Photoacoustic agents combining photodynamic therapy(PDT) and photothermal therapy(PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared...Photoacoustic agents combining photodynamic therapy(PDT) and photothermal therapy(PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared(NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging(PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol,-thio, and-seleno moieties into NIR heptamethine cyanine(Cy7) skeleton(Cy7-X-NH_(2), X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT.Additionally, we designed a series of nitroreductase(NTR)-activated photoacoustic probes(Cy7-X-NO_(2),X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe,Cy7-Se-NO_(2)-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.展开更多
Background:At present,biopsy is essential for the diagnosis of prostate cancer(PCa)before radical prostatectomy(RP).However,with the development of prostate-specific membrane antigen positron emission tomography/compu...Background:At present,biopsy is essential for the diagnosis of prostate cancer(PCa)before radical prostatectomy(RP).However,with the development of prostate-specific membrane antigen positron emission tomography/computed tomography(PSMA PET/CT)and multiparametric magnetic resonance imaging(mpMRI),it might be feasible to avoid biopsy before RP.Herein,we aimed to explore the feasibility of avoiding biopsy before RP in patients highly suspected of having PCa after assessment of PSMA PET/CT and mpMRI.Methods:Between December 2017 and April 2022,56 patients with maximum standardized uptake value(SUVmax)of≥4 and Prostate Imaging Reporting and Data System(PI-RADS)≥4 lesions who received RP without preoperative biopsy were enrolled from two tertiary hospitals.The consistency between clinical and pathological diagnoses was evaluated.Preoperative characteristics were compared among patients with different pathological types,T stages,International Society of Urological Pathology(ISUP)grades,and European Association of Urology(EAU)risk groups.Results:Fifty-five(98%)patients were confirmed with PCa by pathology,including 49(89%)with clinically significant prostate cancer(csPCa,defined as ISUP grade≥2 malignancy).One patient was diagnosed with high-grade prostatic intraepithelial neoplasia(HGPIN).CsPCa patients,compared with clinically insignificant prostate cancer(cisPCa)and HGPIN patients,were associated with a higher level of prostate-specific antigen(22.9 ng/mL vs.10.0 ng/mL,P=0.032),a lower median prostate volume(32.2 mL vs.65.0 mL,P=0.001),and a higher median SUVmax(13.3 vs.5.6,P<0.001).Conclusions:It might be feasible to avoid biopsy before RP for patients with a high probability of PCa based on PSMA PET/CT and mpMRI.However,the diagnostic efficacy of csPCa with PI-RADS≥4 and SUVmax of≥4 is inadequate for performing a procedure such as RP.Further prospective multicenter studies with larger sample sizes are necessary to confirm our perspectives and establish predictive models with PSMA PET/CT and mpMRI.展开更多
Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed ...Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed to design a novel CAR-natural killer(NK)cells with a clinically significant tumoricidal effect on CRPC.Methods:We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector.Different intracellular segments(CD244,NKG2D,or CD3ζ)were screened to identify the best candidate according to cell lysis assay and CD107a expression levels.To enhance the affinity of the CAR to the tumor antigen,we compared an antibody specific for prostate-specific membrane antigen(anti-PSMA)with PSMA-targeted polypeptide(p-PSMA),which was screened by phage display combinatorial library.Then,CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated.In addition,we verified their tumor-killing effect in vitro and in vivo.The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay.Moreover,ferroptosis-related cell death was explored as a possible underlying mechanism.Results:Three different CAR intracellular regions CAR1(CD244),CAR2(CD244,NKG2D)and CAR3(CD244,NKG2D,and CD3ζ)were constructed.CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells.Compared with anti-PSMA,p-PSMA exhibited enhanced affinity for the tumor antigen.Thus,p-PSMA-CAR-NK92MI cells,which expressed CAR with a polypeptide-based antigen-binding region,an intracellular CD244 and a NKG2D costimulatory domain,were generated.They could selectively and successfully kill PSMA+target cells and exhibited specific lysis rate of 73.19%for PSMA-positive C4-2 cells and 33.04%for PSMA-negative PC3 cells.Additionally,p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ,TNF-αand granzyme B than NK92MI cells.In a CRPC cancer xenograft model,p-PSMA-CAR-NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells.Moreover,ferroptosis is a potential mechanism through which CAR-NK92MI cells attack cancer cells,and is triggered by IFN-γ.Conclusions:p-PSMA-CAR-NK92MI cells can effectively kill CRPCPSMA+cells in vitro and in vivo.This strategy may provide additional treatment options for patients with CRPC.展开更多
Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgic...Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.展开更多
基金partially supported by the National Key R&D Program of China (No.2022YFE0199700)the National Natural Science Foundation of China (NSFC) projects (Nos.22077139and 22122705)CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2022-I2M-2–002)。
文摘Photoacoustic agents combining photodynamic therapy(PDT) and photothermal therapy(PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared(NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging(PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol,-thio, and-seleno moieties into NIR heptamethine cyanine(Cy7) skeleton(Cy7-X-NH_(2), X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT.Additionally, we designed a series of nitroreductase(NTR)-activated photoacoustic probes(Cy7-X-NO_(2),X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe,Cy7-Se-NO_(2)-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.
基金supported by the National Key R&D Program of China(No.2022YFE0200800)the Key Project of Tianjin Municipal Science and Technology Commission(No.19ZXDBSY00050)+2 种基金the National Natural Science Foundation of China(Nos.81972400 and 82202962)the CAMS Initiative for Innovative Medicine(Nos.2022-I2M-1-008,2021-I2M-1-015,2022-I2M-2-002,and 2023-I2M-QJ-006)the Capital Health Research and Development of Special Funding(No.2022-1-4021).
文摘Background:At present,biopsy is essential for the diagnosis of prostate cancer(PCa)before radical prostatectomy(RP).However,with the development of prostate-specific membrane antigen positron emission tomography/computed tomography(PSMA PET/CT)and multiparametric magnetic resonance imaging(mpMRI),it might be feasible to avoid biopsy before RP.Herein,we aimed to explore the feasibility of avoiding biopsy before RP in patients highly suspected of having PCa after assessment of PSMA PET/CT and mpMRI.Methods:Between December 2017 and April 2022,56 patients with maximum standardized uptake value(SUVmax)of≥4 and Prostate Imaging Reporting and Data System(PI-RADS)≥4 lesions who received RP without preoperative biopsy were enrolled from two tertiary hospitals.The consistency between clinical and pathological diagnoses was evaluated.Preoperative characteristics were compared among patients with different pathological types,T stages,International Society of Urological Pathology(ISUP)grades,and European Association of Urology(EAU)risk groups.Results:Fifty-five(98%)patients were confirmed with PCa by pathology,including 49(89%)with clinically significant prostate cancer(csPCa,defined as ISUP grade≥2 malignancy).One patient was diagnosed with high-grade prostatic intraepithelial neoplasia(HGPIN).CsPCa patients,compared with clinically insignificant prostate cancer(cisPCa)and HGPIN patients,were associated with a higher level of prostate-specific antigen(22.9 ng/mL vs.10.0 ng/mL,P=0.032),a lower median prostate volume(32.2 mL vs.65.0 mL,P=0.001),and a higher median SUVmax(13.3 vs.5.6,P<0.001).Conclusions:It might be feasible to avoid biopsy before RP for patients with a high probability of PCa based on PSMA PET/CT and mpMRI.However,the diagnostic efficacy of csPCa with PI-RADS≥4 and SUVmax of≥4 is inadequate for performing a procedure such as RP.Further prospective multicenter studies with larger sample sizes are necessary to confirm our perspectives and establish predictive models with PSMA PET/CT and mpMRI.
基金Capital Science and Technology LeadingTalent Project, Grant/Award Number:Z181100006318007National NaturalScience Foundation of China,Grant/Award Numbers: 81972400,32100631+2 种基金Beijing Excellent TalentsProgram-Youth Backbone Project,Grant/Award Number:2018000032600G393Young EliteScientists Sponsorship Program by ChinaAssociation for Science and Technology,Grant/Award Number: YESS20210056Beijing Hope Run Special Fund of CancerFoundation of China, Grant/AwardNumber: LC2019B02。
文摘Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed to design a novel CAR-natural killer(NK)cells with a clinically significant tumoricidal effect on CRPC.Methods:We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector.Different intracellular segments(CD244,NKG2D,or CD3ζ)were screened to identify the best candidate according to cell lysis assay and CD107a expression levels.To enhance the affinity of the CAR to the tumor antigen,we compared an antibody specific for prostate-specific membrane antigen(anti-PSMA)with PSMA-targeted polypeptide(p-PSMA),which was screened by phage display combinatorial library.Then,CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated.In addition,we verified their tumor-killing effect in vitro and in vivo.The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay.Moreover,ferroptosis-related cell death was explored as a possible underlying mechanism.Results:Three different CAR intracellular regions CAR1(CD244),CAR2(CD244,NKG2D)and CAR3(CD244,NKG2D,and CD3ζ)were constructed.CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells.Compared with anti-PSMA,p-PSMA exhibited enhanced affinity for the tumor antigen.Thus,p-PSMA-CAR-NK92MI cells,which expressed CAR with a polypeptide-based antigen-binding region,an intracellular CD244 and a NKG2D costimulatory domain,were generated.They could selectively and successfully kill PSMA+target cells and exhibited specific lysis rate of 73.19%for PSMA-positive C4-2 cells and 33.04%for PSMA-negative PC3 cells.Additionally,p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ,TNF-αand granzyme B than NK92MI cells.In a CRPC cancer xenograft model,p-PSMA-CAR-NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells.Moreover,ferroptosis is a potential mechanism through which CAR-NK92MI cells attack cancer cells,and is triggered by IFN-γ.Conclusions:p-PSMA-CAR-NK92MI cells can effectively kill CRPCPSMA+cells in vitro and in vivo.This strategy may provide additional treatment options for patients with CRPC.
基金supported by the National Natural Science Foundation of China(NSFC)projects(22122705,22077139 and 81972400)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-054 and 2021-I2M-1-015)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China).
文摘Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.
