIGB. Taking all results into consideration, it can be concluded that the hybrid matrix [SBA-15/P(N-iPAAm)] can be considered a potential alternative material for the controlled release delivery of radio-pharmaceuticals.

Recent progress of astatine-211 in endoradiotherapy:Great advances from fundamental properties to targeted radiopharmaceuticals

Astatine-211(^(211)At,t_(1/2)=7.21 h)emitting twoαparticles with energies of 5.87 and 7.45 MeV,can lead to a high linear energy transfer(LET=98.84 ke V/μm)and short tissue range(50~90μm).Since the 1950s,^(211)At had stepped into endoradiotherapy and has always been regarded as one of the most promisingα-emitters for targeted-alpha therapy(TAT)in various malignancies.In the past two decades,^(211)At related radiopharmaceuticals have achieved great progress in the studies of basic physicochemical properties of astatine,^(211)At labeling strategies,preclinical and clinical studies,producing profound effects in nuclear medicine.This work will give a panorama of^(211)At-related researches in the recent 20 years,which will cover both the fundamental insights of^(211)At radiochemistry and applied labeling compounds.It can provide some important hints for the studies of TAT and other radiopharmaceuticals applied in tumor radiotherapy.

A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy

Polyamine metabolism dysregulation is a hallmark of many cancers,offering a promising avenue for early tumor theranostics.This study presents the development of a nuclear probe derived from spermidine(SPM)for dual-purpose tumor PET imaging and internal radiation therapy.The probe,radiolabeled with either[68Ga]Ga for diagnostic applications or[177Lu]Lu for therapeutic use,was synthesized with exceptional purity,stability,and specific activity.Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells,showcasing outstanding tumor localization and target-to-non-target ratio.Mechanistic investigations employing polyamines,non-labeled precursor,and polyamine transport system(PTS)inhibitor,consistently affirmed the probe?s targetability through recognition of the PTS.Notably,while previous reports indicated PTS upregulation in various tumor types for targeted therapy,this study observed no positive signals,highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis.Furthermore,when labeled with[177Lu],the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival.Investigations into biodistribution,excretion,and biosafety in healthy humans laid a robust foundation for clinical translation.This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics,offering promising prospects for clinical implementation.

Comparison of quality control standards of PET radiopharmaceuticals for tumor in Pharmacopoeia of Europe,the United States and People’s Republic of China

To improve the relevant methods of the quality control standards of tumor Positron Emission Computed Tomography(PET)radiopharmaceuticals and to reduce the clinical application risks of such drugs,this article compares and analyzes the similarities and differences of the quality control standards of tumor PET radiopharmaceuticals in the Pharmacopoeia of People’s Republic of China(ChP2020),European Pharmacopoeia(EP8.0)and United States Pharmacopoeia(USP39),focusing on comparing and analyzing the identification(identification method),inspection(pH,residual solvent,bacterial endotoxin,sterility,and impurities),and content determination(radionuclear purity,radiochemical purity,and radioactive concentration)of tumor PET radiopharmaceuticals.The quality control standards of ChP2020 for tumor PET radiopharmaceuticals are relatively equivalent to the quality control standards of USP39 but are not as stringent as those of EP8.0.In general,EP8.0 has the most comprehensive and strict quality control standards for tumor PET radiopharmaceuticals.The quality control standards of tumor PET radiopharmaceuticals in the Chinese Pharmacopoeia can be improved by referring to international standards,especially the European Pharmacopoeia.

Current update on nanoplatforms as therapeutic and diagnostic tools:A review for the materials used as nanotheranostics and imaging modalities

In the last decade,the use of nanotheranostics as emerging diagnostic and therapeutic tools for various diseases,especially cancer,is held great attention.Up to date,several approaches have been employed in order to develop smart nanotheranostics,which combine bioactive targeting on specific tissues as well as diagnostic properties.The nanotheranostics can deliver therapeutic agents by concomitantly monitor the therapy response in real-time.Consequently,the possibility of over-or under-dosing is decreased.Various non-invasive imaging techniques have been used to quantitatively monitor the drug delivery processes.Radiolabeling of nanomaterials is widely used as powerful diagnostic approach on nuclear medicine imaging.In fact,various radiolabeled nanomaterials have been designed and developed for imaging tumors and other lesions due to their efficient characteristics.Inorganic nanoparticles as gold,silver,silica based nanomaterials or organic nanoparticles as polymers,carbon based nanomaterials,liposomes have been reported asmultifunctional nanotheranostics.In this review,the imaging modalities according to their use in various diseases are summarized,providing special details for radiolabeling.In further,the most current nanotheranostics categorized via the used nanomaterials are also summed up.To conclude,this review can be beneficial for medical and pharmaceutical society as well as material scientists who work in the field of nanotheranostics since they can use this research as guide for producing newer and more efficient nanotheranostics.

Radium-223 in metastatic castration resistant prostate cancer

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer （mCRPC）. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleuceI-T, cabazitaxel, abiraterone, enzalutamide and （most recently） radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer （e.g. samarium-153 and strontium-89）, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

Structural Investigation of Technetium-Diphosphonate Complex 99mTc-MDP

Density functional theory method has been employed to investigate the structures of the prototypical technetium-labeled diphosphonate complex 99mTc-MDP, where MDP represents methylenediphosphonic acid. A total of 14 trial structures were generated by allowing for the geometric, conformational, charge, and spin isomerism. Based on the optimized structures and calculated energies at the B3LYP/LANL2DZ level, two stable isomers were determined for the title complex. And they were further studied systematically in comparison with the experimental structure. The basis sets 6-31G＊（LANL2DZ for Tc）, 6-31G＊（cc-pVDZ-pp for Tc）, and DGDZVP have also been employed in combination with the B3LYP functional to study the basis set effect on the geometries of isomers. The optimized structures agree well with the available experimental data, and the bond lengths are more sensitive to the basis set than the bond angles. The charge distributions were studied by the Mulliken population analysis and natural bond orbital analysis. The results reflect a significant ligand-to-metal electron donation.

177Hf as a Competitor in the Synthesis of 177Lu-DOTAtate

This study reveals the interference of 177Hf, a decay product of 177Lu, in the synthesis of 177Lu-DOTAtate, In the experiments we followed three 177Lu t1/2. The molar ratio Lu： DOTAtate used was calculated for each decay, in two situations： 1） without considering the influence of 177Hf; 2） considering the influence of 177Hf. The results compare both the calculated molar ratio and the radionuclide incorporation yields （%） in these situations. The yields increase when 177Hf influence is considered. This suggests that 177Hf is an important competitor for DOTAtate binding site. These data are relevant in the synthesis of the radiopharmaceutical 177Lu-DOTAtate with high specific activity.

What Is Exactly the Scope of Nuclear Chemistry and Its Educational Position between Other Chemistry Branches

The undergraduate chemistry programs of different universities across the world show clearly that nuclear chemistry education doesn’t have a permanent status in chemistry curricula like classical sub-branches of chemistry which means like organic, inorganic, analytical, physical, and biochemistry. Before starting the evaluation of the status of nuclear chemistry education, first of all, nuclear chemistry should correctly be defined and its position in chemistry education programs should correctly be determined. In addition, a confusion of terminology or at least, a terminological turbulence exists in this branch of chemistry about the use of terms such as nuclear chemistry, radiochemistry, nuclear and radiochemistry. Also, the scopes of the expressions used in this field such as radiochemistry, radiation chemistry, radiopharmaceutical chemistry, etc. should be exactly defined and the realtions between them should be clearly understood. Breifly, nuclear chemistry may be difined as a large umbrella which covers all chemical studies related to radioactive materials and nuclear radiation including the fine sub-branches such as radiochemistry, radiation chemistry, radioanalytical chemistry, radiopharmaceutical chemistry, environmental radiochemistry. If these are not done, the educational problems in nuclear chemistry could not be correctly investigated and the remedies could not be correctly determined.

Comparison between Two Ethanolic Solutions for 3’-Deoxy-3’-[¹⁸F]Fluorothymidine Elution

3’-Deoxy-3’-[18F]Fluorothymidine—[18F]FLT is a Positron Emission Tomography (PET) tracer which has been used for noninvasive assessment of proliferation activity in several types of cancer. During the past few years, some novel approaches for [18F]FLT synthesis have been developed, mainly focused on optimization of reaction conditions and purification methods. The present study reports the use of two different eluents in the final step of [18F]FLT production and the evaluation of its effect on radiochemical yield and product quality. The first eluent evaluated was water: ethanol (90:10, v/v), commercially available, and the second was NaCl 0.9% (saline): ethanol (92:8, v/v). The mean of the corrected radiochemical yields corresponded to 27% ± 7% for elution with water and ethanol and to 23% ± 3% for elution with saline and ethanol, which could indicate that the eluent solutions have similar elution strength. Besides, quality control results were in accordance with the requirements and demonstrated that there was no significant difference between both formulations. Considering that pharmaceutical preparations containing ethanol should be preferentially diluted with saline to avoid hemolysis, the eluent saline:ethanol (92:8, v/v) was chosen for [18F]FLT extraction and final formulation.

Synthesis and Radiation Dosimetry of [⁶⁸Ga]-Ga-Lys¹, Lys³-DOTA-Bombesin (1,14) Antagonist for PET-Imaging, as a Potential Theragnostic Tracer in Oncology

This Bombesin (BBN), a tetradecapeptide analog of human gastrin-releasing peptide (GRP) with a high binding affinity for GRP receptors (GRPR), is over- expressed in early stages of androgen-dependent prostate carcinomas, but not in advanced stages. Therefore, there is a need to develop effective tracers for the accurate and specific detection of this disease. The objective of this study was to evaluate Lys1, Lys3-DOTA-BBN (1,14) analog with the radiolabeled positron emitter [68Ga]-Ga-BBN for receptor imaging with PET, and to determine its biodistribution and radiation dosimetry using whole-body (WB) PET scans in healthy volunteers. The highest uptake was in the pancreas, followed by urinary bladder. The critical organ was pancreas with a mean absorbed dose of 206 ± 0.7, 210 ± 0.7, 120 ± 0.9, 390.23 ± 0.6 μGy/MBq and the effective doses were estimated as 73.2 ± 0.6, 49.8 ± 0.3 μGy/MBq (women and men, respectively).

Locally unlocks prodrugs by radiopharmaceutical in tumor for cancer therapy

Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumorselective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [^(18)F]FDG(2-[^(18)F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide18F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note,an OxaliPt(IV) linker is designed to construct an [^(18)F]FDG-activated antibody-drug conjugate(Pt-ADC).Sequential injection of Pt-ADC and [^(18)F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation,and we find that [^(18)F]FDG is capable of deprotecting various radiotherapy-removable protecting groups(RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.

The application of FAPI-targeted theranostics in pancreatic cancer:a narrative review

Pancreatic cancer is one of the most lethal malignancies in the world.Cancer-associated fibroblasts are one of the main components of tumor microenvironment in pancreatic cancer and play an essential role in tumor progression.Fibroblast activation protein that is expressed in specific subtypes of cancer-associated fibroblasts promotes tumor growth and is related to poor survival.Recent researches have preliminarily demonstrated a promising potential of radiopharmaceuticals targeting fibroblast activation protein in diagnosis and therapy of pancreatic cancer.This article comprehensively reviews the current development and clinical translation of fibroblast activation protein inhibitor-targeting radiopharmaceuticals in pancreatic cancer and provides significant perspectives for future investigations.

Bone-targeted therapies to reduce skeletal morbidity in prostate cancer

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including （1） bisphosphonates such as zoledronic acid, which directly target osteoclasts, （2） denosumab, a receptor activator of nuclear factor-kappa B （RANK） ligand inhibitor, which targets a key component of bone stromal interaction, and （3） radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer （mCRPC）. Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.