JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
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
·
分子生物学
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DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2024
·
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
·
分子生物学
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2023
·
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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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
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
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DOI
PubMed
高影响因子
LANGMUIR
·
2026
·
IF 4.4
Youli Zhang,Lulu Wang,Yanmin Zheng,Lei Zhu,Dongsheng Li,Xinwei Zheng
Balancing the thermodynamic stability and biological clearance of supramolecular assemblies represents a fundamental challenge in the design of functional nanomedicines. To address this, we propose a concentration-responsive “assemble-for-uptake, disassemble-for-clearance” strategy implemented via rational molecular engineering of a minimalist, single-component Gd–DOTA amphiphile. We demonstrate that the alkyl chain length acts as a precise molecular dial to tune the critical micelle concentration (CMC), thereby dictating micellar stability, biological identity, and clearance pathways. Through this tuning, we identified Gd–C12 as the optimized agent, which self-assembles into spherical nanomicelles (38.6 ± 8.3 nm) with desirable T1 contrast (r2/r1 < 2) and kinetic stability surpassing unmodified Gd–DOTA. In vivo studies reveal that Gd–C12 provides potent hepatic enhancement (120% increase) via favorable MPS recognition, independent of organic anion-transporting polypeptide (OATP). Crucially, following hepatic uptake, the agent undergoes spontaneous disassembly upon physiological dilution/excretion, facilitating rapid systemic clearance (>97%) to resolve long-term retention concerns. This work presents Gd–C12 as a high-performance, transporter-independent contrast agent that bridges the gap between nanoparticles and small molecules, holding promise for providing reliable hepatic parenchymal enhancement regardless of OATP expression levels.
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高影响因子
Biomaterials Science
·
2024
·
IF 5.8
Jia-Hua Zou,Li-Li Chen,Yong-Guo Hu,Dong Zhou,Yong Li,Bin Zhang,Xin-Yue Xu,Bo Liu,Jin-Xuan Fan,Yuan-Di Zhao
Accurate tumor detection is crucial for the early discovery and subsequent treatment of small neoplastic foci. Molecular imaging, which combines non-invasiveness, high specificity, and strong sensitivity, excels in diagnosing early tumors and stands out among tumor diagnosis methods. Here, we introduced a dual-modal imaging probe capable of actively targeting tumor cells, suitable for both near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI). Dendritic mesoporous silica was used as a carrier for the probe, encapsulating Ag2S quantum dots (QDs) for NIR fluorescence imaging. Additionally, the probe conjugated the MRI contrast agent Gd-DOTA and cetuximab, which targeted EGFR on the tumor cell membrane surface, to achieve dual-modal imaging in the tumor area. This strategy provided a methodology for the accurate diagnosis of early-stage tumor lesions and guides precise lesion resection during surgery, offering significant potential for clinical application.
研究领域:
生物医学工程
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分子成像
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癌症诊断
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纳米技术
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DOI
PubMed
高影响因子
Biomaterials Science
·
2018
·Vol. 6
·期 8
·2209-2218
·
IF 5.831
Siqi Wang,Wenzhi Ren,Jianhua Wang,Zhenqi Jiang,Madiha Saeed,Lili Zhang,Aiguo Li,Aiguo Wu
At present, transmembrane glycoprotein CD133 highly expressed pancreatic cancer stem cells (PCSCs), with the features of chemotherapeutic/radiotherapeutic resistance and exclusive tumorigenic potential, are considered as the primary cause of metastasis and recurrence in pancreatic cancer, and therefore are an effective target in the disease treatment. Furthermore, with the launch of precision medicine, multifunctional nanoprobes have been applied as an efficient strategy for the magnetic resonance imaging (MRI)-guided photothermal therapy (PTT) of pancreatic cancer. In this research, with the aim of achieving precise MRI-guided PTT in CD133 highly expressed PCSCs, novel bTiO2-Gd-CD133mAb nanoprobes were designed and successfully prepared by loading Gd-DOTA and CD133 monoclonal antibodies on black TiO2 nanoparticles. It was very interesting to find that the r1 relaxivity value of the nanoprobes was 34.394 mM−1 s−1, about 7.5 times that of commercial Magnevist (4.5624 mM−1 s−1), which indicates that the nanoprobes have good potential as MRI T1 contrast agents with excellent performance. Herein, CD133 highly expressed PANC-1 cells were selected and verified as PCSCs model. In vitro experiments demonstrated that the nanoprobes exhibited active-targeting ability in PANC-1 cells, and consequently could specially enhance T1-weighted MR imaging and 808 nm near-infrared (NIR)-triggered PTT efficiency in the PCSCs model. Our study not only provides a new strategy for the effective treatment of pancreatic cancer and its’ stem cells, but also further broadens the application of black TiO2 in the field of cancer theranostics.
研究领域:
癌症研究
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纳米技术
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医学成像
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诊疗一体化
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Dinghu Weng,Rong Guo,Changling Dong,Yuan Luo,Dasheng Qiu,Liying Xu,Guobin Xu
The aim of this study was to synthesize a quinoline-based MRI contrast agent, Gd-DOTA-FAPI04, and assess its capacity for targeting fibroblast activation protein (FAP)-positive tumors in vivo. Gd-DOTA-FAPI04 was synthesized by attaching a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complex of gadolinium(III) to FAP inhibitor FAPI04. The longitudinal relaxation time (T1) of the contrast agent was measured using a Siemens Prisma 3.0T MR system, and the CCK-8 assay was performed to evaluate its potential cytotoxicity. Male nude mice bearing tumors grown from FAP-expressing fibrosarcoma cells were divided into experimental (n = 4) and control (n = 4) groups, and T1-weighted image enhancement was measured at different times (0, 10, 30, 60, 90, and 120 min) postinjection of Gd-DOTA-FAPI04. The control group received an additional preinjection of excess FAPI04. FAP expression in tumor tissue was investigated by using immunohistochemistry with an anti-FAP antibody. The longitudinal relaxivities of gadodiamide and Gd-DOTA-FAPI04 were measured to be 3.734 mM–1 s–1 and 5.323 mM–1 s–1, respectively. The CCK-8 assay demonstrated that Gd-DOTA-FAPI04 has minimal toxicity to cultured human fibrosarcoma cells. In vivo MRI showed that peak accumulation of Gd-DOTA-FAPI04 in FAP-expressing tumors occurred 1 h postinjection and could be blocked by preinjection of excess FAPI04. Immunohistochemical analysis of harvested tumor tissue supported the above findings. Gd-DOTA-FAPI04 is a promising contrast agent for in vivo imaging of FAP.
研究领域:
医学成像
·
肿瘤学
·
药物化学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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