T1 Magnetic Resonance Imaging Contrast Research Articles

Controllable synthesis of up-conversion nanoparticles UCNPs@MIL-PEG for pH-responsive drug delivery and potential up-conversion luminescence/magnetic resonance dual-mode imaging

Rare-earth doped up-conversion nanoparticles (UCNPs) with high uniformity and dispersibility were synthesized by a facile solvothermal method. The conditions of synthesis for NaYF4:Yb/Tm were explored, and the NaYF4:Yb/Tm particles with the optimal size (about 300 nm) were obtained. Blue emission was observed with the excitation 980 nm near infrared (NIR) laser, indicating that the UCNPs can be potentially used for up-conversion luminescence (UCL) imaging. On basis of the optimal UCNPs, further coated by poly (ethylene glycol) (PEG) functionalized metal-organic frameworks (MOFs), a multifunctional platform UCNPs@MIL-PEG for cancer diagnosis and treatment was established. The core-shell structure was confirmed by TEM images. Doxorubicin (DOX) was selected as drug model and the drug loading of UCNPs@MIL-PEG was found to be 60%. Cytotoxicity indicated that UCNPs@MIL-PEG were highly biocompatible. The DOX release in different pH value revealed an excellent pH-triggered drug release. In addition, the UCNPs@MIL-PEG nanoparticles can be tracked by magnetic resonance imaging (MRI). A clear dose-dependent contrast enhancement in T2-weighted MR images indicated the potential act as T2 MRI contrast agents. The UCNPs@MIL-PEG nanoparticles are expected to be simultaneously used for UCL/MR dual-mode imaging and pH-responsive drug release.

Melanin-manganese nanoparticles with ultrahigh efficient clearance in vivo for tumor-targeting T1 magnetic resonance imaging contrast agent.

Endogenous biomaterials in organisms, with native biocompatibility and biodegradability, appear more advantageous in the development of nanoscale diagnostic and therapeutic systems for future clinical translation. Herein, a novel tumor-targeting Magnetic Resonance Imaging (MRI) contrast agent was developed based on Mn2+-chelating ultrasmall water-soluble melanin nanoparticles (MNP-PEG-Mn). The nanoparticles, with a size of about 5.6 nm, presented high chelation stability and showed negligible cytotoxicity as estimated by MTT assay. Moreover, the r1 longitudinal relaxivity (20.56 mM-1 s-1) of MNP-PEG-Mn was much higher than that of Gadodiamide (6.00 mM-1 s-1), which is a clinically approved MRI contrast agent. In vivo MRI experiments revealed excellent tumor-targeting specificity after tumor-bearing mice were intravenously injected with MNP-PEG-Mn. Additionally, MNP-PEG-Mn could be excreted via renal and hepatobiliary pathways with negligible toxicity to body tissues. These preliminary results indicated the clinically translatable potential of MNP-PEG-Mn as a T1 MRI contrast agent for tumor-targeted imaging.

顺磁性纳米材料用于T<sub>1</sub>核磁共振成像的研究进展

核磁共振成像技术(MRI)由于其高空间分辨率，无电离辐射，临床实用性广等特点受到了海内外科研工作者的广泛关注。作为核磁造影剂的一种，T1核磁造影剂能够使目标区域信号增强，极大地提高了MRI的精确性和特异性，从而使临床医务人员能更好地辨别正常部位与患病部位的成像对比度，判断体内器官的功能状态。在本文中，我们讨论了当前研究得比较多的几种T1造影剂的研究进程以及其未来发展方向。 Magnetic resonance imaging (MRI) has been widely studied by researchers at home and abroad due to its high spatial resolution, no ionizing radiation and wide clinical practicability. As a kind of MRI contrast agent, T1 MRI contrast agent can enhance the target signal, greatly improving the accuracy and specificity of MRI, so that the clinical medical staff can better identify the image contrast between the normal position and the diseased parts, and determine the internal organs function. In this article, we discuss the research progress of several T1 contrast agents and its future development.

Ultrasmall Gd2O3 nanoparticles surface-coated by polyacrylic acid (PAA) and their PAA-size dependent relaxometric properties

Ultrasmall Gd2O3 nanoparticles can potentially be used as a positive magnetic resonance imaging (MRI) contrast agent owing to their high content of Gd(III), which exhibits the highest spin magnetic moment of all elements due to its seven unpaired 4f electrons. Herein, the above nanoparticles (average diameter = 2.0 nm) were coated with hydrophilic biocompatible polyacrylic acids (PAAs) of different molecular weights (Mw = 1200, 5100, 15000 Da), and the PAA-size-dependent relaxometric properties of the thus obtained composites were investigated. In addition, the biocompatibility of these composites was assessed by in-vitro cell viability measurements. Finally, dose-dependent R1 map images were acquired, proving that PAA-coated nanoparticles can be used as a T1 MRI contrast agent.

Mn(II) based T1 and T2 potential MRI contrast agent appended with tryptamine: Recognition moiety for Aβ-plaques

We report the synthesis and characterization of manganese(II) complexes having pentadentate ligands L1 (2,6-bis(1-(2-phenyl-2-(pyridin-2-yl)hydrazono)ethyl)pyridine), L2 (methyl 2,6-bis((E)-1-(2-phenyl-2-(pyridin-2yl)hydrazono)ethyl)isonicotinate), L3 (N-(2-(1H-indol-3-yl)ethyl)-2,6-bis((E)-1-(2-phenyl-2-(pyridin2yl)hydrazono)ethyl)isonicotiamide) and their application as dual contrast agents for simultaneous T1 and T2 weighted magnetic resonance imaging. Single crystal analysis of all the complexes [MnIIL1, MnIIL2 and MnIIL3] confirm the formation of novel seven-coordinate manganese complexes with an inner sphere water and perchlorate ion. The Magnetic Resonance Imaging (MRI) contrast agent [MnL2] was further modified by incorporating tryptamine as a binding moiety specific to Amyloid Beta-fibrils (Aβ-fibrils) in Alzhiemer's disease (AD) and it's in vitro evaluation for specific binding with Aβ-fibrils indicated as a bio-marker of AD.

Double-receptor-targeting multifunctional iron oxide nanoparticles drug delivery system for the treatment and imaging of prostate cancer.

As an alternative therapeutic treatment to reduce or eliminate the current side effects associated with advanced prostate cancer (PCa) chemotherapy, a multifunctional double-receptor-targeting iron oxide nanoparticles (IONPs) (luteinizing hormone-releasing hormone receptor [LHRH-R] peptide- and urokinase-type plasminogen activator receptor [uPAR] peptide-targeted iron oxide nanoparticles, LHRH-AE105-IONPs) drug delivery system was developed. Two tumor-targeting peptides guided this double-receptor-targeting nanoscale drug delivery system. These peptides targeted the LHRH-R and the uPAR on PCa cells. Dynamic light scattering showed an increase in the hydrodynamic size of the LHRH-AE105-IONPs in comparison to the non-targeted iron oxide nanoparticles (NT-IONPs). Surface analysis showed that there was a decrease in the zeta potential values for drug-loaded LHRH-AE105-IONPs compared to the NT-IONPs. Prussian blue staining demonstrated that the LHRH-AE105-IONPs were internalized efficiently by the human PCa cell line, PC-3. In vitro, magnetic resonance imaging (MRI) results confirmed the preferential binding and accumulation of LHRH-AE105-IONPs in PC-3 cells compared to normal prostate epithelial cells (RC77N/E). The results also showed that LHRH-AE105-IONPs significantly maintained T2 MRI contrast effects and reduced T2 values upon internalization by PC-3 cells. These paclitaxel-loaded double-receptor-targeting IONPs also showed an approximately twofold reduction in PC-3 cell viability compared to NT-IONPs.

Erratum to: Plasmonic enhancement of the upconversion luminescence in a Yb3+ and Ho3+ co-doped gold-ZnO nanocomposite for use in multimodal imaging

The authors report on upconversion (UC) nanocrystals based on a gold-ZnO nanocomposite that enables HeLa cells to be characterizes via fluorescence imaging (FI), magnetic resonance imaging (MRI) and upconversion luminescence (UCL) imaging. The Yb3+ and Ho3+ doped gold-ZnO nanocomposite (Au-ZnO:Yb3+/Ho3+) was fabricated through a microwave-assisted route and possesses an irregular morphology. Inductively coupled plasma mass spectrometry (ICP-MS) shows the doping fractions of Yb3+ and Ho3+ to be 4.0% and 0.38% respectively. The nanocomposite shows UCL upon NIR irradiation at a wavelength of 980 nm. The emission spectrum has two main emission bands, one peaking at 544 nm (green emission), and the other at 658 nm (red emission). The red emission is stronger than the green emission, and the pump power dependence of upconversion intensity underpins a 2-photon UC process. The inherent down-conversion luminescence (DCL) of ZnO is preserved with enhanced intensity in the gold-ZnO nanocomposite. The plasmonic enhancement of both UCL and DCL can be clearly observed. Doping with Ho3+ renders paramagnetism to the nanocomposite, with a magnetization value of 18.91 emu⋅g−1 at room temperature. The Au-ZnO:Yb3+/Ho3+ nanocomposite exhibit a longitudinal relaxivity (r1) of 0.12 s−1⋅mM−1 and a transverse relaxivity (r2) of 27.23 s−1⋅mM−1. Their substantial transverse relaxivity makes the nanocrystals most viable T2 MRI contrast agents. The cytotoxicity of nanocomposite was tested in HeLa cells by applying the MTT assay and by morphological studies. The nanocrystals are found to be biocompatible in up to50 μg⋅mL−1 concentration for an incubation time of 48 h. The nanocomposite is well taken up by HeLa cells. Its biocompatibility, UCL, DCL and its substantial magnetism make this nanocomposite as most viable nanoprobe for multimodal imaging.

ZnO@Gd2O3 core/shell nanoparticles for biomedical applications: Physicochemical, in vitro and in vivo characterization

The chemical composition of nanoparticles (NPs) may be so designed as to provide measurability for numerous imaging techniques in order to achieve synergistic advantages. Innovative and unique structure of the core/shell ZnO@Gd2O3 NPs possesses luminescent and magnetic properties, and is expected that they will become a new generation of contrast agents for Magnetic Resonance Imaging (MRI) and nanocarriers for theranostics. Thus, by surface biofunctionalization, it is possible to indicate particular nanoparticle compositions which provide efficient imaging, targeted drug delivery, and biocompatibility.Novel ZnO@Gd2O3 NPs were synthesized and biofunctionalized by folic acid (FA) and doxorubicin (Doxo) to provide target and anticancer functions. Physicochemical analyses of the nanoparticles were performed. The biological study included a cytotoxicity in vitro, cellular distribution evaluation, as well as toxicity analyses, performed for the first time, on the in vivo zebrafish (Danio rerio) model.Nanoparticles were found to be effective double-function biomarkers (MRI T2 contrast agents, fluorescent imaging). The biological study showed that ZnO@Gd2O3 and ZnO@Gd2O3@OA-polySi@FA NPs are biocompatible in a particular concentration ranges. Conjugation with folic acid and/or doxorubicin resulted in effective drug delivery targeting. The in vivo results described the toxicology profile toward the zebrafish embryo/larvae, including new data concerning the survival, hatching ratio, and developmental malformations.

Fe3O4 nanoparticles modified by CD-containing star polymer for MRI and drug delivery

Fe3O4 nanoparticles with ultrasmall sizes show good T1 or T1+T2 contrast abilities, and have attracted considerable interest in the field of magnetic resonance imaging (MRI) contrast agents. For effective biomedical applications, the colloidal stability and biocompatibility of the Fe3O4 nanoparticles need to be improved without reducing MRI relaxivity. In this paper, star polymers were used as coating materials to modify Fe3O4 nanoparticles in view of their dense molecular architecture with moderate flexibility. The star polymer was composed of a β-cyclodextrin (β-CD) core and poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) arms. Meanwhile, reduced glutathione (GSH), as a model drug, was also associated with the star polymer. Thus, a new platform for simultaneous diagnosis and treatment was achieved. Compared to the Fe3O4 nanoparticles coated with linear polymers, the Fe3O4 nanoparticles coated with star polymers (Fe3O4@GCP) possessed higher GSH association capacity and better stability in serum-containing solution. GSH could be released from Fe3O4@GCP nanoparticles in response to pH value of the solution. Since the sulfhydryl group on GSH is able to combine free radicals, Fe3O4@GCP nanoparticles exhibited less cytotoxicity compared to the Fe3O4 nanoparticles without including GSH. Furthermore, the nanoparticles could also serve as good T1 MRI contrast agent, and the MRI relaxivity of Fe3O4@GCP nanoparticles did not decrease after coated with the star polymer. These results indicate that the precisely designed Fe3O4@GCP nanoparticles could be used as a versatile promising theranostic nano-platform.

Surface Engineered Ho3+ Incorporated Fluorescent Dye-Doped Bifunctional Silica Nanoparticles for Receptor Targeted Fluorescence Imaging and Potential Magnetic Resonance Imaging.

The authors report Ho3+ ion incorporated and fluorescent dye-doped silica nanoparticles which are engineered to enable the imaging modalities of receptor targeted fluorescence imaging (FI) and magnetic resonance imaging (MRI). The silica nanoparticles synthesized through a modified Stöber method is luminomagnetic by virtue of the luminescence of organic dye fluorophore (FITC) and magnetism of Ho3+. The doping concentration of Ho3+ is estimated by inductively coupled plasma mass spectrometry (ICP-MS) as 0.97%. The presence of Ho3+ has a little effect on the luminescence intensity but impart strong paramagnetism of 27.217emu/g at room temperature. The relaxivity measurements shown that the nanoparticles exhibit a longitudinal relaxivity (r1) of 0.12s-1mM-1 and transverse relaxivity (r2) of 26.96s-1mM-1, which makes the system potentially suitable for developing T2 MRI contrast agents based on holmium. The luminomagnetic nanoparticles were surface engineered through aminization and conjugated with folic acid (FA) to address the folate receptor targeted imaging of the cancer cells. The biocompatibility studies revealed no apparent toxicity even at higher doses of 750μg/mL and at 48h of incubation. The as prepared nanoparticles were demonstrated as a bioimaging probe in the in vitro receptor targeted fluorescence imaging of HeLa cells. The luminescence and magnetism together with biocompatibility enables the adaptability of the present system as a nano platform for potential bimodal imaging. Graphical Abstract ᅟ.

Enhancing T1 magnetic resonance imaging contrast with internalized gadolinium(III) in a multilayer nanoparticle

Multifunctional nanoparticles for biomedical applications have shown extraordinary potential as contrast agents in various bioimaging modalities, near-IR photothermal therapy, and for light-triggered therapeutic release processes. Over the past several years, numerous studies have been performed to synthesize and enhance MRI contrast with nanoparticles. However, understanding the MRI enhancement mechanism in a multishell nanoparticle geometry, and controlling its properties, remains a challenge. To systematically examine MRI enhancement in a nanoparticle geometry, we have synthesized MRI-active Au nanomatryoshkas. These are Au core-silica layer-Au shell nanoparticles, where Gd(III) ions are encapsulated within the silica layer between the inner core and outer Au layer of the nanoparticle (Gd-NM). This multifunctional nanoparticle retains its strong near-IR Fano-resonant optical absorption properties essential for photothermal or other near-IR light-triggered therapy, while simultaneously providing increased T1 contrast in MR imaging by concentrating Gd(III) within the nanoparticle. Measurements of Gd-NM revealed a strongly enhanced T1 relaxivity (r1 ∼ 24 mM-1⋅s-1) even at 4.7 T, substantially surpassing conventional Gd(III) chelating agents (r1 ∼ 3 mM-1⋅s-1 at 4.7 T) currently in clinical use. By varying the thickness of the outer gold layer of the nanoparticle, we show that the observed relaxivities are consistent with Solomon-Bloembergen-Morgan (SBM) theory, which takes into account the longer-range interactions between the encapsulated Gd(III) and the protons of the H2O molecules outside the nanoparticle. This nanoparticle complex and its MRI T1-enhancing properties open the door for future studies on quantitative tracking of therapeutic nanoparticles in vivo, an essential step for optimizing light-induced, nanoparticle-based therapies.

Activated Surface Charge‐Reversal Manganese Oxide Nanocubes with High Surface‐to‐Volume Ratio for Accurate Magnetic Resonance Tumor Imaging

Investigating the surface structure, including crystal surface and surface‐coating ligands, of nanoparticulate T1 contrast agent may help to understand the T1 relaxation enhancement in vitro and in vivo. This study presents a novel strategy to develop high‐performance T1 magnetic resonance imaging (MRI) contrast agents through optimizing the nanocrystal surface and the nanobio interface. Based on the optimized crystal surface, the novel manganese oxide nanocubes (MOCs) show significantly higher surface‐to‐volume ratio and an approximately threefold higher r1 value compared to traditional manganese oxide nanospheres. Concurrently, transferring MOCs into aqueous media by dopamine derivatization can avoid the oxidation of Mn(II) ions and provide abundant magnetic core. This optimized surface endows MOCs with a high chemical exchange efficiency during T1 relaxation. Of particular significance, a rationally designed pH‐induced charge‐switchable surfaces can be negatively charged and corona‐free in blood and positively charged surface in tumor sites. This unique feature improves the circulation behavior of this intelligent T1 contrast agent in blood and increases cancer cell uptake to achieve accurate detection of solid tumor, holding great potential in aiding early and precise tumor diagnosis. This study provides a novel tool for sophisticated design of high‐performance T1 MRI contrast agents in bioimaging applications.

Ultrasmall graphene oxide based T1 MRI contrast agent for in vitro and in vivo labeling of human mesenchymal stem cells

Herein, we report on development of a two-dimensional nanomaterial graphene oxide (GO)-based T1 magnetic resonance imaging (MRI) contrast agent (CA) for in vitro and in vivo labeling of human mesenchymal stem cells (hMSCs). The CA was synthesized by PEGylation of ultrasmall GO, followed by conjugation with a chelating agent DOTA and then gadolinium(III) to form GO-DOTA-Gd complexes. Thus-prepared GO-DOTA-Gd complexes exhibited significantly improved T1 relaxivity, and the r1 value was 14.2 mM−1s−1 at 11.7 T, approximately three times higher than Magnevist, a commercially available CA. hMSCs can be effectively labeled by GO-DOTA-Gd, leading to remarkably enhanced cellular MRI effect without obvious adverse effects on proliferation and differentiation of hMSCs. More importantly, in vivo experiment revealed that intracranial detection of 5×105 hMSCs labeled with GO-DOTA-Gd is achieved. The current work demonstrates the feasibility of the GO-based T1 MRI CA for stem cell labeling, which may find potential applications in regenerative medicine.

Synthesis of cytocompatible Fe3O4@ZSM-5 nanocomposite as magnetic resonance imaging contrast agent

In this study, ZSM-5 nano zeolite was used as a support material for iron oxide nanoparticles and the potential ability of the nanocomposite for magnetic resonance imaging (MRI) contrast agent was investigated. The nanocomposite was synthesized by hydrothermal method and characterized using X-ray diffraction and scanning electron microscopy. MRI was carried out by use of a 1.5Tesla clinical scanner. The T2 weighted images were prepared and the r2 relaxivity was calculated. The sizes of Fe3O4 nanoparticles and related nanocomposite were 13–24nm and 80–150nm, respectively. Results of MTT assay confirmed that the prepared nanocomposite is cytocompatible. The r2 relaxivity of the Fe3O4@ZSM-5 nanocomposite was 457.1mM−1s−1. This study suggests that the Fe3O4@ZSM-5 nanocomposite has potential to use as an MRI T2 contrast agent.

High-Density Lipoprotein-like Magnetic Nanostructures (HDL-MNS): Theranostic Agents for Cardiovascular Disease

We report the development of potential theranostic agents for cardiovascular disease that are based on high-density lipoprotein-like magnetic nanostructures (HDL-MNS). The HDL-MNS offer prospects for diagnosis via noninvasive magnetic resonance imaging for anatomic detection and also serve as effective cholesterol efflux agents to address atherosclerotic vascular lesions. The HDL-MNS are synthesized by adding phospholipids and the HDL-defining apolipoprotein A1 to the surface of magnetic nanostructures (MNS) to mimic some aspects of natural HDL particles. From a diagnostic perspective, HDL-MNS show a 5 times higher contrast (r2 relaxivity up to 383 mM–1 s–1) in magnetic resonance imaging (MRI) than commercially available T2 MRI contrast agents (e.g., Ferumoxytol). Internalization of HDL-MNS by macrophage cells was confirmed by transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDX), inductive-coupled plasma mass spectrometry (ICP-MS), and successfully imaged via MRI. Also, the H...

The upconversion luminescence and magnetism in Yb3+/Ho3+ co-doped LaF3 nanocrystals for potential bimodal imaging

Biocompatible upconversion nanoparticles with multifunctional properties can serve as potential nanoprobes for multimodal imaging. Herein, we report an upconversion nanocrystal based on lanthanum fluoride which is developed to address the imaging modalities, upconversion luminescence imaging and magnetic resonance imaging (MRI). Lanthanide ions (Yb3+ and Ho3+) doped LaF3 nanocrystals (LaF3 Yb3+/Ho3+) are fabricated through a rapid microwave-assisted synthesis. The hexagonal phase LaF3 nanocrystals exhibit nearly spherical morphology with average diameter of 9.8 nm. The inductively coupled plasma mass spectrometry (ICP-MS) analysis estimated the doping concentration of Yb3+ and Ho3+ as 3.99 and 0.41%, respectively. The nanocrystals show upconversion luminescence when irradiated with near-infrared (NIR) photons of wavelength 980 nm. The emission spectrum consists of bands centred at 542, 645 and 658 nm. The stronger green emission at 542 nm and the weak red emissions at 645 and 658 nm are assigned to 5S2 → 5I8 and 5F5 → 5I8 transitions of Ho3+, respectively. The pump power dependence of luminescence intensity confirmed the two-photon upconversion process. The nanocrystals exhibit paramagnetism due to the presence of lanthanide ion dopant Ho3+ and the magnetization is 19.81 emu/g at room temperature. The nanocrystals exhibit a longitudinal relaxivity (r 1) of 0.12 s−1 mM−1 and transverse relaxivity (r 2) of 28.18 s−1 mM−1, which makes the system suitable for developing T2 MRI contrast agents based on holmium. The LaF3 Yb3+/Ho3+ nanocrystals are surface modified by PEGylation to improve biocompatibility and enhance further functionalisation. The PEGylated nanocrystals are found to be non-toxic up to 50 μg/mL for 48 h of incubation, which is confirmed by the MTT assay as well as morphological studies in HeLa cells. The upconversion luminescence and magnetism together with biocompatibility enables the adaptability of the present system as a nanoprobe for potential bimodal imaging.

Superparamagnetic Nanoparticles as High Efficiency Magnetic Resonance Imaging T2 Contrast Agent.

Nanoparticle-based magnetic resonance imaging T2 negative agents are of great interest, and much effort is devoted to increasing cell-loading capability while maintaining low cytotoxicity. Herein, two classes of mixed-ligand protected magnetic-responsive, bimetallic gold/iron nanoparticles (Au/Fe NPs) synthesized by a two-step method are presented. Their structure, surface composition, and magnetic properties are characterized. The two classes of sulfonated Au/Fe NPs, with an average diameter of 4 nm, have an average atomic ratio of Au to Fe equal to 7 or 8, which enables the Au/Fe NPs to be superparamagnetic with a blocking temperature of 56 K and 96 K. Furthermore, preliminary cellular studies reveal that both Au/Fe NPs show very limited toxicity. MRI phantom experiments show that r2/r1 ratio of Au/Fe NPs is as high as 670, leading to a 66% reduction in T2 relaxation time. These nanoparticles provide great versatility and potential for nanoparticle-based diagnostics and therapeutic applications and as imaging contrast agents.

Functional magnetic porous silica for T1–T2 dual-modal magnetic resonance imaging and pH-responsive drug delivery of basic drugs

A smart magnetic-targeting drug carrier γ-Fe2O3@p-silica comprising a γ-Fe2O3 core and porous shell has been prepared and characterized. The particles have a uniform size of about 60 nm, and a porous shell of thickness 3 nm. Abundant hydroxyl groups and a large surface area enabled the γ-Fe2O3@p-silica to be readily loaded with a large payload of the basic model drug rhodamine B (RB) (up to 73 mg g−1). Cytotoxicity assays of the γ-Fe2O3@p-silica particles indicated that the particles were biocompatible and suitable for carrying drugs. It was found that the RB was released rapidly at pH 5.5 but at pH 7.4 the rate and extent of release was greatly attenuated. The particles therefore demonstrate an excellent pH-triggered drug release. In addition, the γ-Fe2O3@p-silica particles could be tracked by magnetic resonance imaging (MRI). A clear dose-dependent contrast enhancement in both T1-weighted and T2-weighted MR images indicated the potential of the γ-Fe2O3@p-silica particles to act as dual-mode T1 and T2 MRI contrast agents.

Fluorescein-labeled fluoroapatite nanocrystals codoped with Yb(III) and Ho(III) for trimodal (downconversion, upconversion and magnetic resonance) imaging of cancer cells

The authors report on upconversion nanocrystals (NCs) based on a fluoroapatite (FAp) support that was engineered to enable multimodal imaging by fluorescence imaging (FI), magnetic resonance imaging (MRI), and upconversion luminescence imaging. A fluorescein based fluorophore (FITC) was incorporated into the FAp nanocrystals and then doped with Yb(III) and Ho(III) by microwave-assisted solution combustion synthesis. The hexagonal phase nanocrystals (FITC-FAp:Yb/Ho) exhibit spindle like morphology with an average diameter and length of 15 nm and 196 nm, respectively. The doping concentration of the Yb (5 %) and Ho (0.6 %) was determined by ICP-MS. The nanocrystals exhibit upconversion luminescence when irradiated with NIR light of wavelength 980 nm. The emission spectrum consists of two bands centered at 542 nm (green emission) and 654 nm (red emission) corresponding to two transitions of Ho(III). The pump power dependence of upconversion luminescence intensity confirmed the 2-photon process. The presence of FITC in the nanocrystal imparts green fluorescence (peaking at 521 nm) by a conventional downconversion process. The presence of Ho(III) endows the NCs with paramagnetism. The magnetization is 21.063 emu∙g−1 at room temperature. The NCs exhibit a longitudinal relaxivity (r1) of 0.12 s−1∙mM−1, and a transverse relaxivity (r2) of 29 s−1∙mM−1, which makes the system suitable for developing T2 MRI contrast agents. The nanocrystals are surface aminized using polyethyleneimine (PEI) and covalently conjugated to folic acid (FA) in order to target the folate receptors that are overexpressed in many cancer cells. The FA-conjugated nanocrystals have been tested for their applicability in fluorescence imaging of HeLa cells. Their biocompatibility, upconversion and downconversion luminescence, and magnetism render these NCs potentially powerful nanoprobes for trimodal imaging.

Targeted multimodal nano-reporters for pre-procedural MRI and intra-operative image-guidance.

Multimodal-imaging probes offer a novel approach, which can provide detail diagnostic information for the planning of image-guided therapies in clinical practice. Here we report targeted multimodal Nd3+-doped upconversion nanoparticle (UCNP) imaging reporters, integrating both magnetic resonance imaging (MRI) and real-time upconversion luminescence imaging (UCL) capabilities within a single platform. Nd3+-doped UCNPs were synthesized as a core-shell structure showing a bright visible emission upon excitation at the near infrared (minimizing biological overheating and increasing tissue penetration depth) as well as providing strong MRI T2 contrast (high r2/r1 ratio). Transcatheter intra-arterial infusion of Nd3+-doped UCNPs conjugated with anti-CD44-monoclonal antibody allowed for high performance invivo multimodal UCL and MR imaging of hepatocellular carcinoma (HCC) in an orthotopic rat model. The resulted invivo multimodal imaging of Nd3+ doped core-shell UCNPs combined with transcatheter intra-arterial targeting approaches successfully discriminated liver tumors from normal hepatic tissues in rats for surgical resection applications. The demonstrated multimodal UCL and MRI imaging capabilities of our multimodal UCNPs reporters suggest strong potential for invivo visualization of tumors and precise surgical guidance to fill the gap between pre-procedural imaging and intraoperative reality.