Rhenium-188 is prospectively effective for both diagnosis and radiotherapy as it appropriately emits gamma rays and beta particles.Lacosamide(LCM)is a newly approved antiepileptic medication for focal drug-resistant e...Rhenium-188 is prospectively effective for both diagnosis and radiotherapy as it appropriately emits gamma rays and beta particles.Lacosamide(LCM)is a newly approved antiepileptic medication for focal drug-resistant epilepsy.Rhenium-188 was separated with high elution yield and high purity using the new 188W/188Re generator based on the ZrSiW gel matrix.188Re-LCM was prepared with high radiochemical yield and high purity.Biodistribution of 188Re-LCM in normal Swiss albino mice was investigated to determine its utility as a potential brain therapy agent.The 188W/188Re generator was used to obtain 188Re based on the ZrSi188W gel matrix,and the chemical,radiochemical,and radionuclidic purity of the obtained 188Re was determined using inductively coupled plasma optical emission spectrometry(ICP-AES),a paper chromatography technique,and high-purity germanium(HPGe)detection,respectively,to assess its validity for LCM labeling.Various factors,such as the pH,reaction time,and LCM quantity,were therefore studied in order to improve the yield and purity of 188Re-LCM,as determined by various chromatographic techniques such as electrophoresis,thin layer chromatography(TLC),and highpressure liquid chromatography(HPLC).188Re was obtained with a high elution yield(75±3%)and a low 188W breakthrough(0.001±0.0001%).The maximum radiochemical yield of 188Re-LCM(87.5±1.8%)was obtained using 50 ll LCM(4 mM),250 ll stannous chloride(4.4 mM)at pH 4,100 ll 188Re(37 MBq),within 30 min,at room temperature(25±3C),as determined by TLC,electrophoresis,and HPLC techniques.Biodistribution analysis showed that 188Re-LCM was primarily localized in the brain(5.1%)with a long residence time(240 min).展开更多
As a robust platform for genome editing,CRISPR/Cas9 is currently being explored for engineering biology or therapeutics,yet means for quantitative detection of Cas9 proteins remain to be fully realized.Here,we express...As a robust platform for genome editing,CRISPR/Cas9 is currently being explored for engineering biology or therapeutics,yet means for quantitative detection of Cas9 proteins remain to be fully realized.Here,we expressed Cas9 proteins and developed a novel detection method that traced Cas9 based on radiolabeled iodine.Through optimizing the reaction conditions of reaction time,temperature and cycles,we obtained ^(125)I-Cas9 of high labeling yield.The prepared ^(125)I-Cas9 was stable in various media and preserved excellent genome editing efficiency.Thus,our strategy provides a convenient and efficient tool for further tracing biological behaviors of Cas9 proteins in living systems.展开更多
Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolutionizing drug dis...Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolutionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase III clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by establishing a physiologically based pharmacokinetics(PBPK)model.For in vitro–in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.展开更多
IBI351,a synthetic compound,exerts its anti-tumor effects by specifically,covalently,and irreversibly modifying the 12th cysteine residue of KRAS G12C.However,the pharmacokinetic profile of IBI351 in humans has not ye...IBI351,a synthetic compound,exerts its anti-tumor effects by specifically,covalently,and irreversibly modifying the 12th cysteine residue of KRAS G12C.However,the pharmacokinetic profile of IBI351 in humans has not yet been reported.The current study aimed to investigate the pharmacokinetics and safety of IBI351 in healthy Chinese male subjects.A single oral dose of 600 mg combined with 150μCi[^(14)C]IBI351 was administered to six healthy male volunteers.Blood,urine,and fecal samples were collected at multiple time points to quantify the parent drug and its metabolites.IBI351 showed favorable pharmacokinetic characteristics and was well tolerated by all participants.Seventeen major metabolites were identified in plasma,urine,and feces.The main metabolic pathways included oxidation,hydrogenation,sulfonate conjugation,glucuronide conjugation,and cysteine conjugation.Excretion of IBI351 and its metabolites occurred mainly through feces.Collectively,this first-in-human study provides essential data on the metabolism and safety of IBI351 in Chinese subjects and lays the foundation for its further clinical development as a novel anti-tumor drug.展开更多
AIM:To explore and compare the radiochemical behavior and biological property of anti-sense oligonuc-leotide (ASON) labeled with technetium-99m using N-hydroxysuccinimidyl S-acetylmercaptoacetyltriglycl ine (NHS-MAG3)...AIM:To explore and compare the radiochemical behavior and biological property of anti-sense oligonuc-leotide (ASON) labeled with technetium-99m using N-hydroxysuccinimidyl S-acetylmercaptoacetyltriglycl ine (NHS-MAG3) and hydrazinonictinamide derivative (HYNIC). METHODS:After HYNIC and NHS-MAG3 were synthesized, ASON was labeled with technetium-99m using HYNIC and NHS-MAG3 as a bifunctional chelator. The in vivo and in vitro stability, binding rates of labeled compounds to serum albumen, biodistribution of 99mTc-MAG3-ASON and 99mTc-HYNIC-ASON in BALB/C mouse and its HT29 tumor cellular uptake were compared. RESULTS:The labeling efficiency and stability of 99mTc-MAG3-ASON were significantly higher than those of 99mTc-HYNIC-ASON (P = 0.02, and P = 0.03, respectively). 99mTc-MAG3-ASON had a significantly lower rate of binding to serum albumen than 99mTc-HYNIC-ASON (P < 0.05). In contrast to 99mTc-HYNIC-ASON, the biodistribution of 99mTc-MAG3-ASON was significantly lower in blood, heart, liver and stomach (P < 0.05), slightly lower in intestines and spleen (P > 0.05) and significantly higher in lung and kidney (P < 0.05). The HT29 tumor cellular uptake rate of 99mTc-MAG3-ASON was significantly higher than that of 99mTc-HYNIC-ASON (P < 0.05). CONCLUSION:99mTc-MAG3-ASON shows superior radiochemical behaviors and biological properties than 99mTc-HYNIC-ASON. 99mTc-MAG3-ASON is a potential radiopharmaceutical agent for in vivo application.展开更多
The prevalence of positron emission tomography(PET)imaging has advanced biomedical applications for its ultrahigh sensitivity,deep tissue penetration and quantitative visualization of diseases in vivo.^(64)Cu with ide...The prevalence of positron emission tomography(PET)imaging has advanced biomedical applications for its ultrahigh sensitivity,deep tissue penetration and quantitative visualization of diseases in vivo.^(64)Cu with ideal half-life and decay characteristics has been designed as radioactive probes for disease diagnosis.The currently reported ^(64)Cu-labeled nanomaterials have the advantages of long circulation time in serum,good biocompatibility and mature preparation methods,and have been used in vivo PET imaging,biodistribution and pharmacokinetic monitoring,and imaging guided therapy.At the same time,suitable carrier characteristics and radiolabeling strategies are particularly important in the ^(64)Cu PET imaging process.In this review,we summarize different imaging probe designs and ^(64)Cu radiolabeling strategies,as well as their eventual applications in biomedicine.The potential challenges and prospects of ^(64)Cu labeled nanomaterials are also described,which provides broad prospects for radiolabeling strategies and further applications.展开更多
Targeted alpha-therapy(TAT) is increasingly attractive due to its extraordinary antitumor efficacy.However,the supply of α-emitters for TAT is insufficient and under control by a limited number of countries.^(212)Pb ...Targeted alpha-therapy(TAT) is increasingly attractive due to its extraordinary antitumor efficacy.However,the supply of α-emitters for TAT is insufficient and under control by a limited number of countries.^(212)Pb is a promising α-emitter with an optimal half-life(10.6 h) and favored decay chain.Of interest,^(212)Pb can be extracted directly from natural thorium,which may be abundant in the mining waste of rare-earth,uranium,etc.Indeed,radioactive thorium waste has been a longstanding environmental challenge that needs immediate action.Developing an on-demand and facile process to isolate ^(212)Pb from natural thorium would be ideal to meet the above challenges,yet is difficult.In theory,the ratio of ^(212)Pb tonatTh is below 10^(-13)in commercially available thorium salts.As a pilot study,2.2 MBq of ^(212)Pb was successfully extracted from a 5 L solution of thorium nitrate by using a Pb-selective resin.The radiochemical purity of ^(212)Pb is over 99.9% according to gamma-ray analysis.The purified^(212)Pb was applied to radiolabel a couple of peptides used in clinics(i.e.PSMA,TATE and FAPI-04),and the radiochemical yields are>85%.Of note,^(212)Pb can be repeatedly separated from the thorium solution every 2 days.In summary,a practical and scalable method was developed to isolate^(212)Pb for potentially clinical use,which may be of great importance as it does not require either cyclotron or nuclear reactor.展开更多
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 importa...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.展开更多
Peptides have an important role in organism and its high quantity present in tumors leading to development of radiolabeled peptides for tumor-specific imaging. Once the traditional methodologies used for radiofluorina...Peptides have an important role in organism and its high quantity present in tumors leading to development of radiolabeled peptides for tumor-specific imaging. Once the traditional methodologies used for radiofluorination do not work with peptides, due to their harsh conditions, other radiolabeling strategies had to be developed to supply the need. Direct radiofluorination is either an inefficient method, and the use of bidirectional groups, or prosthetic groups, is needed to enable the binding between the radionuclide fluorine-18 and a peptide functionalized. New peptides radiolabeling strategies have been developed sourcing increase the synthesis yield, its chemoselectivity, and the binding stability, and reduce the total process time and the number of steps required. The progress of radiofluorination methodologies led to development of the amidation, acylation, imidation, and alkylation techniques, the use of thiol groups, photochemical conjugation, chemoselective reactions, and “click chemistry”, in addition to use of FDG molecule and heteroatoms as linkers. This paper presents the main strategies used for peptides radiofluorination, presenting their positive and negative points, and the prosthetic groups most used in each method.展开更多
The thiol components of the nonhistone proteins prepared from isolated nuclei from rat liver, regenerating liver and hepatoma 223 cells have been investigated after reaction with radio labelled N-ethylmaleimide and 5-...The thiol components of the nonhistone proteins prepared from isolated nuclei from rat liver, regenerating liver and hepatoma 223 cells have been investigated after reaction with radio labelled N-ethylmaleimide and 5-5’-dithiobis-(2-nitrobenzoic acid) (DTNB). The labelled adducts formed were examined by isoelectric focusing analysis in polyacrylamide gel and the distribution of the radiolabels within sliced portions of the gels determined. In the case of the 14C labelled NEM adduct the label was found to be spread amongst numerous protein components within the gel however, in the case of the 35S labelled DTNB adducts, only a small proportion of the label was found in the protein material which was retained in the acidic isoelectric point (pI) region of the gel. The bulk of the 35S labelled adduct (56% - 60%) was found to have migrated into the anode solution (10 mM phosphoric acid). This could be adsorbed onto a hydrophobic resin (XAD2) resin and eluted with methanol. Gel filtration chromatographic analysis of this adduct material on BioGel P2, (exclusion limit 1500 daltons) showed low molecular weight components to be present. Slightly different patterns were obtained for these nuclei, each containing several 35S components with molecular weights greater than the Ellman reagent itself. These 35S labelled thiol components did not contain any protein, peptide or amino acid components indicating strongly that a novel species of thiols could be present in these nuclei bound within the non-histone protein matrices.展开更多
99mTc-labelled metallothionein (99mTc-MT) was prepared through both direct and transcomplexation labelling approaches. Buffer systems and a variety of other parameters in the direct labelling procedure were studied in...99mTc-labelled metallothionein (99mTc-MT) was prepared through both direct and transcomplexation labelling approaches. Buffer systems and a variety of other parameters in the direct labelling procedure were studied in detail. High radiolabelling yields of 93-96% and the specific radioactivity of 3.7 MB/μg were obtained under optimal conditions by the direct labelling method. The prepared 99mTc-MT was stable in vitro. The chelate-exchange kinetics of MT with 99mTc-glucohepatonate and 99mTc-citrate were also studied. Biodistribution and imaging studies showed that 99mTc-MT was accumulated in the animal kidneys at an exceptionally high level, indicating that 99mTc-MT might be a potential renal imaging agent.展开更多
Increased nighttime respiratory losses decrease the amount of photoassimilates available for plant growth and yield. We hypothesized that the increased respiratory carbon loss under high night temperatures(HNT) could ...Increased nighttime respiratory losses decrease the amount of photoassimilates available for plant growth and yield. We hypothesized that the increased respiratory carbon loss under high night temperatures(HNT) could be compensated for by increased photosynthesis during the day following HNT exposure. Two rice genotypes, Vandana(HNT-sensitive) and Nagina 22(HNT-tolerant), were exposed to HNT(4 ℃ above the control) from flowering to physiological maturity. They were assessed for alterations in the carbon balance of the source(flag leaf) and its subsequent impact on grain filling dynamics and the quality of spatially differentiated sinks(superior and inferior spikelets). Both genotypes exhibited significantly higher night respiration rates. However, only Nagina 22 compensated for the high respiration rates with an increased photosynthetic rate, resulting in a steady production of total dry matter under HNT. Nagina 22 also recorded a higher grain-filling rate, particularly at 5 and 10 d after flowering, with 1.5- and 4.0-fold increases in the translocation of ^(14)C sugars to the superior and inferior spikelets, respectively. The ratio of photosynthetic rate to respiratory rate on a leaf area basis was negatively correlated with spikelet sterility, resulting in a higher filled spikelet number and grain weight per plant, particularly for inferior grains in Nagina 22. Grain quality parameters such as head rice recovery, high-density grains, and gelatinization temperature were maintained in Nagina 22. An increase in the rheological properties of rice flour starch in Nagina 22 under HNT indicated the stability of starch and its ability to reorganize during the cooling process of product formation. Thus, our study showed that sink adjustments between superior and inferior spikelets favored the growth of inferior spikelets, which helped to offset the reduction in grain weight under HNT in the tolerant genotype Nagina 22.展开更多
α,ε-N,N'-bis(L-cysteinyl)-L-lysine was synthesized and char- acterized for the first time.It was then employed as a bifunctional chelating agent to chelate technetium-99m and subsequently conjugated to fragment ...α,ε-N,N'-bis(L-cysteinyl)-L-lysine was synthesized and char- acterized for the first time.It was then employed as a bifunctional chelating agent to chelate technetium-99m and subsequently conjugated to fragment F(ab')_2 of anti-gastric tumor monoclonal antibody 3G9.The radiolabelled antibody was satisfactorily stable and immunoreactive.展开更多
Carbon-11 radiolabeled amines constitute a very important class of radioligands that are widely used for positron emission tomography (PET) imaging. Radiolabeling of amines is often achieved through radiomethylation u...Carbon-11 radiolabeled amines constitute a very important class of radioligands that are widely used for positron emission tomography (PET) imaging. Radiolabeling of amines is often achieved through radiomethylation using [11C]CH3I or [11C]CH3OTf under basic conditions in a strictly anhydrous environment. Functional groups such as hydroxyl and carboxyl groups that are often present in the molecules are normally base sensitive and require protection and deprotection, which substantially prolongs and complicates the radiolabeling process. Here we report a versatile approach to a series of C-11 radiolabeled amines prepared through reductive amination using [11C]formaldehyde. Using a variety of substrates bearing different functional groups, we demonstrate the general utility of this method. In contrast to conventional radiomethylation methods, the reductive amination using [11C]formaldehyde can be carried out in an aqueous environment relatively quickly without the need of protection of base-sensitive functional groups.展开更多
Molecular imaging techniques are increasingly being used in the localization of disease, the staging of disease and for therapy control. The objective of current study focused on the optimization of synthesis, quality...Molecular imaging techniques are increasingly being used in the localization of disease, the staging of disease and for therapy control. The objective of current study focused on the optimization of synthesis, quality control, in vitro and in vivo evaluation of 123I radiopharmaceuticals based on the chemotactic peptide N-formyl-Met-Leu-Phe. Labeling studies were done both by direct method using chloramine-Y according to Khawli （1989） and indirect method using [125I and 131I] S1B according to Zalutsky （1987）. Then, biodistribution studies were performed both in normal mice and the one bearing 50 laL turpentine for 24h, promoted inflammation in right leg. Furthermore, the ability of the labeled peptide conjugate to bind to human polymorph nuclear leukocytes was determined using in vitro assay. With increasing in pl-l, yield of labeled FMLF （N-formyl-Met-Leu-Phe） decreased perhaps because of interaction OH to carboxyl group of SIB. The maximum activity was observed in the right leg which injected with turpentine due to infection and increase in blood circulation. Also, this peptide was conjugated to PMN （Poly morph nuclear） specifically and maximum activity was 66%. The highest absorption of FLMF was seen in kidney, liver, stomach and gut. The small size of this protein causes passing through the glomerular of kidney, so high activity was observed in urine and bladder.展开更多
Monoamine oxidases(MAOs)are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central ...Monoamine oxidases(MAOs)are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system.Furthermore,expression of MAOs is associated with the functions of peripheral organs.Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases,heart failure,metabolic disor-ders,and cancers.Monoamine oxidases have two isoenzymes,namely,monoamine oxidase A(MAO-A)and monoamine oxidase B(MAO-B).Therefore,the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in-depth understanding of their functions in biological systems,and for further promoting the clinical diag-nosis and treatment of MAO-related diseases.This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO-A and MAO-B,including radiolabeled probes,fluorescent probes,and a 19F magnetic resonance imaging probe.In addition,applications of these probes for detecting MAO expression levels in cells,tissues,animal models,and patients are described.Finally,the challenges and perspectives of developing novel MAO imaging probes are also highlighted.展开更多
Targeting receptors overexpressed on cancer cells with radiolabeled peptides has become a crucial aspect of molecular imaging in oncology.Small peptides offer favorable characteristics for tumor targeting with minimal...Targeting receptors overexpressed on cancer cells with radiolabeled peptides has become a crucial aspect of molecular imaging in oncology.Small peptides offer favorable characteristics for tumor targeting with minimal side effects and toxicity owing to their small size and simple radiolabeling protocols.Among them,somatostatin analogs have received regulatory approval for the diagnosis and treatment of neuroendocrine tumors.Cyclic RGD(Arg-Gly-Asp)peptides,bombesin analogs,and glucagon-like peptide-1 analogs are currently under development and/or undergoing clinical trials.The most used radionuclides for tumor imaging include^(99m)Tc and ^(111)In for single-photon emission computed tomography,^(68)Ga and^(18)F for positron emission tomography.This review highlights the clinical potential and future prospects of^(99m)Tc-labeled peptides for tumor imaging.展开更多
Background Myocardial blood flow(MBF) can be quantified with myocardial contrast echocardiography (MCE) during a venous infusion of microbubble. A minimal MBF is required to maintain cell membrane integrity and myocar...Background Myocardial blood flow(MBF) can be quantified with myocardial contrast echocardiography (MCE) during a venous infusion of microbubble. A minimal MBF is required to maintain cell membrane integrity and myocardial viability in ischemic condition. Thus, we hypothesized that MCE could be used to assess myocardial viability by the determination of MBF. Methods and ResultsMCE was performed at 4 hours after ligation of proximal left anterior descending coronary artery in 7 dogs with constant venous infusions of microbubbles. The video intensity versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: y=A(1-e-βt), where y is Ⅵ at pulsing interval t, A reflects microvascular cross - sectional area (or myocardial blood volume), and βreflects mean myocardial microbubble velocity. The product of A·β represents MBF. MBF was also obtained by ra-diolabeled microsphere method servered as reference. MBF derived by radiolabeled microsphere - method in the regions of normal, ischemia and infarction was 1.5+0.3, 0.7+0.3, 0. 3+0. 2 mL @ min-1@ g-1 respectively. The product of A·β obtained by MCE in those regions was 52. 46±15. 09, 24. 36±3. 89, 3. 74 ±3. 80 respectively. There was good correlation between normalized MBF and the normalized A·β ( r = 0. 81, P=0. 001). Conclusions MCE has an ability to determine myocardial viability in myocardial infarction canine model.展开更多
Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have sh...Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.展开更多
Brachytherapy is an established treatment modality that has been globally utilized for the therapy of malignant solid tumors.However,classic therapeutic sealed sources used in brachytherapy must be surgically implante...Brachytherapy is an established treatment modality that has been globally utilized for the therapy of malignant solid tumors.However,classic therapeutic sealed sources used in brachytherapy must be surgically implanted directly into the tumor site and removed after the requisite period of treatment.In order to avoid the trauma involved in the surgical procedures and prevent undesirable radioactive distribution at the cancerous site,well-dispersed radiolabeled nanomaterials are now being explored for brachytherapy applications.This emerging ffeld has been coined“nanoscale brachytherapy”.Despite present-day advancements,an ongoing challenge is obtaining an advanced,functional nanomaterial that concurrently incorporates features of high radiolabeling yield,short labeling time,good radiolabeling stability,and long tumor retention time without leakage of radioactivity to the nontargeted organs.Further,attachment of suitable targeting ligands to the nanoplatforms would widen the nanoscale brachytherapy approach to tumors expressing various phenotypes.Molecular imaging using radiolabeled nanoplatforms enables noninvasive visualization of cellular functions and biological processes in vivo.In vivo imaging also aids in visualizing the localization and retention of theradiolabeled nanoplatforms at the tumor site for the requisite time period to render safe and effective therapy.Herein,we review theadvancements over the last several years in the synthesis and use of functionalized radiolabeled nanoplatforms as a noninvasivesubstitute to standard brachytherapy sources.The limitations of present-day brachytherapy sealed sources are analyzed,whilehighlighting the advantages of using radiolabeled nanoparticles(NPs)for this purpose.The recent progress in the development ofdifferent radiolabeling methods,delivery techniques and nanoparticle internalization mechanisms are discussed.The preclinicalstudies performed to date are summarized with an emphasis on the current challenges toward the future translation of nanoscalebrachytherapy in routine clinical practices.展开更多
文摘Rhenium-188 is prospectively effective for both diagnosis and radiotherapy as it appropriately emits gamma rays and beta particles.Lacosamide(LCM)is a newly approved antiepileptic medication for focal drug-resistant epilepsy.Rhenium-188 was separated with high elution yield and high purity using the new 188W/188Re generator based on the ZrSiW gel matrix.188Re-LCM was prepared with high radiochemical yield and high purity.Biodistribution of 188Re-LCM in normal Swiss albino mice was investigated to determine its utility as a potential brain therapy agent.The 188W/188Re generator was used to obtain 188Re based on the ZrSi188W gel matrix,and the chemical,radiochemical,and radionuclidic purity of the obtained 188Re was determined using inductively coupled plasma optical emission spectrometry(ICP-AES),a paper chromatography technique,and high-purity germanium(HPGe)detection,respectively,to assess its validity for LCM labeling.Various factors,such as the pH,reaction time,and LCM quantity,were therefore studied in order to improve the yield and purity of 188Re-LCM,as determined by various chromatographic techniques such as electrophoresis,thin layer chromatography(TLC),and highpressure liquid chromatography(HPLC).188Re was obtained with a high elution yield(75±3%)and a low 188W breakthrough(0.001±0.0001%).The maximum radiochemical yield of 188Re-LCM(87.5±1.8%)was obtained using 50 ll LCM(4 mM),250 ll stannous chloride(4.4 mM)at pH 4,100 ll 188Re(37 MBq),within 30 min,at room temperature(25±3C),as determined by TLC,electrophoresis,and HPLC techniques.Biodistribution analysis showed that 188Re-LCM was primarily localized in the brain(5.1%)with a long residence time(240 min).
基金supported by the National Key Research and Development Program(No.2016YFA0400902)the Ministry of Science and Technology of China(Nos.2012CB825805,2012CB932600)+3 种基金the National Natural Science Foundation of China(Nos.11675251 and 11275251)Shanghai Rising-Star Program(No.14QA1404400)Distinguished Scientist Fellowship Program of King Saud Universitythe Youth Innovation Promotion Association of CAS(No.2016236)
文摘As a robust platform for genome editing,CRISPR/Cas9 is currently being explored for engineering biology or therapeutics,yet means for quantitative detection of Cas9 proteins remain to be fully realized.Here,we expressed Cas9 proteins and developed a novel detection method that traced Cas9 based on radiolabeled iodine.Through optimizing the reaction conditions of reaction time,temperature and cycles,we obtained ^(125)I-Cas9 of high labeling yield.The prepared ^(125)I-Cas9 was stable in various media and preserved excellent genome editing efficiency.Thus,our strategy provides a convenient and efficient tool for further tracing biological behaviors of Cas9 proteins in living systems.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82373938,82104275,and 82204585)Key Technologies R&D Program of Guangdong Province,China(Grant No.:2023B1111030004)National Key R&D Program of China(Grant No.:2022YFF1202600).
文摘Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolutionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase III clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by establishing a physiologically based pharmacokinetics(PBPK)model.For in vitro–in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.
基金supported by funding from the 13th Five-Year Plan New Drug Creation Program—Isotope Tracer Technology Platform for Clinical Evaluation of Innovative Drugs(Grant No.2017ZX09304032 with project leaders Jun Zhao and Chen Zhou).
文摘IBI351,a synthetic compound,exerts its anti-tumor effects by specifically,covalently,and irreversibly modifying the 12th cysteine residue of KRAS G12C.However,the pharmacokinetic profile of IBI351 in humans has not yet been reported.The current study aimed to investigate the pharmacokinetics and safety of IBI351 in healthy Chinese male subjects.A single oral dose of 600 mg combined with 150μCi[^(14)C]IBI351 was administered to six healthy male volunteers.Blood,urine,and fecal samples were collected at multiple time points to quantify the parent drug and its metabolites.IBI351 showed favorable pharmacokinetic characteristics and was well tolerated by all participants.Seventeen major metabolites were identified in plasma,urine,and feces.The main metabolic pathways included oxidation,hydrogenation,sulfonate conjugation,glucuronide conjugation,and cysteine conjugation.Excretion of IBI351 and its metabolites occurred mainly through feces.Collectively,this first-in-human study provides essential data on the metabolism and safety of IBI351 in Chinese subjects and lays the foundation for its further clinical development as a novel anti-tumor drug.
基金The National Natural Science Foundation of China, No. 39870200
文摘AIM:To explore and compare the radiochemical behavior and biological property of anti-sense oligonuc-leotide (ASON) labeled with technetium-99m using N-hydroxysuccinimidyl S-acetylmercaptoacetyltriglycl ine (NHS-MAG3) and hydrazinonictinamide derivative (HYNIC). METHODS:After HYNIC and NHS-MAG3 were synthesized, ASON was labeled with technetium-99m using HYNIC and NHS-MAG3 as a bifunctional chelator. The in vivo and in vitro stability, binding rates of labeled compounds to serum albumen, biodistribution of 99mTc-MAG3-ASON and 99mTc-HYNIC-ASON in BALB/C mouse and its HT29 tumor cellular uptake were compared. RESULTS:The labeling efficiency and stability of 99mTc-MAG3-ASON were significantly higher than those of 99mTc-HYNIC-ASON (P = 0.02, and P = 0.03, respectively). 99mTc-MAG3-ASON had a significantly lower rate of binding to serum albumen than 99mTc-HYNIC-ASON (P < 0.05). In contrast to 99mTc-HYNIC-ASON, the biodistribution of 99mTc-MAG3-ASON was significantly lower in blood, heart, liver and stomach (P < 0.05), slightly lower in intestines and spleen (P > 0.05) and significantly higher in lung and kidney (P < 0.05). The HT29 tumor cellular uptake rate of 99mTc-MAG3-ASON was significantly higher than that of 99mTc-HYNIC-ASON (P < 0.05). CONCLUSION:99mTc-MAG3-ASON shows superior radiochemical behaviors and biological properties than 99mTc-HYNIC-ASON. 99mTc-MAG3-ASON is a potential radiopharmaceutical agent for in vivo application.
基金supported by the National Natural Science Foundation of China(Nos.U2067214,21727817)Beijing municipal education commission-Beijing natural science foundation joint funding project(No.KZ202010005006)。
文摘The prevalence of positron emission tomography(PET)imaging has advanced biomedical applications for its ultrahigh sensitivity,deep tissue penetration and quantitative visualization of diseases in vivo.^(64)Cu with ideal half-life and decay characteristics has been designed as radioactive probes for disease diagnosis.The currently reported ^(64)Cu-labeled nanomaterials have the advantages of long circulation time in serum,good biocompatibility and mature preparation methods,and have been used in vivo PET imaging,biodistribution and pharmacokinetic monitoring,and imaging guided therapy.At the same time,suitable carrier characteristics and radiolabeling strategies are particularly important in the ^(64)Cu PET imaging process.In this review,we summarize different imaging probe designs and ^(64)Cu radiolabeling strategies,as well as their eventual applications in biomedicine.The potential challenges and prospects of ^(64)Cu labeled nanomaterials are also described,which provides broad prospects for radiolabeling strategies and further applications.
基金funded by Beijing Municipal Natural Science Foundation (No. Z200018)the Special Foundation of Beijing Municipal Education Commission (No. 3500–12020123)+2 种基金the National Natural Science Foundation of China (Nos. U1867209 and 21778003)the Ministry of Science and Technology of the People’s Republic of China (No. 2017YFA0506300)Li Ge-Zhao Ning Life Science Youth Research Foundation (No. LGZNQN202004)。
文摘Targeted alpha-therapy(TAT) is increasingly attractive due to its extraordinary antitumor efficacy.However,the supply of α-emitters for TAT is insufficient and under control by a limited number of countries.^(212)Pb is a promising α-emitter with an optimal half-life(10.6 h) and favored decay chain.Of interest,^(212)Pb can be extracted directly from natural thorium,which may be abundant in the mining waste of rare-earth,uranium,etc.Indeed,radioactive thorium waste has been a longstanding environmental challenge that needs immediate action.Developing an on-demand and facile process to isolate ^(212)Pb from natural thorium would be ideal to meet the above challenges,yet is difficult.In theory,the ratio of ^(212)Pb tonatTh is below 10^(-13)in commercially available thorium salts.As a pilot study,2.2 MBq of ^(212)Pb was successfully extracted from a 5 L solution of thorium nitrate by using a Pb-selective resin.The radiochemical purity of ^(212)Pb is over 99.9% according to gamma-ray analysis.The purified^(212)Pb was applied to radiolabel a couple of peptides used in clinics(i.e.PSMA,TATE and FAPI-04),and the radiochemical yields are>85%.Of note,^(212)Pb can be repeatedly separated from the thorium solution every 2 days.In summary,a practical and scalable method was developed to isolate^(212)Pb for potentially clinical use,which may be of great importance as it does not require either cyclotron or nuclear reactor.
文摘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.
文摘Peptides have an important role in organism and its high quantity present in tumors leading to development of radiolabeled peptides for tumor-specific imaging. Once the traditional methodologies used for radiofluorination do not work with peptides, due to their harsh conditions, other radiolabeling strategies had to be developed to supply the need. Direct radiofluorination is either an inefficient method, and the use of bidirectional groups, or prosthetic groups, is needed to enable the binding between the radionuclide fluorine-18 and a peptide functionalized. New peptides radiolabeling strategies have been developed sourcing increase the synthesis yield, its chemoselectivity, and the binding stability, and reduce the total process time and the number of steps required. The progress of radiofluorination methodologies led to development of the amidation, acylation, imidation, and alkylation techniques, the use of thiol groups, photochemical conjugation, chemoselective reactions, and “click chemistry”, in addition to use of FDG molecule and heteroatoms as linkers. This paper presents the main strategies used for peptides radiofluorination, presenting their positive and negative points, and the prosthetic groups most used in each method.
文摘The thiol components of the nonhistone proteins prepared from isolated nuclei from rat liver, regenerating liver and hepatoma 223 cells have been investigated after reaction with radio labelled N-ethylmaleimide and 5-5’-dithiobis-(2-nitrobenzoic acid) (DTNB). The labelled adducts formed were examined by isoelectric focusing analysis in polyacrylamide gel and the distribution of the radiolabels within sliced portions of the gels determined. In the case of the 14C labelled NEM adduct the label was found to be spread amongst numerous protein components within the gel however, in the case of the 35S labelled DTNB adducts, only a small proportion of the label was found in the protein material which was retained in the acidic isoelectric point (pI) region of the gel. The bulk of the 35S labelled adduct (56% - 60%) was found to have migrated into the anode solution (10 mM phosphoric acid). This could be adsorbed onto a hydrophobic resin (XAD2) resin and eluted with methanol. Gel filtration chromatographic analysis of this adduct material on BioGel P2, (exclusion limit 1500 daltons) showed low molecular weight components to be present. Slightly different patterns were obtained for these nuclei, each containing several 35S components with molecular weights greater than the Ellman reagent itself. These 35S labelled thiol components did not contain any protein, peptide or amino acid components indicating strongly that a novel species of thiols could be present in these nuclei bound within the non-histone protein matrices.
文摘99mTc-labelled metallothionein (99mTc-MT) was prepared through both direct and transcomplexation labelling approaches. Buffer systems and a variety of other parameters in the direct labelling procedure were studied in detail. High radiolabelling yields of 93-96% and the specific radioactivity of 3.7 MB/μg were obtained under optimal conditions by the direct labelling method. The prepared 99mTc-MT was stable in vitro. The chelate-exchange kinetics of MT with 99mTc-glucohepatonate and 99mTc-citrate were also studied. Biodistribution and imaging studies showed that 99mTc-MT was accumulated in the animal kidneys at an exceptionally high level, indicating that 99mTc-MT might be a potential renal imaging agent.
基金the financial assistance provided by ICAR-IARI in the form of IARI Fellowship and Department of Science and Technology, Innovation in Science Pursuit for Inspired Research during the PhD programme。
文摘Increased nighttime respiratory losses decrease the amount of photoassimilates available for plant growth and yield. We hypothesized that the increased respiratory carbon loss under high night temperatures(HNT) could be compensated for by increased photosynthesis during the day following HNT exposure. Two rice genotypes, Vandana(HNT-sensitive) and Nagina 22(HNT-tolerant), were exposed to HNT(4 ℃ above the control) from flowering to physiological maturity. They were assessed for alterations in the carbon balance of the source(flag leaf) and its subsequent impact on grain filling dynamics and the quality of spatially differentiated sinks(superior and inferior spikelets). Both genotypes exhibited significantly higher night respiration rates. However, only Nagina 22 compensated for the high respiration rates with an increased photosynthetic rate, resulting in a steady production of total dry matter under HNT. Nagina 22 also recorded a higher grain-filling rate, particularly at 5 and 10 d after flowering, with 1.5- and 4.0-fold increases in the translocation of ^(14)C sugars to the superior and inferior spikelets, respectively. The ratio of photosynthetic rate to respiratory rate on a leaf area basis was negatively correlated with spikelet sterility, resulting in a higher filled spikelet number and grain weight per plant, particularly for inferior grains in Nagina 22. Grain quality parameters such as head rice recovery, high-density grains, and gelatinization temperature were maintained in Nagina 22. An increase in the rheological properties of rice flour starch in Nagina 22 under HNT indicated the stability of starch and its ability to reorganize during the cooling process of product formation. Thus, our study showed that sink adjustments between superior and inferior spikelets favored the growth of inferior spikelets, which helped to offset the reduction in grain weight under HNT in the tolerant genotype Nagina 22.
文摘α,ε-N,N'-bis(L-cysteinyl)-L-lysine was synthesized and char- acterized for the first time.It was then employed as a bifunctional chelating agent to chelate technetium-99m and subsequently conjugated to fragment F(ab')_2 of anti-gastric tumor monoclonal antibody 3G9.The radiolabelled antibody was satisfactorily stable and immunoreactive.
文摘Carbon-11 radiolabeled amines constitute a very important class of radioligands that are widely used for positron emission tomography (PET) imaging. Radiolabeling of amines is often achieved through radiomethylation using [11C]CH3I or [11C]CH3OTf under basic conditions in a strictly anhydrous environment. Functional groups such as hydroxyl and carboxyl groups that are often present in the molecules are normally base sensitive and require protection and deprotection, which substantially prolongs and complicates the radiolabeling process. Here we report a versatile approach to a series of C-11 radiolabeled amines prepared through reductive amination using [11C]formaldehyde. Using a variety of substrates bearing different functional groups, we demonstrate the general utility of this method. In contrast to conventional radiomethylation methods, the reductive amination using [11C]formaldehyde can be carried out in an aqueous environment relatively quickly without the need of protection of base-sensitive functional groups.
文摘Molecular imaging techniques are increasingly being used in the localization of disease, the staging of disease and for therapy control. The objective of current study focused on the optimization of synthesis, quality control, in vitro and in vivo evaluation of 123I radiopharmaceuticals based on the chemotactic peptide N-formyl-Met-Leu-Phe. Labeling studies were done both by direct method using chloramine-Y according to Khawli （1989） and indirect method using [125I and 131I] S1B according to Zalutsky （1987）. Then, biodistribution studies were performed both in normal mice and the one bearing 50 laL turpentine for 24h, promoted inflammation in right leg. Furthermore, the ability of the labeled peptide conjugate to bind to human polymorph nuclear leukocytes was determined using in vitro assay. With increasing in pl-l, yield of labeled FMLF （N-formyl-Met-Leu-Phe） decreased perhaps because of interaction OH to carboxyl group of SIB. The maximum activity was observed in the right leg which injected with turpentine due to infection and increase in blood circulation. Also, this peptide was conjugated to PMN （Poly morph nuclear） specifically and maximum activity was 66%. The highest absorption of FLMF was seen in kidney, liver, stomach and gut. The small size of this protein causes passing through the glomerular of kidney, so high activity was observed in urine and bladder.
基金Natural Science Foundation of Jiangsu Province,Grant/Award Number:BK20210062National Natural Science Foundation of China,Grant/Award Number:82172054Project of Key Laboratory of Organic Synthesis of Jiangsu Province,College of Chemistry,Chemical Engineering and Materials Science,Soochow University,Grant/Award Number:KJS2326。
文摘Monoamine oxidases(MAOs)are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system.Furthermore,expression of MAOs is associated with the functions of peripheral organs.Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases,heart failure,metabolic disor-ders,and cancers.Monoamine oxidases have two isoenzymes,namely,monoamine oxidase A(MAO-A)and monoamine oxidase B(MAO-B).Therefore,the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in-depth understanding of their functions in biological systems,and for further promoting the clinical diag-nosis and treatment of MAO-related diseases.This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO-A and MAO-B,including radiolabeled probes,fluorescent probes,and a 19F magnetic resonance imaging probe.In addition,applications of these probes for detecting MAO expression levels in cells,tissues,animal models,and patients are described.Finally,the challenges and perspectives of developing novel MAO imaging probes are also highlighted.
基金National Natural Science Foundation of China,Grant/Award Number:81971676。
文摘Targeting receptors overexpressed on cancer cells with radiolabeled peptides has become a crucial aspect of molecular imaging in oncology.Small peptides offer favorable characteristics for tumor targeting with minimal side effects and toxicity owing to their small size and simple radiolabeling protocols.Among them,somatostatin analogs have received regulatory approval for the diagnosis and treatment of neuroendocrine tumors.Cyclic RGD(Arg-Gly-Asp)peptides,bombesin analogs,and glucagon-like peptide-1 analogs are currently under development and/or undergoing clinical trials.The most used radionuclides for tumor imaging include^(99m)Tc and ^(111)In for single-photon emission computed tomography,^(68)Ga and^(18)F for positron emission tomography.This review highlights the clinical potential and future prospects of^(99m)Tc-labeled peptides for tumor imaging.
基金This work was supported in part by grants from thescience and technology foundation of China(39870329).
文摘Background Myocardial blood flow(MBF) can be quantified with myocardial contrast echocardiography (MCE) during a venous infusion of microbubble. A minimal MBF is required to maintain cell membrane integrity and myocardial viability in ischemic condition. Thus, we hypothesized that MCE could be used to assess myocardial viability by the determination of MBF. Methods and ResultsMCE was performed at 4 hours after ligation of proximal left anterior descending coronary artery in 7 dogs with constant venous infusions of microbubbles. The video intensity versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: y=A(1-e-βt), where y is Ⅵ at pulsing interval t, A reflects microvascular cross - sectional area (or myocardial blood volume), and βreflects mean myocardial microbubble velocity. The product of A·β represents MBF. MBF was also obtained by ra-diolabeled microsphere method servered as reference. MBF derived by radiolabeled microsphere - method in the regions of normal, ischemia and infarction was 1.5+0.3, 0.7+0.3, 0. 3+0. 2 mL @ min-1@ g-1 respectively. The product of A·β obtained by MCE in those regions was 52. 46±15. 09, 24. 36±3. 89, 3. 74 ±3. 80 respectively. There was good correlation between normalized MBF and the normalized A·β ( r = 0. 81, P=0. 001). Conclusions MCE has an ability to determine myocardial viability in myocardial infarction canine model.
基金supported by the National Natural Science Foundation of China(No.82071961)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Yong Scholars in Fujian(No.2021ZQNZD016,China)+5 种基金Fujian Natural Science Foundation for Distinguished Young Scholars(No.2022D005,China)Innovation of Science and Technology,Fujian Province(No.2021Y9134,China)National University of Singapore(No.NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(No.MOH-001388-00,MOH-001041,CG21APR1005,Singapore)Singapore Ministry of Education(No.MOE-000387-00,Singapore)National Research Foundation(No.NRF-000352-00,Singapore).
文摘Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.
基金support from the Bhabha Atomic Research Centre,the University of Wiscon-sin〓〓Madison,and the National Institutes of Health(P30 CA014520 and T32 CA009206).
文摘Brachytherapy is an established treatment modality that has been globally utilized for the therapy of malignant solid tumors.However,classic therapeutic sealed sources used in brachytherapy must be surgically implanted directly into the tumor site and removed after the requisite period of treatment.In order to avoid the trauma involved in the surgical procedures and prevent undesirable radioactive distribution at the cancerous site,well-dispersed radiolabeled nanomaterials are now being explored for brachytherapy applications.This emerging ffeld has been coined“nanoscale brachytherapy”.Despite present-day advancements,an ongoing challenge is obtaining an advanced,functional nanomaterial that concurrently incorporates features of high radiolabeling yield,short labeling time,good radiolabeling stability,and long tumor retention time without leakage of radioactivity to the nontargeted organs.Further,attachment of suitable targeting ligands to the nanoplatforms would widen the nanoscale brachytherapy approach to tumors expressing various phenotypes.Molecular imaging using radiolabeled nanoplatforms enables noninvasive visualization of cellular functions and biological processes in vivo.In vivo imaging also aids in visualizing the localization and retention of theradiolabeled nanoplatforms at the tumor site for the requisite time period to render safe and effective therapy.Herein,we review theadvancements over the last several years in the synthesis and use of functionalized radiolabeled nanoplatforms as a noninvasivesubstitute to standard brachytherapy sources.The limitations of present-day brachytherapy sealed sources are analyzed,whilehighlighting the advantages of using radiolabeled nanoparticles(NPs)for this purpose.The recent progress in the development ofdifferent radiolabeling methods,delivery techniques and nanoparticle internalization mechanisms are discussed.The preclinicalstudies performed to date are summarized with an emphasis on the current challenges toward the future translation of nanoscalebrachytherapy in routine clinical practices.
