Preparation and Biological Evaluation of [99mTc]Tc-CNGU as a PSMA-Targeted Radiotracer for the Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with ^99mTc to prepare [^99mTc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (K_i value is 8.79 nM) in LNCaP cells. The [^99mTc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = −1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [^99mTc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [^99mTc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.     

前列腺癌相关肿瘤标志物分析方法的研究进展

肿瘤标志物是在恶性肿瘤细胞中过表达的一类蛋白质,能反映肿瘤的发生、发展,并能监测肿瘤治疗的效果.因此,癌症患者血清中的肿瘤标志物的分析对于癌症状态的监测具有重要意义.常见的前列腺肿瘤标志物包括前列腺特异性抗原(PSA)、前列腺特异性膜抗原(PSMA)、α-甲酰基辅酶A消旋酶(AMACR, P504S)、前列腺酸性磷酸酶(PAP)和钙磷脂结合蛋白3(ANXA3)等.基于对前列腺肿瘤标志物的相关研究,本综述简要介绍了前列腺癌肿瘤标志物的组成、生物功能和生理意义,重点归纳了前列腺癌特异性抗原和前列腺酸性磷酸酶的检测技术,总结了当前前列腺癌肿瘤标志物检测技术的不足,并展望了前列腺癌肿瘤标志物检测在临床应用中的前景.     

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.     

Prostate Cancer Review: Genetics,Diagnosis, Treatment Options,and Alternative Approaches

Simple SummaryProstate cancer affects men of all racial and ethnic groups and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to late detection of the disease. There is growing evidence that suggests the contribution of an individual’s genetic profile to prostate cancer. Currently used prostate cancer treatments have serious adverse effects; therefore, new research is focusing on alternative treatment options such as the use of genetic biomarkers for targeted gene therapy, nanotechnology for controlled targeted treatment, and further exploring medicinal plants for new anticancer agents. In this review, we describe the recent advances in prostate cancer research.AbstractProstate cancer is one of the malignancies that affects men and significantly contributes to increased mortality rates in men globally. Patients affected with prostate cancer present with either a localized or advanced disease. In this review, we aim to provide a holistic overview of prostate cancer, including the diagnosis of the disease, mutations leading to the onset and progression of the disease, and treatment options. Prostate cancer diagnoses include a digital rectal examination, prostate-specific antigen analysis, and prostate biopsies. Mutations in certain genes are linked to the onset, progression, and metastasis of the cancer. Treatment for localized prostate cancer encompasses active surveillance, ablative radiotherapy, and radical prostatectomy. Men who relapse or present metastatic prostate cancer receive androgen deprivation therapy (ADT), salvage radiotherapy, and chemotherapy. Currently, available treatment options are more effective when used as combination therapy; however, despite available treatment options, prostate cancer remains to be incurable. There has been ongoing research on finding and identifying other treatment approaches such as the use of traditional medicine, the application of nanotechnologies, and gene therapy to combat prostate cancer, drug resistance, as well as to reduce the adverse effects that come with current treatment options. In this article, we summarize the genes involved in prostate cancer, available treatment options, and current research on alternative treatment options.     

Synthesis and Evaluation of GdIII‐Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate‐Specific Membrane Antigen

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast. We hypothesize that the prostate‐specific membrane antigen (PSMA), an attractive target for imaging and therapy of prostate cancer, could serve as a suitable biomarker for MR‐based molecular imaging. We have synthesized three new high‐affinity, low‐molecular‐weight Gd^III‐based PSMA‐targeted contrast agents containing one to three Gd^III chelates per molecule. We evaluated the relaxometric properties of these agents in solution, in prostate cancer cells, and in an in vivo experimental model to demonstrate the feasibility of PSMA‐based MR molecular imaging.     

What We Can Really Do with Bioresponsive MRI Contrast Agents

Bioresponsive MRI contrast agents hold great promise for monitoring major physiological and pathological processes in a non‐invasive manner. They are capable of altering the acquired MRI signal as a consequence of changes in their microenvironment, thus allowing real‐time functional reporting in living organisms. Importantly, chemistry offers diverse solutions for the design of agents which respond to a great number of specific targets. However, the path to the successful utilization of these biomarkers in the desired functional MRI studies involves careful consideration of multiple scientific, technical, and practical issues across various research disciplines. This Minireview highlights the critical steps for planning and executing such multidisciplinary projects with an aim to substantially improve our knowledge of essential biological processes.     

New designs for MRI contrast agents

New designs for Magnetic Resonance Imaging contrast agents are presented. Essentially, they all are host–guest inclusion complexes between -cyclodextrins and polyazamacrocycles of gadolinium (III) ion. Substitutions have been made to the host to optimise the host–guest association. Molecular mechanics calculations have been performed, using the UFF force field for metals, to decide on the suitability of the substitutions, and to evaluate the host–guest energies of association. Interesting general conclusions have been obtained, concerning the improvement of Magnetic Resonance Imaging contrast agents; namely, a set of rational methodologies have been deduced to improve the association between the gadolinium (III) chelates and the cyclodextrins, and their efficiency is demonstrated with a large set of substituted complexes, opening new doors to increase the diagnostic capabilities of Magnetic Resonance Imaging.     

One-pot Synthesis of PEGylated Gd-based Nanoparticles as High-performance and Biocompatibility Contrast Agents for T1-Weighted Magnetic Resonance Imaging In vivo

Polyethylene glycol modified(PEGylated) NaGdF4(PEG-NaGdF4) nanoparticles as a novel T1-weighted magnetic resonance imaging(MRI) contrast agent was successfully constructed by a one-pot hydrothermal synthesis method. Because of the functionalization of PEG, the nanoprobes had excellent dispersity, excellent stability and high biocompatibility. More importantly, the as-prepared PEG-NaGdF4 nanoprobes revealed the high longitudinal relaxivity value and prominent -weighted MRI contrast performance, which was superior to the commercial MRI contrast agents. With the facile synthesis, excellent dispersity, outstanding stability, remarkable contrast performance and high biocompatibility, the PEGylated NaGdF4 nanoparticles brought more opportunities to the new generation of nanoparticulate-based T1-weighted MRI contrast agents in clinic.     

Practical Synthesis of FEt-penta-cyclofenil and Its Derivatives for Potential PET Imaging

Generally, FEt-penta-cyclofenil and its derivatives have greater relative binding affinity to estradiol receptors than estradiol. (4-Fluoroethoxyphenyl)–(4′-hydroxyphenyl) methylenecyclopentane and its derivatives were synthesized for potential radioactive image agents, and their structures were characterized by ultraviolet, infrared, ¹H NMR, ¹⁹F NMR, and high-resolution mass spectrometry.     

超声造影和MRI在胃癌新辅助治疗后再分期的一致性

将2017年1月至2018年12月于西宁市第二人民医院行新辅助治疗的72例胃癌患者纳入研究,同时给予患者超声造影(contrast-enhanced ultrasonography,CEUS)检查及磁共振成像(magnetic resonance imaging, MRI)增强扫描,比较并分析二者对治疗后分期及肿瘤周围侵犯情况的检查结果,以探究CEUS在评估胃癌新辅助治疗后分期及侵犯情况方面与MRI的一致性。研究结果显示,MRI和CEUS评估胃癌T分期的诊断一致率为91.67%,具有较高一致性;CEUS和MRI评估病灶的左右径、纵轴直径和前后径具有较好的一致性,且两者无明显差异;CEUS与MRI评估其侵袭横结肠及其系膜、肝/脾、十二指肠/胰腺的诊断,具有较高的一致性。本研究证实,CEUS与MRI在评估胃癌T分期、病灶大小及周围组织侵犯情况时结果基本一致。     

荧光/MRI双模态靶向成像诊疗试剂的制备

在聚乙二醇二胺(NH_2-PEG-NH_2)修饰的石墨烯量子点(GODs)表面以酰胺键偶联二乙基三胺五乙酸(DTPA)分子,之后将Gd~(3+)离子与其进行配合,得到了GODs-Gd(DTPA)复合纳米粒子,然后再通过酰胺键在GODs-Gd(DTPA)的表面修饰叶酸(FA)靶分子,最后进一步将阿霉素(DOX)通过π-π堆垛吸附在造影剂的表面,制备了FA/GODs-Gd(DTPA)/DOX荧光/MRI双模态靶向肺癌细胞成像诊疗试剂,通过透射电子显微镜、紫外可见吸收光谱、荧光光谱和激光共聚焦扫描显微镜等手段表征了其形貌、发光性能和靶向成像性能。MRI、激光共聚焦扫描显微镜和MTT等结果表明,相对于正常的HLF细胞,所制备的FA/GODs-Gd(DTPA)/DOX纳米粒子能够靶向检测FA受体高表达的肺癌H460细胞,并具有明显的抗肿瘤活性。     

Cyclodextrin‐Based Bimodal Fluorescence/MRI Contrast Agents: An Efficient Approach to Cellular Imaging

A novel bimodal fluorescence/MRI probe based on a cyclodextrin scaffold has been synthesized and characterized. The final agent employs the fluorescein (F) functionality as a fluorescence marker and the Gd^III complex of a macrocyclic DOTA‐based ligand (GdL) having one aminobenzyl‐phosphinic acid pendant arm as an MRI probe, and has a statistical composition of (GdL)_6.9‐F_0.1‐β‐CD. Slow rotational dynamics (governed by a very rigid cyclodextrin scaffold) combined with fast water exchange (ensured by the chosen macrocyclic ligand) resulted in a high relaxivity of ～22 s^?1 mM ^?1 per Gd^III or ～150 s^?1 mM ^?1 per molecule of the final conjugate (20 MHz, 25 °C). In vitro labelling of pancreatic islets (PIs) and rat mesenchymal stem cells has been successfully performed. The agent is not cytotoxic and is easily internalized into cells. The labelled cells can be visualized by MRI, as proved by the detection of individual labelled PIs. A fluorescence study performed on mesenchymal stem cells showed that the agent stays in the intracellular space for a long time.     

Multifunctional Core–Shell Upconverting Nanoparticles for Imaging and Photodynamic Therapy of Liver Cancer Cells

Lanthanide‐doped upconversion nanoparticles (UCNPs) have attracted considerable attention for their application in biomedicine. Here, silica‐coated NaGdF₄:Yb,Er/NaGdF₄ nanoparticles with a tetrasubstituted carboxy aluminum phthalocyanine (AlC₄Pc) photosensitizer covalently incorporated inside the silica shells were prepared and applied in the photodynamic therapy (PDT) and magnetic resonance imaging (MRI) of cancer cells. These UCNP@SiO₂(AlC₄Pc) nanoparticles were uniform in size, stable against photosensitizer leaching, and highly efficient in photogenerating cytotoxic singlet oxygen under near‐infrared (NIR) light. In vitro studies indicated that these nanoparticles could effectively kill cancer cells upon NIR irradiation. Moreover, the nanoparticles also demonstrated good MR contrast, both in aqueous solution and inside cells. This is the first time that NaGdF₄:Yb,Er/NaGdF₄ upconversion‐nanocrystal‐based multifunctional nanomaterials have been synthesized and applied in PDT. Our results show that these multifunctional nanoparticles are very promising for applications in versatile imaging diagnosis and as a therapy tool in biomedical engineering.     

Dysprosium Complexes and Their Micelles as Potential Bimodal Agents for Magnetic Resonance and Optical Imaging

Six diethylene triamine pentaacetic acid (DTPA) bisamide derivatives functionalized with p‐toluidine (DTPA‐BTolA), 6‐aminocoumarin (DTPA‐BCoumA), 1‐naphthalene methylamine (DTPA‐BNaphA), 4‐ethynylaniline (DTPA‐BEthA), p‐dodecylaniline (DTPA‐BC₁₂PheA) and p‐tetradecyl‐aniline (DTPA‐BC₁₄PheA) were coordinated to dysprosium(III) and the magnetic and optical properties of the complexes were examined in detail. The complexes consisting of amphiphilic ligands (DTPA‐BC₁₂PheA and DTPA‐BC₁₄PheA) were further assembled into mixed micelles. Upon excitation into the ligand levels, the complexes display characteristic Dy^III emission with quantum yields of 0.3–0.5 % despite the presence of one water molecule in the first coordination sphere. A deeper insight into the energy‐transfer processes has been obtained by studying the photophysical properties of the corresponding Gd^III complexes. Since the luminescence quenching effect is decreased by the intervention of non‐ionic surfactant, quantum yields up to 1 % are obtained for the micelles. The transverse relaxivity r₂ per Dy^III ion at 500 MHz and 310 K reaches a maximum value of 27.4 s^?1 mM ^?1 for Dy‐DTPA‐BEthA and 36.0 s^?1 mM ^?1 for the Dy‐DTPA‐BC₁₂PheA assemblies compared with a value of 0.8 s^?1 mM ^?1 for Dy‐DTPA. The efficient T₂ relaxation, especially at high magnetic field strengths, is sustained by the high magnetic moment of the dysprosium ion, the coordination of water molecules with slow water exchange kinetics and long rotational correlation times. These findings open the way to the further development of bimodal optical and magnetic resonance imaging probes starting from single lanthanide compounds.     

Volume-related Efficiency of Gadolinium Polyoxometalates as MRI Contrast Agents

Two gadolinium polyoxometalates, KCs4[Gd（a-SiW11O39）].25HzO（POM-1） and K13[Gd（f12-SiWllO39）a]·27H2O（POM-2）, have been evaluated as the candidates of potential magnetic resonance imaging Tl（longitudinal relaxation） contrast agents. Longitudinal relaxivities of POM-2 are much higher than those of POM-1 in pure water and protein solution, respectively. However, compared with POM-1, POM-2 interacts with protein more strongly through electrostatic interaction, which is comfirmed by the fluoresence quenching of human serum albumin（HSA） in solu- tions with different polyoxometalate concentrations. Meanwhile, POM-1 presentes much lower cytotoxicity in the cell viability tests.     

Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI,EPRI, and PET

Radiation therapy is one of the main modalities to treat cancer/tumor. The response to radiation therapy, however, can be influenced by physiological and/or pathological conditions in the target tissues, especially by the low partial oxygen pressure and altered redox status in cancer/tumor tissues. Visualizing such cancer/tumor patho-physiological microenvironment would be a useful not only for planning radiotherapy but also to detect cancer/tumor in an earlier stage. Tumor hypoxia could be sensed by positron emission tomography (PET), electron paramagnetic resonance (EPR) oxygen mapping, and in vivo dynamic nuclear polarization (DNP) MRI. Tissue oxygenation could be visualized on a real-time basis by blood oxygen level dependent (BOLD) and/or tissue oxygen level dependent (TOLD) MRI signal. EPR imaging (EPRI) and/or T₁-weighted MRI techniques can visualize tissue redox status non-invasively based on paramagnetic and diamagnetic conversions of nitroxyl radical contrast agent. ¹³C-DNP MRI can visualize glycometabolism of tumor/cancer tissues. Accurate co-registration of those multimodal images could make mechanisms of drug and/or relation of resulted biological effects clear. A multimodal instrument, such as PET-MRI, may have another possibility to link multiple functions. Functional imaging techniques individually developed to date have been converged on the concept of theranostics.