Synthesis, binding affinity, and relaxivity of target-specific MRI contrast agents

Although magnetic resonance imaging (MRI) is one of the most important imaging modalities of the central nervous system (CNS), one of the main drawbacks of MRI is its limited specificity. This can potentially be partially alleviated by target-specific contrast agents. In the present paper we describe a simple high yield synthesis of two such gadolinium-based spiperone targeted MRI contrast agents, 1a and 1b. The R₁ relaxivities of 1a and 1b were evaluated and found to be 5.94 and 8.31 mM⁻¹ s⁻¹, respectively at 9.4T, while their R₂ relaxivities at the same magnetic field were found to be 18.05 and 22.60 mM⁻¹ s⁻¹, respectively. In addition and very importantly compound 1a, which is a gadolinium-based, spiperone-targeted MRI contrast agent, was found to preserve some of the spiperone affinity toward the dopamine D2 receptor. Compounds 1a and 1b thus represent potential agents for in vitro dopamine receptor imaging using MRI in experimental models. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A mathematical model for a distributed attack on targeted resources in a computer network

A mathematical model has been developed to analyze the spread of a distributed attack on critical targeted resources in a network. The model provides an epidemic framework with two sub-frameworks to consider the difference between the overall behavior of the attacking hosts and the targeted resources. The analysis focuses on obtaining threshold conditions that determine the success or failure of such attacks. Considering the criticality of the systems involved and the strength of the defence mechanism involved, a measure has been suggested that highlights the level of success that has been achieved by the attacker. To understand the overall dynamics of the system in the long run, its equilibrium points have been obtained and their stability has been analyzed, and conditions for their stability have been outlined.     

Opportunities for innovation: Building on the success of lipid nanoparticle vaccines

Lipid nanoparticle (LNP) formulations of messenger RNA (mRNA) have demonstrated high efficacy as vaccines against SARS-CoV-2. The success of these nanoformulations underscores the potential of LNPs as a delivery system for next-generation biological therapies. In this article, we highlight the key considerations necessary for engineering LNPs as a vaccine delivery system and explore areas for further optimisation. There remain opportunities to improve the protection of mRNA, optimise cytosolic delivery, target specific cells, minimise adverse side-effects and control the release of RNA from the particle. The modular nature of LNP formulations and the flexibility of mRNA as a payload provide many pathways to implement these strategies. Innovation in LNP vaccines is likely to accelerate with increased enthusiasm following recent successes; however, any advances will have implications for a broad range of therapeutic applications beyond vaccination such as gene therapy.     

Multivalent Aptamer-modified DNA Origami as Drug Delivery System for Targeted Cancer Therapy

In spite of great development in nanoparticle-based drug delivery systems(DDSs)for improved therapeutic efficacy,it remains challenging for effective delivery of chemotherapeutic drugs to targeted tumor cells.In this work,we report a triangle DNA origami as targeted DDS for cancer therapy.DNA origami shows excellent biocompatibility and stability in cell culture medium for 24 h.In addition,the DNA origami structures conjugated with multivalent aptamers enable for efficient delivery of anticancer drug doxorubicin(Dox)into targeted cancer cell due to their targeting function,reducing side effects associated with nonspecific distribution.Moreover,we also demonstrated that the multivalent aptamer-modified DNA origami loading Dox exhibits prominent therapeutic efficacy in vitro.Accordingly,this work provides a good paradigm for the development of DNA origami nanostructure-based targeted DDS for cancer therapy.     

靶向纳米钻石-甲氨蝶呤药物体系制备及与MCF-7细胞作用

以羧基化纳米钻石(ND-COOH)为基体, 通过共价键合方法将聚乙二醇二胺(H₂N-PEG-NH₂)、 叶酸(FA)和缩水甘油(GLY)偶联于ND-COOH表面, 赋予纳米钻石载体较好的水溶分散性和靶向性, 借助氢键和范德华力等作用力负载甲氨蝶呤(MTX), 得到靶向纳米钻石-聚乙二醇二胺-叶酸/缩水甘油/甲氨蝶呤(ND-PEG-FA/GLY/MTX NPF/G/M)纳米药物体系. 采用透射电子显微镜、 X射线能量色散谱、 粒径及电位测试证实已制备NPF/G/M. 体外释药发现NPF/G/M在肿瘤环境(pH=5.5)中的药物释放量为正常生理环境(pH=7.4)中的3倍, 表明其具有良好的药物输送特性. 此外, 利用流式细胞术和MTT毒性测试探究了MCF-7细胞摄取NPF/G/M的机制及动力学特性和细胞毒性, 结果表明NPF/G/M以依赖能量、 温度、 网格蛋白、 小窝蛋白和叶酸受体介导的机制进入细胞, 从而将药物缓慢释放于细胞内, 进而诱导细胞凋亡. 研究结果表明, NPF/G/M可作为一种良好的药物输送体系, 为其应用于乳腺癌的临床治疗提供理论参考.     

基于框架核酸的细胞表面受体配体相互作用研究进展

细胞表面受体与配体之间的特异性相互作用在细胞生物学过程中起着重要作用。然而,与均相溶液不同,受体分子在细胞膜上的分布是非连续的、动态的,因此细胞表面的受体配体相互作用通常呈现复杂的非线性结合模式。框架核酸作为一类具有确定几何形状的DNA纳米支架,可用于多价配体的偶联,为深入揭示受体配体相互作用机制提供了可靠的工具。利用框架核酸纳米分辨率的可寻址特性,可实现对配体数目、间距及空间构象等参数的精确调控,进而研究细胞表面受体配体的结合特性及影响因素,优化结合条件最终实现高效的分子识别及靶向治疗。本文综述了基于框架核酸的细胞表面受体配体相互作用研究进展,通过探讨细胞表面受体配体相互作用的重要影响因素及生物学应用,对该研究领域的发展前景和未来趋势予以展望。     

Development of a competitive ELISA for the quantification of F5 conjugate in HER2-targeted STEALTH immunoliposome doxorubicin in plasma samples

HER2 (human epidermal growth factor receptor 2, erbB2, or neu) is overexpressed by a large number of tumor types and has been identified as an important target for cancer therapy. F5 is a single-chain human antibody fragment that recognizes HER2 receptor and is covalently conjugated to PEGylated lipid to form F5 conjugate (F5CG) in the product HER2 targeted STEALTH immunoliposome doxorubicin. Here we described the method development of a competitive enzyme-linked immunosorbent assay (ELISA) for the determination of total concentration of F5 conjugate in plasma samples. The method involved the biotinylation of F5CG, detergent treatment of plasma sample to solubilize F5CG into monomeric form, and competitive ELISA for solubilized F5CG competitively binding to anti-F5CG antibody with biotinylated F5CG for the determination of total F5CG in plasma. The detection range of this method was from 0.2 ng/mL to 125 ng/mL for F5CG in plasma. The lower limit of quantification (LLOQ) was 0.2 ng/mL. This method was established and used for the measurement of F5CG concentration to provide information about F5CG circulation after the administration of immunoliposome in preclinical studies.      

Cathepsin B-responsive nanodrug delivery systems for precise diagnosis and targeted therapy of malignant tumors

The tumor microenvironment (TME) significantly influences cancer evolution and therapeutic efficacy. Targeting biofunctional molecules to the TME has long been appreciated as a means of raising local drug concentrations and reducing systemic toxicities. The booming nanotechnology field has realized the importance of cathepsin B to derive a variety of intelligent enzyme-responsive nanosized drug delivery systems (nanoDDS) to improve treatment responses and clinical outcomes. In this tutorial review, after introducing the molecular structure and physiological/pathological functions of cathepsin B, the outstanding achievements of cathepsin B-responsive nanoplatforms in the precise diagnosis, targeted therapy, and synergistic theranostics of malignant tumors are systematically described. Finally, the challenges of enzyme-substrate incompatibility, low diagnostic sensitivity, mass production and biocompatibility of multifunctional nanoDDS are considered in order to successfully promote them to clinical applications     

Multi-functionalized single-walled carbon nanotubes as tumor cell targeting biological transporters

Multi-functionalized single walled carbon nanotubes (SWNTs) were prepared and applied as tumor cell targeting biological transporters. A positive charge was introduced on SWNTs to get high loading efficiency of fluorescein (FAM) labeled short double strands DNA (20 base pairs). The SWNTs were encapsulated with the folic acid modified phospholipids for active targeting into tumor cell. The tumor cell-targeting properties of these multi-functionalized SWNTs were investigated by active targeting into mouse ovarian surface epithelial cells. The experimental results show that these multi-functionalized SWNTs have good tumor cell targeting property.     

点击功能化的叶酸受体靶向荧光纳米探针用于肿瘤细胞成像

采用点击化学偶联法对荧光二氧化硅纳米粒子表面进行叶酸功能化修饰,构建了一种叶酸受体靶向的荧光纳米探针,并成功用于肿瘤细胞的成像研究.首先通过St?ber法制备包裹钌联吡啶的荧光二氧化硅纳米粒子(RSiNPs),然后利用叠氮化硅烷偶联剂(Az-PTES)的水解反应在其表面引入叠氮基团,最后通过点击化学反应将炔丙基叶酸衍生物偶联到粒子表面.利用红外光谱对其偶联前后的叠氮基特征峰(2105 cm-1)进行表征,证实了叶酸功能化的荧光纳米探针(RSiNPs-Folate)已被成功制备.在生理pH条件下,以458 nm为激发波长,RSiNPs-Folate在601 nm处发射较强的红色荧光,且光稳定性较好.细胞成像结果表明,这种叶酸受体靶向的荧光纳米探针能够有效地标记叶酸受体呈阳性的人宫颈癌细胞(HeLa),而叶酸受体呈阴性的人肺癌细胞(A549)未观察到明显的荧光.叶酸竞争性结合实验证明了这种叶酸受体介导的肿瘤细胞成像机制.此探针能够实现混合细胞体系中HeLa细胞的选择性识别与荧光成像.与酰胺化反应偶联叶酸相比,这种点击功能化的纳米探针的合成方法简单、反应条件温和、产率高,可用于不同肿瘤细胞的荧光标记与成像.