A novel rigid Mn2+ complex (MnL) with pyridine and pyrrolidine rings was designed and synthesized. The complex was further modified with alkyne, and conjugated to azide-terminated PEG by click chemistry. PEGylated MnL shows considerably higher relaxivity (MnL-PEG2k-MnL: r1 = 6.38 mmol−1 s−1; MnL-PEG4.6k-MnL: r1 = 5.63 mmol−1 s−1) and much longer blood circulation time than free Mn2+ complexes (MnL: r1 = 3.73 mmol−1 s−1), providing a prolonged time window to acquire longitudinal images for rat contrast enhanced magnetic resonance angiography.

•A high-performance fluoride ion fluorescence sensor was developed, namely NIMS.•As a rapid response colorimetric/fluorometric F− sensor, NIMS can detect fluoride ion via a desilylation mechanism.•NIMS can be used for practical applications to detect F− in solid films state and in commercial toothpaste.A novel naphthalimide-based fluorescent sensor, namely NIMS, is designed and synthesized for fluoride ion detection. NIMS undergoes a desilylation reaction upon addition of F− ion, thereby shows a colorimetric/fluorometric dual-channel spectral response, i.e., a huge ratiometric absorption value of 229 nm together with distinct colour change from yellow to blue, and drastically quenched fluorescence as well. Additionally, NIMS shows high selectivity, good sensitivity and rapid response toward F− ion, and could be used in qualitative detection of F− ion in the solid state and quantitative detection F− ion in toothpaste samples.

Superparamagnetic iron oxide (SPIO) nanoparticle clusters are one unique form which can enhance magnetic relaxivity and improve the magnetic resonance imaging contrast at the same iron concentration, comparing to single SPIO nanoparticles. Controlling of cluster size and other structural parameters have drawn great interests in this field to further improve their magnetic properties. In this study, we investigated how the interparticle distance (also known as neighbor distance) of SPIO nanocrystals within clusters affect their magnetic relaxation behaviors. To adjust the neighbor distance, different amount of cholesterol (CHO) was chosen as model spacers embedded into SPIO nanocluster systems with the help of amphiphilic diblock copolymer poly(ethylene glyco)-polyester. Small-angle X-ray scattering was applied to quantify the neighbor distance of SPIO clusters. The results demonstrated that the averaged SPIO nanocrystal neighbor distance of nanoclusters increased with higher amount of added CHO. Moreover, these SPIO nanocrystal clusters had the prominent magnetic relaxation properties. Simultaneously, controlling of SPIO nanocrystal neighbor distance can regulate the saturation magnetization (Ms) and magnetic resonance (MR) T2 relaxation of the aggregation, and ultimately obtain better MR contrast effects with decreased neighbor distance.相对单个超顺磁氧化铁纳米颗粒(SPIO),在相同铁浓度条件下,SPIO纳米团簇明显具有更强的弛豫效能和更高的磁共振成像对比度。研究如何控制SPIO团簇大小以及一些其他结构参数,从而进一步提高其磁学性能有重要意义。本文研究了磁性纳米团簇中SPIO纳米晶体间距大小与其弛豫性能之间的关系。本文使用两亲性高分子聚乙二醇-聚酯自组装制备磁性纳米团簇,并加入不同量的刚性小分子胆固醇作为媒介嵌入至SPIO纳米晶体之间调控SPIO晶体间距,然后使用小角X射线散射技术精确测量其间距大小。结果显示,实验制备的SPIO纳米团簇具有优异的弛豫效能,且随着胆固醇量的增加SPIO纳米晶体间距也随之变大。此外,控制SPIO纳米晶体间距能够有效调控磁性纳米团簇的饱和磁化强度和T2弛豫效率,并可通过降低其间距以获得更好的磁共振对比度。

T 1 contrast agents based on Mn(II) were conjugated on amphiphilic dextran micelles via click chemistry. The obtained paramagnetic nanomicelle contrast agent has a higher T1 relaxivity (13.3 Mn mmol−1 s−1) and better sensitivity than those of free Mn(II) complexes. Studies carried out in vivo suggest that this contrast agent has a better and long-acting vascular enhancement effect at a lower manganese dosage (0.1 Mn mmol kg−1 BW).

Multifunctional nanoparticles combining diagnostic and therapeutic agents into a single platform make cancer theranostics possible and have attracted wide interests in the field. In this study, a multifunctional nanocomposite based on dextran and superparamagnetic iron oxide nanoparticles (SPIO) was prepared for drug delivery and magnetic resonance imaging (MRI). Amphiphilic dextran was synthesized by grafting stearyl acid onto the carbohydrate backbone, and micelle was formed by the resulted amphiphilic dextran with low critical micelle concentration at 1.8 mg L−1. Doxorubicin (DOX) and a cluster of the manganese-doped iron oxide nanoparticles (Mn-SPIO) nanocrystals were then coencapsulated successfully inside the core of dextran micelles, resulting in nanocomposites with diameter at about 100 nm. Cell culture experiments demonstrated the potential of these Mn-SPIO/DOX nanocomposites as an effective multifunctional nanoplatform for the delivery of anticancer drug DOX with a loading content (DLC) of 16 %. Confocal laser scanning microscopy reveals that the Mn-SPIO/DOX had excellent internalization ability against MCF-7/Adr cells after 2-h labeling compared with free DOX·HCl. Under a 3.0-T MRI scanner, Mn-SPIO/DOX nanocomposite-labeled cells in gelatin phantom show much darker images than the control. Their transverse relaxation (T2) rate is also significantly higher than that of the control cells (33.9 versus 2.3 s−1). Our result offers an effective strategy to treat MCF-7/Adr at optimized low dosages with imaging capability.多功能纳米颗粒能同时结合诊断和治疗试剂,有望实现肿瘤诊疗的一体化。本文制备了基于葡聚糖和超顺磁氧化铁纳米颗粒的多功能纳米复合物DOX/Mn-SPIO,用于药物传递和磁共振成像(MRI)。通过接枝硬脂酸到糖单元骨架上,获得临界胶束浓度为1.8 mg L−1的两亲性葡聚糖。经自组装的葡聚糖胶束可在疏水核负载抗肿瘤药物阿霉素和超顺磁氧化锰铁纳米晶体,形成粒径约100 nm的纳米复合物。体外细胞实验表明,该DOX/Mn-SPIO纳米复合物能作为有效传递抗肿瘤药物阿霉素的多功能纳米载体。相比游离的阿霉素药物,激光共聚焦显微镜结果表明该复合物在标记2 h时可高效进入人乳腺癌耐药细胞MCF-7/Adr。使用临床3 T磁共振扫描仪成像,该复合物标记的细胞MRI图像与对照组显示出明显对比度。其T2弛豫率达33.9 s−1,显著高于对照组的2.3 s−1。研究表明该葡聚糖纳米胶束复合物作为诊疗一体化载体能在低剂量治疗MCF-7/Adr细胞的同时进行MRI成像,为MCF-7/Adr肿瘤细胞的诊疗提供了一种有效方法。

A dual-channel naphthalimide-based chemosensor for rapid and sensitive detection of fluoride ion has been developed. Upon addition of F–, it undergoes deprotonation reaction through H-bonding interactions, and its maximum absorption wavelength is red-shifted for 214 nm to the far-red region, together with drastically quenched fluorescence. In addition, it shows high selectivity toward F– anion, thus could be used for practical applications to detecting F– in both solution and solid state. Furthermore, the fluorescence of NIM could be enhanced in protein-containing acidic environments, hence NIM could act as lysosome marker to differentiate cancer cells from normal ones in cell imaging.Keywords: cell imaging; chemosensor; dual-channel; fluoride ions; selectivity;

Theranostics have received enormous attentions for individualized diagnosis and treatment in the past few years. Especially, the availability of various nanoplatforms provides great potentials for designing of sophisticated theranostic agents including imaging, targeting and therapeutic functions. Numerous reports have been published on how to construct multifunctional nanoparticles for the targeted diagnosis and therapy simultaneously since the concept of “theranostics”. This review presents recent advances of molecular imaging and nanoplatform technology, and their applications in drug discovery and development. Applications of nanoplatform-based theranostics in cancer and cardiovascular diseases will also be covered including diagnosis, assessment of drug biodistribution, and visualization of drug release from nanoparticles, as well as monitoring of therapeutic effects.

Layer-by-layer (LbL) assembled polyelectrolyte capsules have been widely studied as promising delivery systems due to their well-controlled architectures. Although their potential applications in vitro have been widely investigated, at present, it is still a challenging task to track their real-time delivery in vivo, where and how they would be located following their administration. In this work, the noninvasive magnetic resonance imaging (MRI) technique was applied to monitor the delivery of polyelectrolyte capsules in vivo, incorporating magnetite nanoparticles as imaging components. First, MRI scan was performed over 6 h after sample administration at the magnetic field of 3.0 T; magnetic capsules, both poly(allylamine hydrochloride)/poly(styrenesulfonate sodium salt)-based and poly-l-arginine hydrochloride/dextran sulfate (Parg/DS)-based, were detected mostly in the liver region, where the transverse relaxation time (T2) was shortened and hypointense images were visualized, demonstrating a contrast-enhanced MRI effect between liver and adjacent tissue. A continuous MRI scan found that the contrast-enhanced MRI effect can last up to 30 h; in the mean time, the Parg/DS-based capsules with smaller diameter were found to have a pronounced clearance effect, which resulted in a weakened MRI effect in the liver. No obvious toxicity was found in animal studies, and all mice survived after MRI scans. Histology study provided evidences to support the MRI results, and also revealed the destination of these magnetic capsules over 30 h after administration.

The aza-semi-crown pentadentate ligand rigidified by pyridine and piperidine rings was designed and synthesized. It can react with Mn(II) in water to form complex with improved longitudinal relaxivity, leading to efficient signal intensity enhancement of vascular vessels under a clinical magnetic resonance imaging scanner.

Construction of multifunctional/multimodality nanoparticles for cancer diagnosis and therapy has become an attractive area of investigation. In this report, we designed a multimodality nanoprobe for cell labeling, and can be detectable by both magnetic resonance and near infrared (NIR) fluorescence imaging. Multiple hydrophobic superparamagnetic iron oxide (SPIO) nanocrystals are self-assembled into nanocomposites in water phase with the help of partially alkylated hyperbranched polycation, polyethylenimine (PEI), which already conjugated with the indocyanine dye Cy5.5 and can be used for cell imaging under NIR fluorescence imaging. The amphiphilic PEI/SPIO nanocomposites have a strong T2 relaxivity. The iron uptake process in MCF-7/Adr displays a time dependent behavior. Confocal laser scanning microscopy reveals that the nanoprobes are internalized into the cytoplasm of MCF-7/Adr after 24 h labeling. Both MR and NIR fluorescence imaging showed strong image contrast against unlabeled cells. Under a clinical MRI scanner, labeled cells in gelatin phantom present much darker images than controlled ones. The T2 relaxation rate of the labeled cells is 98.2 s−1, significantly higher than that of the control ones of 2.3 s−1. This study provides an important alternative to label MCF-7/Adr at optimized low dosages with high efficiency, and may be useful to label other biologically important cells and track their behaviors in vivo.

Enormous efforts have been made toward the translation of nanotechnology into medical practice, including cancer management. Generally the applications have fallen into two categories: diagnosis and therapy. Because the targets are often the same, the development of separate approaches can miss opportunities to improve efficiency and effectiveness.The unique physical properties of nanomaterials enable them to serve as the basis for superior imaging probes to locate and report cancerous lesions and as vehicles to deliver therapeutics preferentially to those lesions. These technologies for probes and vehicles have converged in the current efforts to develop nanotheranostics, nanoplatforms with both imaging and therapeutic functionalities. These new multimodal platforms are highly versatile and valuable components of the emerging trend toward personalized medicine, which emphasizes tailoring treatments to the biology of individual patients to optimize outcomes. The close coupling of imaging and treatment within a theranostic agent and the data about the evolving course of an illness that these agents provide can facilitate informed decisions about modifications to treatment.Magnetic nanoparticles, especially superparamagnetic iron oxide nanoparticles (IONPs), have long been studied as contrast agents for magnetic resonance imaging (MRI). Owing to recent progress in synthesis and surface modification, many new avenues have opened for this class of biomaterials. Such nanoparticles are not merely tiny magnetic crystals, but potential platforms with large surface-to-volume ratios. By taking advantage of the well-developed surface chemistry of these materials, researchers can load a wide range of functionalities, such as targeting, imaging and therapeutic features, onto their surfaces. This versatility makes magnetic nanoparticles excellent scaffolds for the construction of theranostic agents, and many efforts have been launched toward this goal.In this Account, we introduce the surface engineering techniques that we and others have developed, with an emphasis on how these techniques affect the role of nanoparticles as imaging or therapeutic agents. We and others have developed a set of chemical methods to prepare magnetic nanoparticles that possess accurate sizes, shapes, compositions, magnetizations, relaxivities, and surface charges. These features, in turn, can be harnessed to adjust the toxicity and stability of the nanoparticles and, further, to load functionalities, via various mechanisms, onto the nanoparticle surfaces.

An efficient strategy for biomacromolecule encapsulation based on spontaneous deposition into polysaccharide matrix-containing capsules is introduced in this study. First, hybrid microparticles composed of manganese carbonate and ionic polysaccharides including sodium hyaluronate (HA), sodium alginate (SA) and dextran sulfate sodium (DS) with narrow size distribution were synthesized to provide monodisperse templates. Incorporation of polysaccharide into the hybrid templates was successful as verified by thermogravimetric analysis (TGA) and confocal laser scanning microscopy (CLSM). Matrix polyelectrolyte microcapsules were fabricated through layer-by-layer (LbL) self-assembly of oppositely charged polyelectrolytes (PEs) onto the hybrid particles, followed by removal of the inorganic part of the cores, leaving polysaccharide matrix inside the capsules. The loading and release properties of the matrix microcapsules were investigated using myoglobin as a model biomacromolecule. Compared to matrix-free capsules, the matrix capsules had a much higher loading capacity up to four times; the driving force is mostly due to electrostatic interactions between myoglobin and the polysaccharide matrix. From our observations, for the same kind of polysaccharide, a higher amount of polysaccharide inside the capsules usually led to better loading capacity. The release behavior of the loaded myoglobin could be readily controlled by altering the environmental pH. These matrix microcapsules may be used as efficient delivery systems for various charged water-soluble macromolecules with applications in biomedical fields.Graphical abstractMonodisperse uniform sized polysaccharide/MnCO3 hybrid microparticles were designed and fabricated. Layer-by-layer (LbL) self-assembly of polyelectrolyte layers on these templates followed by core dissolution led to polysaccharide matrix containing capsules. These carriers can load up to four times amount of proteins comparing to matrix-free capsules.Research highlights▶ The concept of organic/inorganic hybrid templates has been proposed and demonstrated. ▶ LbL capsules containing polysaccharide matrix are developed on these templates. ▶ Hyaluronic acid, dextran, and alginate are chosen for this study. ▶ These matrix capsules can load proteins up to 4 folds than matrix-free ones.

Recent progress in cell therapy research has raised the need for non-invasive monitoring of transplanted cells. Magnetic resonance imaging (MRI) of superparamagnetic iron oxide (SPIO) labeled cells have been widely used for high resolution monitoring of the biodistribution of cells after transplantation. Here we report that self-assembly of amphiphilic polyethylenimine (PEI)/SPIO nanocomposites can lead to the formation of ultrasensitive MRI probes, which can be used to label chondrocyte cells with good biocompatibility. The labeled cells display strong signal contrast compared to unlabeled ones in a clinical MRI scanner. This probe may be useful for noninvasive MR tracking of implanted cells for tissue regeneration.

Superparamagnetic iron oxide (SPIO) nanoparticles are effective contrast agents for enhancement of magnetic resonance imaging at the tissue, cellular or even molecular levels. High quality SPIO nanoparticles can be synthesized in the organic phase but need to be transferred into water before any biomedical applications. In this study, amphiphilic poly(ε-caprolactone) grafted dextran (Dex-g-PCL) was used as carriers for particle encapsulation and stabilization in the aqueous phase. Multiple SPIO nanoparticles were self-assembled together with the help of Dex-g-PCL during phase transfer from chloroform to water, and diameters of Dex-g-PCL/SPIO nanocomposites were (64 ± 22) nm through dynamic light scattering measurement. These nanocomposites were superparamagnetic at 300 K with saturated magnetization of 88 emu/g Fe. In the magnetic field of 1.5 T, Dex-g-PCL/SPIO nanocomposites had a T2 relaxivity of 363 Fe mL·mol−1·s−1. This unique nanocomposite brought significant mouse liver contrast with signal intensity changes of −60% at 5 min after intravenous administration. However, uptake of Dex-g-PCL/SPIO nanocomposites in liver reticuloendothelial cells (Kupffer cells) did not immediately happen at shorter time points (〈4 h) as verified by histology studies, and it was evident that more iron staining would be located in Kupffer cells 24 h after contrast agent administration. After 24 h and 10 d, the signal intensities (SI) gradually recovered, and SI changes were −44% and −31%, respectively. From our observation, the time window for enhanced-MRI could last at least 12 days and totally recovered after 16 days. This novel sensitive MRI contrast agent may find potential applications in discovering small liver lesions such as early tumor diagnosis.

•Surface engineering of SPION determines their in vivo performance.•Targeting mechanisms of SPION imaging are summarized.•Clinical trial information related to SPION on Clinicaltrials.gov is analyzed.Superparamagnetic iron oxide nanoparticles (SPION) based magnetic resonance imaging (MRI) is a powerful non-invasive tool in biomedical imaging, clinical diagnosis and therapy. In this review, the physicochemical properties of SPION and their in vivo performance were thoroughly discussed, also covering how surface engineering will prolong the circulation time and overcome biological barriers at organ, tissue, and cellular levels. Clinical applications and future potentials of SPION based MR imaging in cancer, cardiovascular, and inflammation diseases were addressed. Targeting mechanisms of SPION in both research and clinical use were summarized for better understanding of their performance. Addition of new targeting mechanisms to clinically approved SPION will bring opportunities to discover early diseases at cellular and molecular levels, and to track MRI-visible drug carriers. Clinical trial information related to SPION on Clinicaltrials.gov was summarized mainly based on their disease categories, therapeutic applications and clinical trial stages. It gives us a brief outlook of their clinical applications in the near future.

Superparamagnetic iron oxide (SPIO) nanoparticle clusters are one unique form which can enhance magnetic relaxivity and improve the magnetic resonance imaging contrast at the same iron concentration, comparing to single SPIO nanoparticles. Controlling of cluster size and other structural parameters have drawn great interests in this field to further improve their magnetic properties. In this study, we investigated how the interparticle distance (also known as neighbor distance) of SPIO nanocrystals within clusters affect their magnetic relaxation behaviors. To adjust the neighbor distance, different amount of cholesterol (CHO) was chosen as model spacers embedded into SPIO nanocluster systems with the help of amphiphilic diblock copolymer poly(ethylene glyco)-polyester. Small-angle X-ray scattering was applied to quantify the neighbor distance of SPIO clusters. The results demonstrated that the averaged SPIO nanocrystal neighbor distance of nanoclusters increased with higher amount of added CHO. Moreover, these SPIO nanocrystal clusters had the prominent magnetic relaxation properties. Simultaneously, controlling of SPIO nanocrystal neighbor distance can regulate the saturation magnetization (Ms) and magnetic resonance (MR) T2 relaxation of the aggregation, and ultimately obtain better MR contrast effects with decreased neighbor distance.

Layer-by-layer (LbL) self-assembled polyelectrolyte capsules have demonstrated their unique advantages and capability in drug delivery applications. These ordered micro/nano-structures are also promising candidates as imaging contrast agents for diagnostic and theranostic applications. Magnetic resonance imaging (MRI), one of the most powerful clinical imaging modalities, is moving forward to the molecular imaging field and requires the availability of advanced imaging probes. In this review, we are focusing on the design of MRI visible LbL capsules, which incorporate either paramagnetic metal-ligand complexes or superparamagnetic iron oxide (SPIO) nanoparticles. The design criteria cover the topics of probe sensitivity, biosafety, long-circulation property, targeting ligand decoration, and drug loading strategies. Examples of MRI visible LbL capsules with paramagnetic or superparamagnetic moieties were given and discussed. This carrier platform can also be chosen for other imaging modalities.Download high-res image (235KB)Download full-size image

The aza-semi-crown pentadentate ligand rigidified by pyridine and piperidine rings was designed and synthesized. It can react with Mn(II) in water to form complex with improved longitudinal relaxivity, leading to efficient signal intensity enhancement of vascular vessels under a clinical magnetic resonance imaging scanner.

T 1 contrast agents based on Mn(II) were conjugated on amphiphilic dextran micelles via click chemistry. The obtained paramagnetic nanomicelle contrast agent has a higher T1 relaxivity (13.3 Mn mmol−1 s−1) and better sensitivity than those of free Mn(II) complexes. Studies carried out in vivo suggest that this contrast agent has a better and long-acting vascular enhancement effect at a lower manganese dosage (0.1 Mn mmol kg−1 BW).