BIOCONJUGATE CHEMISTRY
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2018
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IF 4.485
Jianyue Feng,Qiang Luo,Yun Chen,Bing Li,Kui Luo,Jingbo Lan,Yunlong Yu,Shiyong Zhang
Herein, a new theranostic nanoplatform was built by introducing DOTA on the surface of the cross-linked small molecular micelles. This nanoplatform consisted of three parts: (1) Hydrophobic alkyl chain functioned with alkenes as cross-linkable part to ensure the robust stability in vivo; (2) Hydrophilic DOTA for not only gadolinium ions complexion as MR imaging contrast agents but also platinum ions complexion as drug carriers; (3) Cisplatin as antitumor drug and MR imaging amplifier simultaneously. The metal loading content of the resulting Pt/Gd@DOTA-CSMs was up to 12 and 14 wt % for Gd(III) and Pt(II), respectively. The longitudinal relaxation rate of Gd@DOTA-CSMs (8.46 mM–1 s–1) was 2.6 times than that of the clinical Gd-DTPA (3.23 mM–1 s–1). When cisplatin was involved, not only great antitumor efficiency was achieved, but higher longitudinal relaxation rate of Pt/Gd@DOTA-CSMs (11.17 mM–1 s–1) was carried out due to the extension of rotational correlation time. The experiments of Balb/c mice bearing 4T1 xenograft indicated that Pt/Gd@DOTA-CSMs had better antitumor activity, lower side effect than clinically used cisplatin, and greater MR imaging than Gd-DTPA. All the results proved that the nanoplatform of DOTA-CSMs held remarkable potential in the field of therapeutics.
研究领域:
纳米医学
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生物材料
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肿瘤学
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影像医学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
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2024
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IF 8.6
Song Yangmeihui,Qin Chunxia,Chen Yixiong,Ruan Weiwei,Gai Yongkang,Song Wenyu,Gao Yu,Hu Wenzhu,Qiao Pengxin,Song Xiangming,Lv Xiaoying,Zheng Danzha,Chu Huikuan,Jiang Dawei,Yang Ling,Lan Xiaoli
Purpose The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([ 68 Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. Methods The preclinical study employed [ 68 Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [ 68 Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [ 68 Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). Results [ 68 Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [ 68 Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). Conclusion [ 68 Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. Trial registration NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939
研究领域:
医学影像学
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肝脏病学
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分子影像学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2020
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IF 2.463
Xueyu Wang,Xiaoyang Hu,Lianjun Song,Xiuying Yang,Qian Xiao,Haowei Xu,Songdong Ding
The two DOTA-tetraamide ligands, DOTAM- n -butyl (1,4,7,10-tetrakis[( N - n -butyl; carbamoyl)methyl]-1,4,7,10-tetraazacyclododecane) and DOTAM-benzyl (1,4,7,10- tetrakis[( N -benzylcarbamoyl)methyl]-1,4,7,10-tetraazacyclododecane), were synthesized and characterized by MS, NMR and FTIR spectra. In acid solution, DOTAM- n -butyl was liable to be protonated. FTIR, 1 H NMR, ESI-MS spectra and X-ray diffraction analyses revealed that the nitrogen atoms of cyclen ring combined two protons to form a cation with two positive charges. The protonated DOTAM- n -butyl had strong extraction ability and good selectivity for ReO 4 − . It was extracted by means of the substitution of one ReO 4 − for one NO 3 − in the 1:2 complex of DOTAM- n -butyl with HNO 3 . The solvent extraction and X-ray crystallography demonstrated an anion-exchange extraction model. Meanwhile, X-ray crystal structure analyses of ligand complexes with HReO 4 or HNO 3 also indicated that ReO 4 − or NO 3 − ions were located in the gap between the upper and lower protonated ligands through multiple hydrogen bonds and electrostatic interactions.
研究领域:
化学
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放射化学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Yinghui Ding,Xinzhong Ruan,Kun Shu,Weiyuan Xu,Yao Liu,Gengshen Mo,Jiao Xu,Yong Jian,Jilai Zhang,Lingfeng Zhang,Keren Wang,Ji-Ting Hou,Jianliang Shen,Zhihan Yan,Fangfu Ye,Jiang Zhu,Lixiong Dai
Hepatobiliary-specific magnetic resonance imaging contrast agents (MRI CAs) play a crucial role in the early diagnosis of hepatocellular carcinoma (HCC). However, only two acyclic CAs, Gd-BOPTA and Gd-EOB-DTPA, exhibit unfavorable kinetic inertness. Our study focused on the development of superior stable innovative macrocyclic CAs. By introducing a lipophilic benzyloxy group (OBn) into the H4DOTA ring (Gd-L1), we achieved significant enhancement in kinetic inertness. In vivo experiments in mice demonstrated that 40% of the dosage was distributed to the liver at 5 min, providing sustained hepatic enhancement for over 35 min. We also developed an MPO-responsive MRI CA (Gd-L3), which can participate in the “peroxidase cycle” as the substrate, generating oligomers with a 3.8-fold increase in relaxivity, and selectively enhance the lesion in an acute gout mouse model. Overall, our work represents a significant advancement in the field of hepatic and inflammatory MRI, offering promising avenues for early diagnosis and improved imaging outcomes.
研究领域:
医学成像
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TALANTA
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2016
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IF 4.035
Junyong Dai,Miaode Wang,Hailong Liu
It is urgent to selectively enrich trace phosphorylated proteins or peptides from complex biological sample for mass spectrometry (MS)-based phosphoproteomics. In this study, a novel immobilized metal affinity chromatography (IMAC) material with DOTA(1,4,7,10-tetraazacyclododecane N, N′, N′′, N′′′-tetra-acetic acid) coated on the surface of TiO 2 nanomaterials and functionalized with the metal ion Zr 4+ (TiO 2 @DOTA-Zr) has been synthesized successfully to improve the enrichment specificity and sensitivity for phosphopeptides. TiO 2 nanomaterials were chosen as a support matrix, which will offer a high specific surface area to enhance the amounts of immobilized Zr 4+ ions and will provide an additional selectivity for the special enrichment of phosphopeptides. Also, the introduction of DOTA will endow a stronger binding interaction between the Zr 4+ ion and DOTA to reduce the loss of the metal ion Zr 4+ during sample loading and washing steps. The novel TiO 2 @DOTA-Zr nanohybrids exhibited higher sensitivity and selectivity for phosphopeptides from the standard protein digests, the tryptic digests of nonfat milk and human serum, showing a great selective enrichment capability toward the complicated biological samples.
研究领域:
生物化学
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蛋白质组学
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产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
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2024
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IF 4
Ningxin Yang,Yuelin Huang,Xiaoyu Wang,Dengbin Wang,Defan Yao,Gang Ren
The prevalence and fatality rates of gastric cancer (GC) remain elevated, with advanced stages presenting a grim prognosis. Noninvasive diagnosis of GC cancer often proves challenging until the disease has progressed to an advanced stage or metastasized. Initially, the level of fibronectin (FN) in cancer-associated fibroblasts (CAFs) of GC was at least 3.7 times higher than that in normal fibroblasts. Herein, two FN-targeting magnetic resonance/near-infrared fluorescence (MR/NIRF) imaging contrast agents were developed to detect GC and peritoneal metastasis noninvasively. The probes CREKA-Cy7-(Gd-DOTA) and CREKA-Cy7-(Gd-DOTA)3 demonstrated significant FN-targeting capability (with dissociation constants of 1.0 and 2.1 mM) and effective MR imaging performance (with proton relaxivity values of 9.66 and 27.44 mM–1 s–1 at 9.4 T, 37 °C). In vivo imaging revealed a high signal-to-noise ratio and successful visualization of GC metastasis using NIRF imaging as well as successful tumor detection in MR imaging. Therefore, this study highlights the potential of FN-targeting probes for GC diagnosis and aids in the advancement of new diagnostic strategies for the clinical detection of GC.
研究领域:
医学影像学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
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2025
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IF 4.5
Nianting Ju,Boyu Tan,Hongyue Lou,Ying Zhang,Kun Qian,Chunrong Qu,Quanyong Luo,Zhen Cheng
As an important tumor-associated carbohydrate antigen, the Thomsen–Friedenreich (T or TF) antigen has become an attractive target for tumor diagnosis and treatment. However, there has been very limited success in developing peptide- and small-molecule-based radiopharmaceuticals for this important target. Currently, only 64Cu-NO2A-TFpep has been reported as a radiolabeled peptide targeting the TF antigen, and it shows a low tumor-to-liver ratio due to 64Cu retention in the liver. In this study, a novel PET probe targeting the TF antigen (DOTA-TFpep) was synthesized using 2,2′,2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) chelator for increasing the hydrophilic property and for radiolabeling with different radionuclides. DOTA-TFpep was then radiolabeled with 68Ga for positron emission tomography (PET) imaging of breast tumors expressing the TF antigen. 68Ga-DOTA-TFpep was confirmed by radio-HPLC with a purity greater than 98% and high stability in PBS. Immunofluorescence analysis confirmed the TF antigen expression of 4T1 and K1 cell lines. Cell uptake studies confirmed its targeting specificity. Further in vivo biodistribution studies in high (4T1) and low (K1) TF antigen-expression xenograft models demonstrated the favorable pharmacokinetics property of the probe. PET imaging and biodistribution showed that 68Ga-DOTA-TFpep exhibited specific tumor uptake. Moreover, compared with the widely studied 64Cu-NO2A-TFpep, 68Ga-DOTA-TFpep showed lower liver uptake and a higher tumor-to-liver ratio (1.31 ± 0.20 for 64Cu-NO2A-TFpep and 0.48 ± 0.15 for 68Ga-DOTA-TFpep at 120 min after injection). In summary, this study demonstrates the synthesis and evaluation of the TF antigen-targeting probe 68Ga-DOTA-TFpep. It shows favorable in vivo tumor imaging properties, highlighting it as a promising molecular probe targeting the TF antigen.
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Chunmei Yang,Didi Gu,Xin Zhu,Pan Han,Liping Pan,Xiaoling Che,Xinyao Chen,Qiuyu Meng,Guidong Dai,Lu Yang
Spectral CT can overcome the shortcomings of conventional CT, however, clinically used iodized contrast agents are not ideal for spectral CT imaging, which calls for the development of novel contrast agent with high attenuation coefficient. In this study, a small molecule lanthanide chelate Ytterbium-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Yb-DOTA) was prepared by a simple and green one-step method, and it had multi-advantages such as good stability, excellent biocompatibility and high performance of spectral CT imaging in vitro and in vivo. In addition, Yb-DOTA had more prominent ability to visualize renal tissue, GI tract, the heart and venous system in both conventional and spectral CT imaging compared with clinical iohexol. Moreover, higher tissue contrast and enhanced sensitivity were achieved at high monochromatic energies (70–150 keV) after Yb-DOTA administration, indicating its superior spectral CT imaging performance. Yb-DOTA is expected to be a novel contrast agent to enhance the diagnostic sensitivity and accuracy.
研究领域:
医学影像学
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分子影像
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生物医学工程
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产品关联
DOI
高影响因子
BIOCONJUGATE CHEMISTRY
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2025
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IF 3.9
Jing Wang,Chengxue He,Rui Guo,Li Wen,Jinping Tao,Huimao Zhang,HaiFeng Huang,Hua Zhu,Zhi Yang,Xianteng Yang
Malignant glioma highly expresses carbonic anhydrase IX (CAIX). This study aimed to develop [177Lu]Lu-XYIMSR-01, a small-molecule therapeutic agent CAIX, to assess its potential for treating malignant glioma. [177Lu]Lu-XYIMSR-01 was synthesized by radiolabeling DOTA-XYIMSR-01 with 177Lu. In vitro assays were conducted to evaluate the affinity for U87MG tumor cells. The probe was injected via the tail vein into subcutaneous and orthotopic U87MG models for micro-SPECT/CT imaging. The survival rates of tumor-bearing mice were assessed after [177Lu]Lu-XYIMSR-01 injection by intratumoral in orthotopic models, including untreated controls and those treated with Temozolomide or combination therapy. After purification, the radiochemical yield of [177Lu]Lu-XYIMSR-01 was 86.47 ± 2.42%, with a radiochemical purity (RCP) of 99%. Its cell uptake in U87MG cells was 3.70 ± 0.57 ‰ AD/105 cells, significantly higher than that in HCT116 cells (0.68 ± 0.16 ‰ AD/105 cells, P = 0.001). In the biodistribution study, [177Lu]Lu-XYIMSR-01 uptake in U87MG tumors was 6.19 ± 1.37%ID/g, with a tumor/muscle ratio of 20.14 ± 3.24. In the orthotopic glioma model, local injection combined with Temozolomide significantly improved survival and inhibited tumor growth. The results indicate that [177Lu]Lu-XYIMSR-01 is a promising therapeutic molecular probe for targeting CAIX, and its combination with Temozolomide significantly enhances treatment outcomes for malignant glioma.
研究领域:
肿瘤学
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分子影像学
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核医学
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产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
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2023
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IF 6.2
Shengxiang Fu,Zhongyuan Cai,Li Liu,Xiaomin Fu,Chunchao Xia,Su Lui,Qiyong Gong,Bin Song,Hua Ai
MRI contrast agents with high kinetic stability and relaxivity are the key objectives in the field. We previously reported that Gd-DOTA backboned-bound branched polymers possess high kinetic stability and significantly increased T1 relaxivity than traditional branched polymer contrast agents. In this work, non-PEGylated and PEGylated amphiphilic Gd-DOTA backboned-bound branched polymers [P(GdDOTA-C6), P(GdDOTA-C10), mPEG-P(GdDOTA-C6), and mPEG-P(GdDOTA-C10)] were obtained by sequential introduction of rigid carbon chains (1,6-hexamethylenediamine or 1,10-diaminodecane) and mPEG into the structure of Gd-DOTA backboned-bound branched polymers. It is found that the introduction of both rigid carbon chains, especially the longer one, and mPEG can increase the kinetic stability and T1 relaxivity of Gd-DOTA backboned-bound branched polymers. Among them, mPEG-P(GdDOTA-C10) possesses the highest kinetic stability (significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol) and T1 relaxivity (42.9 mM–1 s–1, 1.5 T), 11 times that of Gd-DOTA and 1.4 times that of previously reported Gd-DOTA backboned-bound branched polymers. In addition, mPEG-P(GdDOTA-C10) showed excellent MRA effect in cardiovascular and hepatic vessels at a dose (0.025 or 0.05 mmol Gd/kg BW) far below the clinical range (0.1–0.3 mmol Gd/kg BW). Overall, effective branched-polymer-based contrast agents can be obtained by a strategy in which rigid carbon chains and PEG were introduced into the structure of Gd-DOTA backbone-bound branched polymers, resulting in excellent kinetic stability and enhanced T1 relaxivity.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 7.3
Weiyuan Xu,Xinjian Ye,Min Wu,Xin Jiang,Lik Hang Hugo TSE,Yanjuan Gu,Kun Shu,Liuhui Xu,Yong Jian,Gengshen Mo,Jiao Xu,Yinghui Ding,Ruonan Gao,Jianliang Shen,Fangfu Ye,Zhihan Yan,Lixiong Dai
The leakage of gadolinium ions (Gd3+) from commercial Gd3+-based contrast agents (GBCAs) in patients is currently the major safety concern in clinical magnetic resonance imaging (MRI) scans, and the lack of task-specific GBCAs limits its usage in the early detection of disease and imaging of specific biological regions. Herein, ultrastable GBCAs were constructed via decorating chiral Gd-DOTA with a phenylic analogue to one of the pendent arms, and the stability constant was determined as high as 27.08, accompanied by negligible decomplexation in 1 M of HCl over 2 years. A hepatic-specific chiral Gd-DOTA was screened out as a potential alternative to commercial Gd-EOB-DTPA, while combination with functional molecules favored chiral Gd-DOTA as tumor targeting probes. Therefore, the novel chiral Gd-DOTA is believed to be an ideal platform for designing the next generation of GBCAs for various clinical purposes due to its outstanding inert nature.
研究领域:
医学影像学
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分子生物学
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化学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2024
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IF 6.1
Mingxing Huang,Weichen Wang,Yingwei Wang,Wang Rang,Lili Pan,Xin Li,Bo Li,Jinsong Zhang,Ruoxiang Wang,Yi Zhang,Rong Tian
Malignant tumors pose substantial treatment challenges due to their heterogeneity, metastatic potential, and therapeutic resistance, underscoring the urgent need for more effective treatment options. This study developed and characterized a novel radionuclide drug conjugate (RDC) employing a tumor-targeting heptamethine carbocyanine dye (DZ) for its high specificity and favorable safety profile. The RDC, DOTA-DZ-HX, was synthesized by conjugating DZ with dodecane tetraacetic acid (DOTA) through a dipeptide linker. The anti-tumor efficacy and biodistribution of [177Lu]Lu-DOTA-DZ-HX were assessed in H1975 and Hela xenograft models. [177Lu]Lu-DOTA-DZ-HX showed high stability, specific tumor accumulation, and substantial radioactivity retention at the tumor site for seven days. Biodistribution analysis revealed that the drug exhibited prolonged blood circulation with gradual clearance. Additionally, [177Lu]Lu-DOTA-DZ-HX could effectively and selectively inhibit tumor growth, as evidenced by a significant reduction in tumor volume. These findings suggest that heptamethine carbocyanine dye-directed radionuclide targeting could provide an effective treatment for cancer and potentially other malignancies, representing a significant advancement in cancer therapy.
研究领域:
肿瘤学
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放射医学
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分子影像学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）