Scientific Reports
·
2021
·Vol. 11
·期 1
·1-10
·
IF 4.38
Chen Huanyu,Cai Ping,Feng Yue,Sun Zhanliang,Wang Yinwen,Chen Yue,Zhang Wei,Liu Nan,Zhou Zhijun
68 Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68 Ga-positron emission tomography ( 68 Ga-PET). Nevertheless, current 68 Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68 Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68 Ga-SC691 and 68 Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68 Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68 Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68 Ga-PSMA-11.
研究领域:
医学影像学
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肿瘤学
·
核医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Zuojie Li,Yuhao Jiang,Qing Ruan,Guangxing Yin,Peiwen Han,Xiaojiang Duan,Junbo Zhang
The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many 99mTc-labeled PSMA-targeted tracers have been developed. However, the high renal uptake of these 99mTc-labeled tracers is a common problem that limits their clinical application. In this work, the ligand (EUKPG) using DPro-Gly as the linker was synthesized and three 99mTc-labeled complexes ([99mTc]Tc-EUKPG-EDDA, [99mTc]Tc-EUKPG-TPPTS, [99mTc]Tc-EUKPG-TPPMS) with different coligands were prepared and evaluated. Among them, [99mTc]Tc-EUKPG-EDDA showed the most favorable pharmacokinetic properties, with significantly reduced uptake in the kidney (14.04 ± 0.23% ID/g), rapid clearance and low uptake in nontarget organs, thus making it to exhibit high tumor-to-background ratios (tumor/blood: 7.47, tumor/muscle: 12.65). Affinity studies have shown that it has high specificity for PSMA both in vivo and in vitro. Therefore, [99mTc]Tc-EUKPG-EDDA has great potential as a promising molecular tracer to target PSMA for tumor imaging.
研究领域:
医学影像学
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肿瘤学
·
放射化学
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DOI
PubMed
高影响因子
Frontiers in Oncology
·
2022
·
IF 5.738
Ren Ya’nan,Liu Chen,Liu Teli,Duan Xiaojiang,Zhang Qian,Liu Jiayue,Wang Pei,Guo Qian,Yang Xing,Du Peng,Zhu Hua,Yang Zhi
Purpose: This study aimed to introduce a novel [18F]AlF-labeled ODAP-Urea-based Prostate-specific membrane antigen (PSMA) probe, named [18F]AlF-PSMA-137, which was derived from the successful modification of glutamate-like functional group. The preclinically physical and biological characteristics of the probe were analyzed. Polit clinical PET/CT translation was performed to analyze its feasibility in clinical diagnosis of prostate cancer.Methods: [18F]AlF-PSMA-137 was maturely labeled with the [18F]AlF2+ labeling technique. It was analyzed by radio-HPLC for radiochemical purity and stability analysis in vitro and in vivo. The PSMA specificity was investigated in PSMA-positive (LNCaP) and PSMA-negative (PC3) cells, and the binding affinity was evaluated in LNCaP cells. Micro-PET/CT imaging was performed in mice bearing LNCaP or PC3 tumors. Thirteen patients with newly diagnosed prostate cancer were included for [18F]AlF-PSMA-137 PET/CT imaging. Physiologic biodistribution and tumor burden were semi-quantitatively evaluated and the radiation dosimetry of [18F]AlF-PSMA-137 was estimated.Results: The radiochemical yield of [18F]AlF-PSMA-137 was 54.2 ± 10.7% (n = 16) with the radiochemical purity over 99% and the specific activity of 26.36 ± 7.33 GBq/μmol. The binding affinity to PSMA was 2.11 ± 0.63 nM. [18F]AlF-PSMA-137 showed high cell/tumor uptake which can be specifically blocked by PSMA inhibitor. According to the biodistribution in patients, [18F]AlF-PSMA-137 was mainly accumulated in kidneys, lacrimal glands, parotid glands, submandibular glands and liver which was similar to the extensive Glu-Ureas based probes. A total of 81 lesions were detected in PET/CT imaging and over 91% of lesions increased between 1 h p.i. (SUVmean: 10.98 ± 18.12) and 2 h p.i. (SUVmean: 14.25 ± 21.28) (p < 0.001). Additionally, the probe showed intensive accumulation in lesions which provided excellent imaging contrast with the high tumor-to-muscle ratio of 15.57 ± 27.21 at 1 h p.i. and 25.42 ± 36.60 at 2 h p.i. (p < 0.001), respectively. The effective dose of [18F]AlF-PSMA-137 was estimated as 0.0119 ± 0.0009 mSv/MBq.Conclusion: An ODAP-Urea-based PSMA probe [18F]AlF-PSMA-137 was successfully prepared with high specificity and binding affinity to PSMA. Micro-PET/CT imaging study demonstrated its feasibility for prostate cancer imaging. Pilot clinical study showed its potential for delay-imaging and prostate cancer detection.
研究领域:
医学影像学
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肿瘤学
·
放射化学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2022
·Vol. 15
·期 5
·513
·
IF 5.215
Ya’nan Ren,Teli Liu,Chen Liu,Xiaoyi Guo,Feng Wang,Hua Zhu,Zhi Yang
Prostate-specific membrane antigen (PSMA) is an ideal target for the diagnosis and treatment of prostate cancer. Due to the short half-life in blood, small molecules/peptides are rapidly cleared by the circulatory system. Prolonging the half-life of PSMA probes has been considered as an effective strategy to improve the tumor detection. Herein, we reported a64Cu-labeled PSMA tracer conjugating with maleimidopropionic acid (MPA),64Cu-PSMA-CM, which showed an excellent ability to detect PSMA-overexpressing tumors in delayed time. Cell experiments in PSMA-positive 22Rv1 cells, human serum albumin binding affinity, and micro-PET imaging studies in 22Rv1 model were performed to investigate the albumin binding capacity and PSMA specificity. Comparisons with64Cu-PSMA-BCH were performed to explore the influence of MPA on the biological properties.64Cu-PSMA-CM could be quickly prepared within 30 min. The uptake of64Cu-PSMA-CM in 22Rv1 cells increased over time and it could bind to HSA with a high protein binding ratio (67.8 ± 1.5%). When compared to64Cu-PSMA-BCH,64Cu-PSMA-CM demonstrated higher and prolonged accumulation in 22Rv1 tumors, contributing to high tumor-to-organ ratios. These results showed that64Cu-PSMA-CM was PSMA specific with a higher tumor uptake, which demonstrated that MPA is an optional strategy for improving the radioactivity concentration in PSMA-expressing tumors and for developing the ligands for PSMA radioligand therapy.Keywords:PSMA;prostate cancer;copper radioisotopes;maleimidopropionic acid;PET imaging
研究领域:
医学影像学
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肿瘤学
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放射化学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2014
·Vol. 9
·期 11
·e112200
·
IF 3.534
Jian Jin,Bowen Sui,Jingxin Gou,Jingshuo Liu,Xing Tang,Hui Xu,Yu Zhang,Xiangqun Jin
In this content, a small molecular ligand of prostate specific membrane antigen (SMLP) conjugated poly (caprolactone) (PCL)-b-poly (ethylene glycol) (PEG) copolymers with different block lengths were synthesized to construct a satisfactory drug delivery system. Four different docetaxel-loaded polymeric micelles (DTX-PMs) were prepared by dialysis with particle sizes less than 60 nm as characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). Optimization of the prepared micelles was conducted based on short-term stability and drug-loading content. The results showed that optimized systems were able to remain stable over 7 days. Compared with Taxotere, DTX-PMs with the same ratio of hydrophilic/hydrophobic chain length displayed similar sustained release behaviors. The cytotoxicity of the optimized targeted DTX-PCL 12K -PEG 5K -SMLP micelles (DTX-PMs2) and non-targeted DTX-PCL 12K -mPEG 5K micelles (DTX-PMs1) were evaluated by MTT assays using prostate specific membrane antigen (PSMA) positive prostate adenocarcinoma cells (LNCaP). The results showed that the targeted micelles had a much lower IC50 than their non-targeted counterparts (48 h: 0.87±0.27 vs 13.48±1.03 µg/ml; 72 h: 0.02±0.008 vs 1.35±0.54 µg/ml). In vitro cellular uptake of PMs2 showed 5-fold higher fluorescence intensity than that of PMs1 after 4 h incubation. According to these results, the novel nano-sized drug delivery system based on DTX-PCL-PEG-SMLP offers great promise for the treatment of prostatic cancer.
研究领域:
药学
·
癌症研究
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纳米技术
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Ping Cai,Sufan Tang,Li Xia,Yinwen Wang,Yang Liu,Yue Feng,Nan Liu,Yue Chen,Zhijun Zhou
Since prostate-specific membrane antigen (PSMA) is upregulated in nearly all stages of prostate cancer (PCa), PSMA can be considered a viable diagnostic biomarker and treatment target in PCa. In this study, we have developed five 68Ga-labeled PSMA-targeted tracers, 68Ga-Flu-1, 68Ga-Flu-2, 68Ga-9-Ant, 68Ga-1-Nal, and 68Ga-1-Noi, to investigate the effect of lipophilic bulky groups on the pharmacokinetics of PSMA inhibitors compared to 68Ga-PSMA-11 and then explore their in vitro and in vivo properties. 68Ga-labeled PSMA inhibitors were obtained in 88.53–99.98% radiochemical purity and at the highest specific activity of up to 20 MBq/μg. These compounds revealed a highly efficient uptake and internalization into LNCaP cells and increased over time. PET imaging and biodistribution studies were performed in mice bearing PSMA expressing LNCaP prostate cancer xenografts. All tracers enabled clear visualization of tumors in PET images with excellent tumor-to-background contrast. The biodistribution studies showed that all these radioligands were excreted mainly via the renal pathway. The in vivo biodistribution of 68Ga-Flu-1 revealed higher tumor uptake (40.11 ± 9.24 %ID/g at 2 h p.i.) compared to 68Ga-PSMA-11 (28.10 ± 5.96 %ID/g at 2 h p.i.). Both in vitro and in vivo experiments showed that chemical modification of the lysine fragment significantly impacts tumor-targeting and pharmacokinetic properties. Great potential to serve as new PET tracers for prostate cancer has been revealed with these radiotracers─68Ga-Flu-1 in particular.
研究领域:
医学影像
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肿瘤学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 5
·964
·
IF 6.525
Yingying Zhang,Hongxia Duan,Heming Zhao,Lingling Qi,Yanhong Liu,Zheao Zhang,Chao Liu,Liqing Chen,Mingji Jin,Youyan Guan,Zhonggao Gao,Wei Huang
Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) during androgen deprivation therapy (ADR) in early stages of prostate cancer. Thus, rather than blocking the androgen-related pathway further, docetaxel (DTX)-based therapy has become the most effective and standard first-line chemotherapy for CRPC. Although the therapy is successful in prolonging the survival of patients with CRPC, chemotherapy resistance develops due to the abnormal activation of the androgen receptor (AR) signaling pathway. Thus, to optimize DTX efficacy, continued maximum suppression of androgen levels and AR signaling is required. Here, we designed a prostate-specific membrane antigen (PSMA)-targeted nanosystem to carry both DTX and AR siRNA (Di-PP/AR-siRNA/DTX) for CRPC treatment. Specifically, DTX was encapsulated into the hydrophobic inner layer, and the AR siRNA was then condensed with the cationic PEI block in the hydrophilic outer layer of the PEI-PLGA polymeric micelles. The micelles were further coated with PSMA-targeted anionic polyethylene glycol-polyaspartic acid (Di-PEG-PLD). In vitro and in vivo results demonstrated that the resulting Di-PP/AR-siRNA/DTX exhibited prolonged blood circulation, selective targeting, and enhanced antitumor effects. Consequently, Di-PP/AR-siRNA/DTX holds great potential for efficient CRPC treatment by combining chemotherapy and siRNA silencing of androgen-related signaling pathways.Keywords:prostate cancer;androgen receptor;siRNA delivery;docetaxel;PSMA targeting
研究领域:
肿瘤学
·
药学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zuojie Li,Xiaojiang Duan,Peiwen Han,Guangxing Yin,Yuhao Jiang,Qing Ruan,Junbo Zhang
The development of novel tracers targeting prostate-specific membrane antigen (PSMA) has great potential for improving the diagnosis and treatment of prostate cancer (PCa). This study aimed to improve the absolute tumor uptake and tumor-to-background ratios (TBRs) of this novel PSMA tracer by increasing the number of pharmacophores, Glu-urea-Lys (EuK), that specifically bind to PSMA. We successfully synthesized four radioligands and prepared a total of 12 stable radiotracers by coordinating 99mTc with various coligands. [99mTc]Tc-EUKD-EDDA showed the best pharmacokinetic properties both in vitro and in vivo. It effectively increased the absolute uptake in tumors and resulted in good tumor retention. Rapid clearance in nontarget organs resulted in high TBRs. High-contrast SPECT/CT images were obtained within 2–6 h after injection, suggesting that [99mTc]Tc-EUKD-EDDA has great application potential in time-lapse imaging of PCa, which is important for improving the diagnostic accuracy of PCa in clinical practice.
研究领域:
医学影像学
·
核医学
·
肿瘤学
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DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 10
·2051
·
IF 6.525
Wei Zhou,Jiandong Huang,Qingwei Xiao,Shunmin Hu,Shijia Li,Jie Zheng,Zhiyun Du,Jiangling Peng,Huixiong Chen
The prostate specific membrane antigen (PSMA), extensively overexpressed on prostate cancer (PCa) cell surface, has been validated as a diagnostic biomarker for PCa. However, insufficient attention has been paid to the development of PSMA-specific probes loaded with small chemical molecules for the in vivo molecular imaging of PCa. In this study, we innovatively labelled superparamagnetic iron oxide nanoparticles with a PSMA-targeting Glu-Urea-Lys scaffold. An optimized synthetic route was developed to offer a physiochemically stable probe. The probe demonstrated high binding affinity (0.38 ± 0.08 μg(Fe)/mL) and binding specificity to PSMA expressed on prostate cancer cell surface in vitro. In a xenograft PCa mouse model, significant negative contrast of the implanted prostate cancer xenograft could be specifically observed by MRI 6 h after tail vein injection of the tracer (Fe, 20 mg/kg), exhibiting its potential to exclusively enhance magnetic resonance detection of PCa.Keywords:prostate cancer;PSMA;molecular imaging;MRI contrast agent;SPIONs
研究领域:
肿瘤学
·
医学成像
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 9
·期 4
·1151-1161
·
IF 5.344
Liqun Dai,Guohua Shen,Yuanyuan Wang,Peng Yang,Hong Wang,Zhenhua Liu
Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of most prostate tumor cells and is considered a promising target for prostate cancer imaging and treatment. It is possible to establish a PSMA-targeted theranostic probe to achieve early diagnosis and treatment of this cancer type. In this contribution, we prepared a multifunctional melanin-like polydopamine (PDA) nanocarrier decorated with a small-molecule PSMA inhibitor, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine (DCL). PDA-DCL was then functionalized with perfluoropentane (PFP) and loaded with the photosensitizer chlorin e6 (Ce6) to give Ce6@PDA-DCL-PFP, which was successfully used for ultrasound-guided combined photodynamic/photothermal therapy (PDT/PTT) of prostate cancer. Compared with the corresponding non-targeted probe (Ce6@PDA-PEG-PFP), our targeted probe induced higher cellular uptake in vitro (6.5-fold) and more tumor accumulation in vivo (4.6-fold), suggesting strong active targeting capacity. Meanwhile, this new nanoplatform significantly enhanced the ultrasound contrast signal at the tumor site in vivo, thus facilitating precise and real-time detection of the tumor. In addition, this Ce6-loaded PDA nanoplatform produced a synergistic effect of PDT and PTT under 660 nm and 808 nm irradiation, inducing a more efficient killing effect compared with the individual therapy in vitro and in vivo. Furthermore, the tumor in the targeted group was more effectively suppressed than that in the non-targeted group under the same irradiation condition. This multifunctional probe may hold great potential for precise and early theranostics of prostate cancer.
研究领域:
癌症生物学
·
纳米技术
·
诊疗一体化
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2026
·Vol. 16
·期 12
·6843
·
IF 14.9
Li Yang,Tingchao Liu,Meng Huo,Weiping Jia,Yu Chen,Maoxu Ge,Yan Pan,Jianfei Shi,Xiaohai Li,Si Wang,Yikang Shi
Background High expression of prostate-specific membrane antigen (PSMA) is observed in advanced prostate cancer, supplying a promising target for precision therapeutic interventions. Despite its efficacy in metastatic castration-resistant disease, cabazitaxel (CTX) is limited by severe systemic toxicity and a narrow therapeutic index, underscoring the urgent demand for tumor-selective delivery systems. Methods A novel PSMA-targeted dextran-based conjugate, Dextran-CTX-GLA-EuK, was synthesized via click chemistry by conjugating CTX, γ-linolenic acid (GLA), and a Glu-urea-Lys (EuK) PSMA-targeting ligand to bifunctionalized dextran. Critical in vitro and in vivo PSMA blocking experiments (using the PSMA inhibitor 2-PMPA) were performed to validate its targeting specificity. A thorough myelosuppression study was performed in murine models to evaluate the systemic hematological safety profile. The biodistribution profile and in vivo antitumor efficacy of the conjugate were evaluated in murine xenograft models. Results The conjugate Dextran-CTX-GLA-EuK exhibited favorable physicochemical properties, high water solubility, and strong PSMA-binding affinity. In vitro and in vivo PSMA blocking experiments conclusively verifying its PSMA-mediated specific cellular internalization and tumor accumulation. In PSMA-overexpressing xenograft models, the conjugate demonstrated selective tumor enrichment, with intratumoral CTX levels up to 98.3-fold higher than those of parent CTX, while reducing exposure in normal tissues. Dextran-CTX-GLA-EuK exerted prominent dose-dependent tumor growth inhibition, attaining a 96.6% suppression rate at a 10 mg/kg dosage in PC-3/PSMA tumors and prolonging the survival of 22Rv1 tumor-bearing mice. Importantly, comprehensive myelosuppression assays revealed that the conjugate only induced a transient reduction in white blood cell and neutrophil counts (which rapidly recovered to baseline) without impairing bone marrow hematopoietic function; unlike CTX, the conjugate did not cause significant weight loss, organ toxicity, or hematological abnormalities in tumor-bearing mice. Conclusions These findings demonstrate that Dextran-CTX-GLA-EuK synergizes active targeting with dextran-based delivery, enhancing antitumor efficacy while abolishing dose-limiting toxicities. This strategy offers a clinically translatable approach for PSMA-directed therapy in prostate cancer.
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DOI
PubMed
高影响因子
TRIBOLOGY INTERNATIONAL
·
2023
·
IF 6.2
Yongqiang Wang,Xiao Liu,Rui Wang,Jiaying Zhang,Yanyan Bai,Qiang Chen,Pingxia Guo,Zhaogang Jing,Yurong Wang,Meirong Cai,Feng Guo,Feng Zhou
In this study, free radical polymerization was employed to prepare a supramolecular polymer gelator called PUMA-PSMA, containing urea groups. The incorporation of this gelator is anticipated to enhance the heat resistance of the gel lubricant. The resulting PUMA-PSMA gels demonstrate favorable mechanical strength and the ability to recover from deformation. Additionally, the PUMA-PSMA gel has a greater film thickness compared to the base oil when the oil supply is abundant. In cases of limited lubricant supply, the PUMA-PSMA gel effectively undergoes shear thinning, reducing the duration of oil starvation. These gel lubricants help prevent the loss of lubricant to some extent and are poised to serve as an innovative type of lubricant.
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）