BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease(CKD).AIM To examine the efficacy of cultured human CD34+cells with enhanced proliferati...BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease(CKD).AIM To examine the efficacy of cultured human CD34+cells with enhanced proliferating potential in kidney injury in mice.METHODS Human umbilical cord blood(UCB)-derived CD34+cells were incubated for one week in vasculogenic conditioning medium.Vasculogenic culture significantly increased the number of CD34+cells and their ability to form endothelial progenitor cell colony-forming units.Adenineinduced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice,and cultured human UCB-CD34+cells were administered at a dose of 1×106/mouse on days 7,14,and 21 after the start of adenine diet.RESULTS Repetitive administration of cultured UCB-CD34+cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group.Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group(P<0.01).Microvasculature integrity was significantly preserved(P<0.01)and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group(P<0.001).CONCLUSION Early intervention using human cultured CD34+cells significantly improved the progression of tubulointerstitial kidney injury.Repetitive administration of cultured human UCB-CD34+cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.展开更多
Background:Patients with cold tumors gain limited benefits from immune checkpoint blockade(ICB)therapy owing to low programmed cell death protein ligand 1(PD-L1)expression and minimal immune cell infiltration.Mild pho...Background:Patients with cold tumors gain limited benefits from immune checkpoint blockade(ICB)therapy owing to low programmed cell death protein ligand 1(PD-L1)expression and minimal immune cell infiltration.Mild photothermal therapy(PTT)using black phosphorus nanosheets(BPNSs)is a promising approach to enhance the efficacy of ICB therapy.However,to ensure that BPNS-based PTT-enhanced ICB therapy is clinically adaptable,a noninvasive,bedside-accessible imaging tool capable of monitoring the status of PD-L1 is imperative.We demonstrated that positron emission tomography(PET)using[64Cu]HKP2202 precisely delineated PD-L1 expression in tumors receiving PTT.Methods:BPNSs were modified with polyethylene glycol to prepare BPNS@PEG,which were then characterized.MC38 cells and tumor allografts were treated with BPNS@PEG followed by 808 nm near-infrared light expo-sure.PET using[64Cu]HKP2202 was performed to monitor PD-L1 expression in vivo.We also evaluated whether the efficacy of ICB therapy improved after delivering BPNS@PEG-based PTT.Results:BPNS@PEG had a well-defined lamellar structure with clear edges and an average size of 150 nm.PET and Western blotting assays indicated that PD-L1 expression was upregulated after BPNS@PEG and NIR-light treatment.Notably,the antitumor effect of anti PD-L1 therapy was enhanced in mice treated with BPNS@PEG-based PTT.Conclusions:BPNS@PEG had the capacity to convert cold tumors into hot tumors to facilitate the efficacy of ICB therapy.Importantly,the comple-mentary diagnostic PET radiotracer targeting PD-L1 allowed real-time moni-toring of PD-L1 expression in the tumor microenvironment to guide ICB administration,holding great potential to achieve efficient and precise tumor immunotherapy.展开更多
BACKGROUND Radionuclides produce Cherenkov radiation(CR),which can potentially activate photosensitizers(PSs)in phototherapy.Several groups have studied Cherenkov energy transfer to PSs using optical imaging;however,c...BACKGROUND Radionuclides produce Cherenkov radiation(CR),which can potentially activate photosensitizers(PSs)in phototherapy.Several groups have studied Cherenkov energy transfer to PSs using optical imaging;however,cost-effectively identifying whether PSs are excited by radionuclide-derived CR and detecting fluorescence emission from excited PSs remain a challenge.Many laboratories face the need for expensive dedicated equipment.AIM To cost-effectively confirm whether PSs are excited by radionuclide-derived CR and distinguish fluorescence emission from excited PSs.METHODS The absorbance and fluorescence spectra of PSs were measured using a microplate reader and fluorescence spectrometer to examine the photo-physical properties of PSs.To mitigate the need for expensive dedicated equipment and achieve the aim of the study,we developed a method that utilizes a chargecoupled device optical imaging system and appropriate long-pass filters of different wavelengths(manual sequential application of long-pass filters of 515,580,645,700,750,and 800 nm).Tetrakis(4-carboxyphenyl)porphyrin(TCPP)was utilized as a model PS.Different doses of copper-64(^(64)CuCl_(2))(4,2,and 1 mCi)were used as CR-producing radionuclides.Imaging and data acquisition were performed 0.5 h after sample preparation.Differential image analysis was conducted by using ImageJ software(National Institutes of Health)to visually evaluate TCPP fluorescence.RESULTS The maximum absorbance of TCPP was at 390-430 nm,and the emission peak was at 670 nm.The CR and CRinduced TCPP emissions were observed using the optical imaging system and the high-transmittance long-pass filters described above.The emission spectra of TCPP with a peak in the 645-700 nm window were obtained by calculation and subtraction based on the serial signal intensity(total flux)difference between^(64)CuCl_(2)+TCPP and^(64)CuCl_(2).Moreover,the differential fluorescence images of TCPP were obtained by subtracting the^(64)CuCl_(2)image from the^(64)CuCl_(2)+TCPP image.The experimental results considering different^(64)CuCl_(2)doses showed a dosedependent trend.These results demonstrate that a bioluminescence imaging device coupled with different longpass filters and subtraction image processing can confirm the emission spectra and differential fluorescence images of CR-induced TCPP.CONCLUSION This simple method identifies the PS fluorescence emission generated by radionuclide-derived CR and can contribute to accelerating the development of Cherenkov energy transfer imaging and the discovery of new PSs.展开更多
Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interven...Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged.Here,we developed a positron emission tomography(PET)imaging platform using l-[5-^(11)C]glutamine([^(11)C]Gln)and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES),a glutaminase 1(GLS1)inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.PET imaging with[^(11)C]Gln effectively delineated the pharmacokinetics of l-glutamine,capturing its temporal-spatial pattern of action within the body.Furthermore,[^(11)C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient(MCD)-fed NASH mice,whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of[^(11)C]Gln in MCD-fed mice.This reduction in[^(11)C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage,indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities.These results suggest that[^(11)C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body,real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH,and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.展开更多
The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the prolifer...The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.展开更多
Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performanc...Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performance owing to limited tumor retention.The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity.Therefore,a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed.Here,we developed a PEGylation-enabled peptide multidisplay platform(PEGibody)for PR_b,anα5β1 targeting peptide.PEGibody generation involved PEGylation and self-assembly.[^(64)Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter.Compared with non-PEGylated radioligands,[^(64)Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability.Importantly,the biodistribution analysis confirmed rapid clearance of[^(64)Cu]QM-2303 from the bloodstream.Administration of a single dose of[^(177)Lu]QM-2303 led to robust antitumor efficacy.Furthermore,[^(64)Cu]/[^(177)Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice.Therefore,this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime.The PEGibody-based radiopharmaceutical[^(64)Cu]/[^(177)Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy forα5β1-overexpressing tumors.展开更多
Peptide-based materials that have diverse structures and functionalities are an important type of biomaterials.In former times,peptide-based nanomaterials with excellent stability were constructed through self-assembl...Peptide-based materials that have diverse structures and functionalities are an important type of biomaterials.In former times,peptide-based nanomaterials with excellent stability were constructed through self-assembly.Compared with individual peptides,peptide-based self-assembly nanomaterials that form well-ordered superstructures possess many advantages such as good thermo-and mechanical stability,semiconductivity,piezoelectricity and optical properties.Moreover,due to their excellent biocompatibility and biological activity,peptide-based self-assembly nanomaterials have been vastly used in different fields.In this review,we provide the advances of peptide-based self-assembly nanostructures,focusing on the driving forces that dominate peptide self-assembly and assembly mechanisms of peptides.After that,we outline the synthesis and properties of peptide-based nanomaterials,followed by the applications of functional peptide nanomaterials.Finally,we provide perspectives on the challenges and future of peptide-based nanomaterials.展开更多
Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the ne...Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.展开更多
The de novo design of new peptide assemblies that expands the repertoire of biomaterial nanostructures has been of a tremendous challenge.Hence,it is evident that a successful research achievement in this area would i...The de novo design of new peptide assemblies that expands the repertoire of biomaterial nanostructures has been of a tremendous challenge.Hence,it is evident that a successful research achievement in this area would increase the understanding of molecular interactions in supramolecules and create novel scaffolds exploitable in biotechnology and synthetic biology.The manipulation of cyclic peptide self-assembly is particularly intriguing for this purpose.Herein,we report that a novel type of cyclic peptides,referred to as chiral tether constrained cyclic peptides(CCP),shows promising self-assembly properties.CCPs are the first example of a controllable assembly of all-L-α-cyclic peptides with different ring sizes.A noteworthy feature of the CCP system is good tolerance of different secondary structures,ring size,and peptide sequence.Based on this system,a variety of nanostructures could be constructed,which display different physical properties,rendering it an excellent platform for molecular interaction studies.Further,demonstrate potential applications of these peptide assemblies in bioimaging and energy storage.展开更多
As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dys...As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.展开更多
Panic disorder (PD) is an acute paroxysmal anxiety disorder with poorly understood pathophysiology. The dorsal periaqueductal gray (dPAG) is involved in the genesis of PD. However, the downstream neurofunctional chang...Panic disorder (PD) is an acute paroxysmal anxiety disorder with poorly understood pathophysiology. The dorsal periaqueductal gray (dPAG) is involved in the genesis of PD. However, the downstream neurofunctional changes of the dPAG during panic attacks have yet to be evaluated in vivo. In this study, optogenetic stimulation to the dPAG was performed to induce panic-like behaviors, and in vivo positron emission tomography (PET) imaging with ,8F-flurodeoxyglucose (18F-FDG) was conducted to evaluate neurofunctional changes before and after the optogenetic stimulation. Compared with the baseline, post-optogenetic stimulation PET imaging demonstrated that the glucose metabolism significantly increased (P < 0.001) in dPAG, the cuneiform nucleus, the cerebellar lobule, the cingulate cortex, the alveus of the hippocampus, the primary visual cortex, the septohypothalamic nucleus, and the retrosplenial granular cortex but significantly decreased (P < 0.001) in the basal ganglia, the frontal cortex, the forceps minor corpus callosum, the primary somatosensory cortex, the primary motor cortex, the secondary visual cortex, and the dorsal lateral geniculate nucleus. Taken together, these data indicated that in vivo PET imaging can successfully detect downstream neurofunctional changes involved in the panic attacks after optogenetic stimulation to the dPAG.展开更多
Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated EGFR.However,the...Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated EGFR.However,the efficacy of EGFR-TKIs in wild-type(wt)EGFR tumours has been shown to be marginal.Methods that can sensitize Erlotinib to EGFR wild-type NSCLC remain rare.Herein,we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt NSCLCs.Our results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor(VEGF)inhibitor,Bevacizumab(Bev),to EGFR-wt tumours.The nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour growth.Moreover,Bev normalizes the tumour embedded vessels,further promoting the therapeutic efficacy of Erlotinib.In addition,the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging(MRI).Collectively,our study,for the first time,demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC,paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.展开更多
文摘BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease(CKD).AIM To examine the efficacy of cultured human CD34+cells with enhanced proliferating potential in kidney injury in mice.METHODS Human umbilical cord blood(UCB)-derived CD34+cells were incubated for one week in vasculogenic conditioning medium.Vasculogenic culture significantly increased the number of CD34+cells and their ability to form endothelial progenitor cell colony-forming units.Adenineinduced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice,and cultured human UCB-CD34+cells were administered at a dose of 1×106/mouse on days 7,14,and 21 after the start of adenine diet.RESULTS Repetitive administration of cultured UCB-CD34+cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group.Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group(P<0.01).Microvasculature integrity was significantly preserved(P<0.01)and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group(P<0.001).CONCLUSION Early intervention using human cultured CD34+cells significantly improved the progression of tubulointerstitial kidney injury.Repetitive administration of cultured human UCB-CD34+cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.
基金National Natural Science Foundation of China,Grant/Award Number:82372002Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2022-RC350-04+7 种基金CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2021-I2M-1-026,2022-I2M-2-002-2,2021-I2M-3-001National Key Research and Development Program of China,Grant/Award Number:2022YFE0111700Beijing Nova Program awarded to K.H.,Grant/Award Number:0104002Beijing Natural Science Foundation,Grant/Award Number:L234044Fundamental Research Funds for the Central Universities,Grant/Award Numbers:3332023044,3332023151CIRP Open Fund of Radiation Protection Laboratories“Technological innovation”special project of CNNC Medical Industry Co.Ltd,Grant/Award Number:ZHYLYB2021005China National Nuclear Corporation Young Talent Program。
文摘Background:Patients with cold tumors gain limited benefits from immune checkpoint blockade(ICB)therapy owing to low programmed cell death protein ligand 1(PD-L1)expression and minimal immune cell infiltration.Mild photothermal therapy(PTT)using black phosphorus nanosheets(BPNSs)is a promising approach to enhance the efficacy of ICB therapy.However,to ensure that BPNS-based PTT-enhanced ICB therapy is clinically adaptable,a noninvasive,bedside-accessible imaging tool capable of monitoring the status of PD-L1 is imperative.We demonstrated that positron emission tomography(PET)using[64Cu]HKP2202 precisely delineated PD-L1 expression in tumors receiving PTT.Methods:BPNSs were modified with polyethylene glycol to prepare BPNS@PEG,which were then characterized.MC38 cells and tumor allografts were treated with BPNS@PEG followed by 808 nm near-infrared light expo-sure.PET using[64Cu]HKP2202 was performed to monitor PD-L1 expression in vivo.We also evaluated whether the efficacy of ICB therapy improved after delivering BPNS@PEG-based PTT.Results:BPNS@PEG had a well-defined lamellar structure with clear edges and an average size of 150 nm.PET and Western blotting assays indicated that PD-L1 expression was upregulated after BPNS@PEG and NIR-light treatment.Notably,the antitumor effect of anti PD-L1 therapy was enhanced in mice treated with BPNS@PEG-based PTT.Conclusions:BPNS@PEG had the capacity to convert cold tumors into hot tumors to facilitate the efficacy of ICB therapy.Importantly,the comple-mentary diagnostic PET radiotracer targeting PD-L1 allowed real-time moni-toring of PD-L1 expression in the tumor microenvironment to guide ICB administration,holding great potential to achieve efficient and precise tumor immunotherapy.
基金This study was reviewed and approved by the Institutional Review Board of National Institutes for Quantum Science and Technology,No.07-1064-28.No animals or animal-derived samples or patients or patient-derived samples were included in this study.
文摘BACKGROUND Radionuclides produce Cherenkov radiation(CR),which can potentially activate photosensitizers(PSs)in phototherapy.Several groups have studied Cherenkov energy transfer to PSs using optical imaging;however,cost-effectively identifying whether PSs are excited by radionuclide-derived CR and detecting fluorescence emission from excited PSs remain a challenge.Many laboratories face the need for expensive dedicated equipment.AIM To cost-effectively confirm whether PSs are excited by radionuclide-derived CR and distinguish fluorescence emission from excited PSs.METHODS The absorbance and fluorescence spectra of PSs were measured using a microplate reader and fluorescence spectrometer to examine the photo-physical properties of PSs.To mitigate the need for expensive dedicated equipment and achieve the aim of the study,we developed a method that utilizes a chargecoupled device optical imaging system and appropriate long-pass filters of different wavelengths(manual sequential application of long-pass filters of 515,580,645,700,750,and 800 nm).Tetrakis(4-carboxyphenyl)porphyrin(TCPP)was utilized as a model PS.Different doses of copper-64(^(64)CuCl_(2))(4,2,and 1 mCi)were used as CR-producing radionuclides.Imaging and data acquisition were performed 0.5 h after sample preparation.Differential image analysis was conducted by using ImageJ software(National Institutes of Health)to visually evaluate TCPP fluorescence.RESULTS The maximum absorbance of TCPP was at 390-430 nm,and the emission peak was at 670 nm.The CR and CRinduced TCPP emissions were observed using the optical imaging system and the high-transmittance long-pass filters described above.The emission spectra of TCPP with a peak in the 645-700 nm window were obtained by calculation and subtraction based on the serial signal intensity(total flux)difference between^(64)CuCl_(2)+TCPP and^(64)CuCl_(2).Moreover,the differential fluorescence images of TCPP were obtained by subtracting the^(64)CuCl_(2)image from the^(64)CuCl_(2)+TCPP image.The experimental results considering different^(64)CuCl_(2)doses showed a dosedependent trend.These results demonstrate that a bioluminescence imaging device coupled with different longpass filters and subtraction image processing can confirm the emission spectra and differential fluorescence images of CR-induced TCPP.CONCLUSION This simple method identifies the PS fluorescence emission generated by radionuclide-derived CR and can contribute to accelerating the development of Cherenkov energy transfer imaging and the discovery of new PSs.
基金supported in part by the Moonshot Research and Development Program(Grant No.21zf0127003h001,Japan)JSPS A3 Foresight Program(Grant No.JPJSA3F20230001,Japan)JSPS KAKENHI(Grants No.23H02867,23H05487,and 21K07659,Japan).
文摘Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged.Here,we developed a positron emission tomography(PET)imaging platform using l-[5-^(11)C]glutamine([^(11)C]Gln)and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES),a glutaminase 1(GLS1)inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.PET imaging with[^(11)C]Gln effectively delineated the pharmacokinetics of l-glutamine,capturing its temporal-spatial pattern of action within the body.Furthermore,[^(11)C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient(MCD)-fed NASH mice,whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of[^(11)C]Gln in MCD-fed mice.This reduction in[^(11)C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage,indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities.These results suggest that[^(11)C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body,real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH,and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2024-12M-ZH-009,2023-I2M-2-006,2023-I2M-QJ010,2021-I2M-1-026,and 2021-I2M-3-001,China)the Beijing Nova Program and Beijing Nova Program Interdisciplinary Cooperation Project to Ksupported by the Beijing Natural Science Foundation(Nos.L234044,L248087,L246051 and 7252206,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044,3332023151,China)the China Postdoctoral Science Foundation(No.2025M773592)the China National Nuclear Corporation Young Talent Program,the special project of“Technological Innovation”project of CNNC Medical Industry Co.Ltd(ZHYLYB2021005)Medical+X Innovation Team of the Discipline Construction Enhancement Project,the Second Affiliated Hospital of Soochow University(XKTJ-TD202410).
文摘The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04,China)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-026(2023),2022-I2M-2-002-2,and 2021-I2M-3-001(2023),China)the National Key Research and Development Program of China(No.2022YFE0111700)the Beijing Nova Program to Kuan Hu(No.0104002,China)supported by the Beijing Natural Science Foundation(No.L234044,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044 and 3332023151,China)the CIRP Open Fund of Radiation Protection Laboratories(No.ZHYLYB2021005,China)the China National Nuclear Corporation Young Talent Program.
文摘Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performance owing to limited tumor retention.The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity.Therefore,a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed.Here,we developed a PEGylation-enabled peptide multidisplay platform(PEGibody)for PR_b,anα5β1 targeting peptide.PEGibody generation involved PEGylation and self-assembly.[^(64)Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter.Compared with non-PEGylated radioligands,[^(64)Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability.Importantly,the biodistribution analysis confirmed rapid clearance of[^(64)Cu]QM-2303 from the bloodstream.Administration of a single dose of[^(177)Lu]QM-2303 led to robust antitumor efficacy.Furthermore,[^(64)Cu]/[^(177)Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice.Therefore,this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime.The PEGibody-based radiopharmaceutical[^(64)Cu]/[^(177)Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy forα5β1-overexpressing tumors.
基金supported by Beijing Natural Science Foundation(JQ20038)the National Natural Science Foundation of China(61875015,T2125003,and 21801019)+1 种基金JSPS KAKENHI(Grant No.21H02873)JSPS International Joint Research Program(JPJSBP120207203).
文摘Peptide-based materials that have diverse structures and functionalities are an important type of biomaterials.In former times,peptide-based nanomaterials with excellent stability were constructed through self-assembly.Compared with individual peptides,peptide-based self-assembly nanomaterials that form well-ordered superstructures possess many advantages such as good thermo-and mechanical stability,semiconductivity,piezoelectricity and optical properties.Moreover,due to their excellent biocompatibility and biological activity,peptide-based self-assembly nanomaterials have been vastly used in different fields.In this review,we provide the advances of peptide-based self-assembly nanostructures,focusing on the driving forces that dominate peptide self-assembly and assembly mechanisms of peptides.After that,we outline the synthesis and properties of peptide-based nanomaterials,followed by the applications of functional peptide nanomaterials.Finally,we provide perspectives on the challenges and future of peptide-based nanomaterials.
基金financial support from the JSPS KAKENHI grant Nos.19K17156,21H02873,21K07659,and 20H03635,Japansupported by QST President’s Strategic Grant(Exploratory Research,Japan)+3 种基金financial support from the National Natural Science Foundation of China(82003532)General Project of Science and Technology Development Fund of Nanjing Medical University(NMUB2019154,China)the second round of Nanjing Clinical Medical Center"Nanjing Nuclear Medicine Center"the China Postdoctoral Science Foundation(2019M650302)。
文摘Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.
基金We acknowledge financial support from the Natural Science Foundation of China(grant nos.21778009,21801019,21977010,81701818,and 51803006)the Shenzhen Science and Technology Innovation Committee(nos.JCYJ20170817172023838 and JCYJ20180507181527112).
文摘The de novo design of new peptide assemblies that expands the repertoire of biomaterial nanostructures has been of a tremendous challenge.Hence,it is evident that a successful research achievement in this area would increase the understanding of molecular interactions in supramolecules and create novel scaffolds exploitable in biotechnology and synthetic biology.The manipulation of cyclic peptide self-assembly is particularly intriguing for this purpose.Herein,we report that a novel type of cyclic peptides,referred to as chiral tether constrained cyclic peptides(CCP),shows promising self-assembly properties.CCPs are the first example of a controllable assembly of all-L-α-cyclic peptides with different ring sizes.A noteworthy feature of the CCP system is good tolerance of different secondary structures,ring size,and peptide sequence.Based on this system,a variety of nanostructures could be constructed,which display different physical properties,rendering it an excellent platform for molecular interaction studies.Further,demonstrate potential applications of these peptide assemblies in bioimaging and energy storage.
基金the financial support from the NIH grants (DA038000 and DA043507 to S. H. L. and DA033760 to B. F. C.)the Swiss National Science Foundation for a postdoctoral fellowship to Michael A. Schafroth (Grant No. P2EZP3_175137, Switzerland)。
文摘As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.
基金We thank Prof.Binggui Sun for providing devices and laboratory space in virus injection, Binbin Nie for technical support in Statistical Parametric Mapping analysis and Qianyun Liu (Hopstem Biotechnology LLC) for technical support on immunostaining.Help from the Zhejiang University Intelligence Convergence was greatly appreciated.This work was supported by grants from the National Natural Science Foundation of China (No.81425015)the National Key Research and Development Program of China (No.2016YFA0100900)+1 种基金the National Natural Science Foundation of China (Nos.81725009, 81761148029, and 81571711)Zhejiang University K.P.Chao’s High Technology Development Foundation.
文摘Panic disorder (PD) is an acute paroxysmal anxiety disorder with poorly understood pathophysiology. The dorsal periaqueductal gray (dPAG) is involved in the genesis of PD. However, the downstream neurofunctional changes of the dPAG during panic attacks have yet to be evaluated in vivo. In this study, optogenetic stimulation to the dPAG was performed to induce panic-like behaviors, and in vivo positron emission tomography (PET) imaging with ,8F-flurodeoxyglucose (18F-FDG) was conducted to evaluate neurofunctional changes before and after the optogenetic stimulation. Compared with the baseline, post-optogenetic stimulation PET imaging demonstrated that the glucose metabolism significantly increased (P < 0.001) in dPAG, the cuneiform nucleus, the cerebellar lobule, the cingulate cortex, the alveus of the hippocampus, the primary visual cortex, the septohypothalamic nucleus, and the retrosplenial granular cortex but significantly decreased (P < 0.001) in the basal ganglia, the frontal cortex, the forceps minor corpus callosum, the primary somatosensory cortex, the primary motor cortex, the secondary visual cortex, and the dorsal lateral geniculate nucleus. Taken together, these data indicated that in vivo PET imaging can successfully detect downstream neurofunctional changes involved in the panic attacks after optogenetic stimulation to the dPAG.
基金This study was supported partly by grants from the Natural Science Foundation of China(81771973,81971672 and 82102005)Key Program of the Natural Science Foundation of Guangdong Province(2018B0303110011)+3 种基金Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation(201905010003)Fundamental Research Funds for the Central Universities(21620308 and 21620101)JSPS KAKENHI grant Nos.21H02873,21K07659,and 20H03635the AMED Moonshot Research and Development Program(Grant No 21zf0127003h001).
文摘Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated EGFR.However,the efficacy of EGFR-TKIs in wild-type(wt)EGFR tumours has been shown to be marginal.Methods that can sensitize Erlotinib to EGFR wild-type NSCLC remain rare.Herein,we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt NSCLCs.Our results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor(VEGF)inhibitor,Bevacizumab(Bev),to EGFR-wt tumours.The nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour growth.Moreover,Bev normalizes the tumour embedded vessels,further promoting the therapeutic efficacy of Erlotinib.In addition,the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging(MRI).Collectively,our study,for the first time,demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC,paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.
