Magnetic Resonance Imaging Probes Research Articles

Highly Sensitive Detection of Caspase-3/7 Activity in Living Mice Using Enzyme-Responsive 19F MRI Nanoprobes.

Highly sensitive imaging of enzymatic activities in the deep tissues of living mammals provides useful information about their biological functions and for developing new drugs; however, such imaging is challenging. 19F magnetic resonance imaging (MRI) is suitable for noninvasive visualization of enzymatic activities without endogenous background signals. Although various enzyme-responsive 19F MRI probes have been developed, most cannot be used for in vivo imaging because of their low sensitivity. Recently, we developed unique nanoparticles, called FLAMEs, that are composed of a liquid perfluorocarbon core and a robust silica shell, and demonstrated their outstanding sensitivity in vivo. Here, we report a highly functionalized nanoprobe, FLAME-DEVD 2, with an OFF/ON 19F MRI switch for detecting caspase-3/7 activity based on the paramagnetic relaxation enhancement effect. To improve the cleavage efficiency of peptides by caspase-3, we designed a novel Gd3+ complex-conjugated peptide, DEVD X ( X = 1, 2), which is a substrate peptide sequence tandemly repeated X times, and demonstrated that DEVD 2 showed faster cleavage kinetics than DEVD 1. By incorporating this novel concept into a signal activation strategy, FLAME-DEVD 2 showed a high 19F MRI signal enhancement rate in response to caspase-3 activity. After intravenous injection of FLAME-DEVD 2 and an apoptosis-inducing reagent, caspase-3/7 activity in the spleen of a living mouse was successfully imaged by 19F MRI. This imaging platform shows great potential for highly sensitive detection of enzymatic activities in vivo.

Timely Visualization of the Collaterals Formed during Acute Ischemic Stroke with Fe3 O4 Nanoparticle-based MR Imaging Probe.

Ischemic stroke is one of the major leading causes for long-term disability and mortality. Collateral vessels provide an alternative pathway to protect the brain against ischemic injury after arterial occlusion. Aiming at visualizing the collaterals occurring during acute ischemic stroke, an integrin αv β3 -specific Fe3 O4 -Arg-Gly-Asp (RGD) nanoprobe is prepared for magnetic resonance imaging (MRI) of the collaterals. Rat models are constructed by occluding the middle cerebral artery for imaging studies of cerebral ischemia and ischemia-reperfusion on 7.0 Tesla MRI using susceptibility-weighted imaging sequence. To show the binding specificity to the collaterals, the imaging results acquired with the Fe3 O4 -RGD nanoprobe and the Fe3 O4 mother nanoparticles, respectively, are carefully compared. In addition, an RGD blocking experiment is also carried out to support the excellent binding specificity of the Fe3 O4 -RGD nanoprobe. Following the above experiments, cerebral ischemia-reperfusion studies show the collateral dynamics upon reperfusion, which is very important for the prognosis of various revascularization therapies in the clinic. The current study has, for the first time, enabled the direct observation of collaterals in a quasi-real time fashion and further disclosed that the antegrade flow upon reperfusion dominates the blood supply of primary ischemic tissue during the early stage of infarction, which is significantly meaningful for clinical treatment of stroke.

Asymmetric attachment and functionalization of plasmonic nanoparticles on ceramic interfaces

The demands for materials that integrate more than one functional imaging or therapeutic unit are of increasing interest for biomedical applications. Here, we present the step-by-step preparation of asymmetric and optically active particles, namely, Gd2O3@Ag, Gd2O3@Au, SiO2–N3@Au, and SiO2–SH@Au . Successful attachment of plasmonic nanoparticles to the surface of metal-oxide spheres without necessity of a potentially toxic inter-adhesive layer was proven by optical methods as well as X-ray photoelectron spectroscopy. The combination of optical and magnetic properties as present in Gd2O3@Ag and Gd2O3@Au Janus-type particles leads to dual-imaging probes for optical and magnetic resonance imaging. In addition, functional groups, such as azide groups, were linked to the surface of silica particles previous to Au nanoparticle attachment. Subsequent site-selective click reactions with 5-FAM were successfully performed as demonstrated by UV–Vis measurements. All described systems exhibited excellent long-term stability and can, therefore, be considered as promising candidates for theranostic applications.Graphical abstract

A new downhole magnetic resonance imaging tool

This paper presents a novel inside-out magnetic resonance imaging (MRI) device with axial, radial and circumferential measurements. The designed MRI probe employs array antenna and phase-controlled transmitters to accomplish spin echo data acquisition. Nuclear Magnetic Resonance (NMR) has been successfully applied to downhole formation evaluation with unique information of in-situ reservoir properties for decades. Traditional NMR logging measurements, however, are averaged the whole sensitive volume. The designed downhole MRI tool overcomes the weakness of traditional technique and raise new applications such as for heterogeneous formation evaluation around well bore and for harsh borehole conditions. We demonstrate the feasibility with a prototype in a calibration tank. The acquired echo trains from different direction and different radial depth are in good quality.

One-pot synthesis of albumin-gadolinium stabilized polypyrrole nanotheranostic agent for magnetic resonance imaging guided photothermal therapy

Theranostic agents with perfect properties are needed urgently for the development of imaging guided photothermal therapy (PTT). In this work, Gd-integrated polypyrrole nanotheranostic agent (PPy@BSA-Gd) was successfully built through selecting bovine serum albumin (BSA) as both stabilizers for polymerization and biomimetic mineralization in "one pot". The obtained PPy@BSA-Gd possessed high stability and excellent photothermal property. Besides, relevant cellular assays indicated that PPy@BSA-Gd had fantastic cytocompatibility which could be further internalized by cancer cells. Due to their high longitudinal relaxivity value (r1 = 10.203 mM−1 s−1), PPy@BSA-Gd could serve as considerable probe for T1-weighted magnetic resonance imaging (MRI). After tail vein injection of PPy@BSA-Gd, the MR signal of tumor section exhibited a time-dependent increase, indicating effective tumor accumulation of PPy@BSA-Gd. Notably, when exposed to 808 nm laser, the tumor growth of PPy@BSA-Gd treated mice could be inhibited by photothermal ablation successfully. All the results demonstrated the well-designed PPy@BSA-Gd have the potential for tumor diagnose and photothermal therapy.

One-pot hydrothermal preparation of gadolinium-doped silicon nanoparticles as a dual-modal probe for multicolor fluorescence and magnetic resonance imaging.

At present, multimodal probes for fluorescence and magnetic resonance imaging based on gadolinium-silicon hybrid nanoparticles have been reported. However, the existing preparations for these nanoparticles usually involve multi-step complicated processes and harsh conditions. Herein, to avoid complex procedures, we conveniently adopted a one-pot hydrothermal method to synthesize gadolinium (Gd)-doped silicon nanoparticles (D-SiGdNPs) using gadolinium chloride and diethylenetriaminepentaacetic acid (DTPA) as dopants. This is the first report on the synthesis of Gd-doped silicon nanoparticles. The D-SiGdNPs presented bright fluorescence (QY: 38%), good stability, and low biotoxicity. In particular, due to the dopants, the nanoparticles exhibited higher longitudinal relaxivity than the commercial contrast agent (Gd-DTPA) and obvious excitation-dependent photoluminescence whose emission wavelength ranged from 467 nm to 557 nm under serial excitation from 400 to 510 nm; thus, these NPs could be used for magnetic resonance imaging (MRI) and anti-counterfeiting stain applications. Moreover, the successful application of D-SiGdNPs, such as in the T1-weight MRI of mice and cellular fluorescence imaging, proves that the D-SiGdNPs have the potential to become an efficient dual-modal nanoprobe for multicolor fluorescence and magnetic resonance imaging in the future.

Diagnostic Value of ER, PR, FR and HER-2-Targeted Molecular Probes for Magnetic Resonance Imaging in Patients with Breast Cancer

Background/Aims: Smart molecular probes are required in the application of Magnetic resonance imaging (MRI) for biochemical and clinical research. This study aims to investigate the diagnostic values of estrogen receptor (ER), progesterone receptor (PR), folate receptor (FR) and human epidermal growth factor receptor 2 (HER-2)-targeted molecular probes in the MRI diagnosis of breast cancer. Methods: Initially, a total of 508 female breast cancer patients were selected for breast cancer subtype classification by immunohistochemistry. Subsequently, the tumor size, lymph node metastasis, and histological grade of different breast cancer subtypes were compared. Molecular probes of Ab-ER-USPIO, Ab-PR-USPIO, Ab-FR-USPIO and Ab-HER-2-USPIO were constructed and screened. The specific binding of molecular probes to breast cancer cells was detected both in vitro and in vivo by Prussian blue staining and MRI using T1 and T2 weighted images. Finally, in vivo toxicity of Ab-HER-2-USPIO was analyzed using hematoxylin and eosin staining. Results: We identified the following subtypes of breast cancer: Luminal A (ER-positive, FR-positive, HER-2-negative), Luminal B (ER-positive, FR-positive, HER-2-positive), HER-2 overexpression (ER-negative, FR-negative, HER-2-positive), and triple-negative breast cancer (ER-negative, FR-negative, HER-2-negative). Featuring favorable in vitro biocompatibility and low in vivo toxicity, Ab-HER-2-USPIO can specifically bind to breast cancer cells BT47 and SKBR3, thus enhancing the quality of T1 weighted MRI images. Conclusion: The results indicate that HER-2-targeted MRI molecular probes may be used in the clinical diagnosis of breast cancer and facilitate the development of promising strategies for breast cancer treatments.

Mesoporous 3D carbon framework encapsulated manganese oxide nanoparticles as biocompatible T1 MR imaging probe

Magnetic resonance imaging (MRI) is one of the widely used medical diagnostic techniques due to its non-invasive nature, higher resolution and efficiency in soft tissue imaging. MRI contrast agents with high relaxivity and biocompatibility are of great importance for successful clinical diagnosis. Manganese based substances have emerged as new class of MR imaging agents due to their impressive contrast ability. In this study, we have reported development of manganese oxide (Mn3O4) nanoparticles encapsulated in mesoporous 3D carbon framework (CF) functionalized by polyethylene glycol (PEG) as T1 based MRI contrast agent. PEG functionalization endowed solubility and stability of the contrast agent in water which are highly essential traits of MRI contrast agents. The carbon framework provided excellent biocompatibility by ruling out possibility of metal ion exposure (offering suitability for in vivo application) and simultaneously enabled water exchange through its pores which led to T1 contrast improvement. The as-prepared PEG modified manganese oxide@CF nanosystem exhibited paramagnetic behaviour at room temperature, enhanced water proton relaxation and facilitated contrast of T1-weighted MR images.

CM-101: Type I Collagen-targeted MR Imaging Probe for Detection of Liver Fibrosis.

Purpose To evaluate the biodistribution, metabolism, and pharmacokinetics of a new type I collagen-targeted magnetic resonance (MR) probe, CM-101, and to assess its ability to help quantify liver fibrosis in animal models. Materials and Methods Biodistribution, pharmacokinetics, and stability of CM-101 in rats were measured with mass spectrometry. Bile duct-ligated (BDL) and sham-treated rats were imaged 19 days after the procedure by using a 1.5-T clinical MR imaging unit. Mice were treated with carbon tetrachloride (CCl4) or with vehicle two times a week for 10 weeks and were imaged with a 7.0-T preclinical MR imaging unit at baseline and 1 week after the last CCl4 treatment. Animals were imaged before and after injection of 10 µmol/kg CM-101. Change in contrast-to-noise ratio (ΔCNR) between liver and muscle tissue after CM-101 injection was used to quantify liver fibrosis. Liver tissue was analyzed for Sirius Red staining and hydroxyproline content. The institutional subcommittee for research animal care approved all in vivo procedures. Results CM-101 demonstrated rapid blood clearance (half-life = 6.8 minutes ± 2.4) and predominately renal elimination in rats. Biodistribution showed low tissue gadolinium levels at 24 hours (<3.9% injected dose [ID]/g ± 0.6) and 10-fold lower levels at 14 days (<0.33% ID/g ± 12) after CM-101 injection with negligible accumulation in bone (0.07% ID/g ± 0.02 and 0.010% ID/g ± 0.004 at 1 and 14 days, respectively). ΔCNR was significantly (P < .001) higher in BDL rats (13.6 ± 3.2) than in sham-treated rats (5.7 ± 4.2) and in the CCl4-treated mice (18.3 ± 6.5) compared with baseline values (5.2 ± 1.0). Conclusion CM-101 demonstrated fast blood clearance and whole-body elimination, negligible accumulation of gadolinium in bone or tissue, and robust detection of fibrosis in rat BDL and mouse CCl4 models of liver fibrosis. © RSNA, 2017 Online supplemental material is available for this article.

Hydration number: crucial role in nuclear magnetic relaxivity of Gd(III) chelate-based nanoparticles

Today, nanostructure-based contrast agents (CA) are emerging in the field of magnetic resonance imaging (MRI). Their sensitivity is reported as greatly improved in comparison to commercially used chelate-based ones. The present work is aimed at revealing the factors governing the efficiency of longitudinal magnetic relaxivity (r1) in aqueous colloids of core-shell Gd(III)-based nanoparticles. We report for the first time on hydration number (q) of gadolinium(III) as a substantial factor in controlling r1 values of polyelectrolyte-stabilized nanoparticles built from water insoluble complexes of Gd(III). The use of specific complex structure enables to reveal the impact of the inner-sphere hydration number on both r1 values for the Gd(III)-based nanoparticles and the photophysical properties of their luminescent Tb(III) and Eu(III) counterparts. The low hydration of TTA-based Gd(III) complexes (q ≈ 1) agrees well with the poor relaxivity values (r1 = 2.82 mM−1s−1 and r2 = 3.95 mM−1s−1), while these values tend to increase substantially (r1 = 12.41 mM−1s−1, r2 = 14.36 mM−1s−1) for aqueous Gd(III)-based colloids, when macrocyclic 1,3-diketonate is applied as the ligand (q ≈ 3). The regularities obtained in this work are fundamental in understanding the efficiency of MRI probes in the fast growing field of nanoparticulate contrast agents.

Fluorine-19 magnetic resonance imaging probe for the detection of tau pathology in female rTg4510 mice.

Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine-19 magnetic resonance imaging (19 F-MRI) may be extremely useful for tau imaging once a high-quality probe has been formulated. In this investigation, a novel fluorine-19-labeling compound has been developed as a probe for tau imaging using 19 F-MRI. This compound is a buta-1,3-diene derivative with a polyethylene glycol side chain bearing a CF3 group and is known as Shiga-X35. Female rTg4510 mice (a mouse model of tauopathy) and wild-type mice were intravenously injected with Shiga-X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0-T horizontal-bore magnetic resonance scanner. The 19 F-MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine-19 magnetic resonance signal in the rTg4510 mice compared with the wild-type mice. Histological analysis showed fluorescent signals of Shiga-X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that 19 F-MRI using Shiga-X35 could be a promising tool to evaluate tau pathology in the brain.

A gadolinium-based magnetic resonance imaging contrast agent for nucleotides sensing

A new magnetic resonance imaging probe(Gd-NAPTA) with 2-amino-7-methyl-1, 8-naphthyridine as the nucleotide triggering site incorporating into gadolinium-based contrast agent through 2,6-dimethylpyridine linker, preferentially responding to guanosine 5′-triphosphate and adenine 5′-triphosphate has been developed. The formation of strong multi-hydrogen bonds between naphthyridine and nucleotide bases made the phosphate in guanosine 5′-triphosphate and adenine 5′-triphosphate positioned on a suitable site to coordinate to the lanthanide ion, such the substitute of the coordinated pyridine promotes the water molecule close to Gd center and the relaxivity increase of the contrast agent. The longitudinal relaxivity(r1) of Gd-NAPTA could linearly respond to the concentration of guanosine 5′-triphosphate and adenine 5′- triphosphate. The limit of detection (LOD) is about 0.03mM. The negligible cytotoxicity and appropriate blood circulation time of Gd-NAPTA allow potential application of Magnetic Resonance Imaging in vivo.

Fluorinated Mesoporous Silica Nanoparticles for Binuclear Probes in 1H and 19F Magnetic Resonance Imaging

The development of molecular and cellular magnetic resonance imaging (MRI) procedures has always represented a challenge because of the fact that conventional MRI contrast agents are not directly detected in vivo; in proton MRI (e.g., with the nucleus 1H), their local concentration is measured through the effect they exert on the signal of hydrogen protons present in their immediate vicinity. Because the contrast effects generated by conventional MRI probes superpose to and can often impede the anatomical information contained in 1H MRI images, new probes based on a nucleus other than 1H, are being developed. In this study, we report on the development of fluorinated mesoporous silica nanoparticles (MSNs), which could represent an interesting dual probe that allows two MRI modes: 1H for high-resolution anatomical information and 19F for the detection of MSNs used as drug delivery agents. MSNs were synthesized and covalently functionalized either with fluorosilane (FMSNs) or polyfluorosiloxane (polyFMSNs) to enable their detection in 19F MRI. Then, gadolinium chelates were grafted on the particles to enhance their detectability in 1H MRI. The physicochemical, textural, and relaxometric properties (1H and 19F relaxation times) of the nanoparticles were measured and compared. The 19F relaxation properties were found to be dependent on the concentration of fluorine; they were also highly sensitive to the presence of gadolinium. The shortest relaxation times were obtained with polyFMSNs. At clinical magnetic field strengths, high 1H relaxivities and low relaxometric ratios (r2/r1 = 1.45; 2.2 for nanoparticles entrapped in hydrogel) were found for both nanoparticle systems. Finally, the visibility of both systems was confirmed in 1H, and the detectability of polyFMSNs was confirmed in 19F MRI. This physicochemical and relaxometric study opens the door to the applications of fluorinated silica nanoparticles as theranostic materials allowing dual MRI (1H and 19F).

One-Step Fast Synthesis of Nanoparticles for MRI: Coating Chemistry as the Key Variable Determining Positive or Negative Contrast.

Iron oxide nanomaterial is a typical example of a magnetic resonance imaging probe for negative contrast. It has also been shown how this nanomaterial can be synthesized for positive contrast by modification of the composition and size of the core. However, the role of the organic coating in the relaxometric properties is largely unexplored. Here, maghemite nanoparticles with either excellent positive or very good negative contrast performance are obtained by modifying coating thickness while the core is kept unchanged. Different nanoparticles with tailored features as contrast agent according to the coating layer thickness have been obtained in a single-step microwave-driven synthesis by heating at different temperatures. A comprehensive analysis is conducted of how the composition and structure of the coating affects the final magnetic, relaxometric, and imaging performance. These results show how the organic coating plays a fundamental role in the intrinsic relaxometric parameters of iron oxide-based contrast media.

A New Magnetic Resonance Imaging Probe Specifically Targeting Vascular Endothelial Growth Factor Receptor 2:Synthesis, Characterization and Biological Evaluation

Vascular endothelial growth factor (VEGF) is strongly expressed in most tumours and promotes both tumour growth and vascularization. The peptide, VEGF 125-136 , consisting of 12 amino acids is encoded by exon 6 of the VEGF gene and inhibits VEGF activity by blocking the binding of VEGF to the VEGFR2 receptor. The aim of the present study was to develop a targeting probe for magnetic resonance imaging (MRI) of tumours by conjugating VEGF 125-136 to gadolinium (III) (Gd(III)) (VGd) through the formation of chelates. The targeting efficiency of VGd to human hepatocellular carcinoma (HCC) cell line, BEL-7402, was subsequently determined both in vitro and in vivo . In the in vitro studies, the MRI results of BEL-7402 cells treated with VGd showed significantly higher T1 signal-to-noise ratio than that of both the competitive group, namely, those treated with VGd and VEGF125-136 and the control group, a scramble peptide conjugated to Gd(III) (SGd). In vivo , when xenografts of BEL-7402 cells were established in mice and then VGd or SGd were injected via tail vein, MRI showed that the tumour signal from VGd initially decreased from 5 to 120 min and then it increased at 120 min post injection. The peak signal was observed at 120 min after injection. In contrast, no distinct peak was observed for SGd. These findings indicate that VGd can target VEGFR2, highly expressed by BEL-7402 cells, enabling targeting MRI with high efficacy to be achieved both in vitro and in vivo .

Structure-Dependent Antimicrobial Theranostic Functions of Self-Assembled Short Peptide Nanoagents.

Gadolinium (Gd[III])-based nanoaggregates are potential noninvasive magnetic resonance imaging (MRI) probes with excellent spatial and temporal resolution for cancer diagnosis. Peptides conjugated with Gd3+ can aid in supramolecular scaffolding for MRI nanoagents because of their inherent biocompatibility and degradability. We report here a strategy to tune the MR relaxivity of tumor cell-targeted nanoagents and enhance the antimicrobial and anticancer activities of nanoagents based on rationally designed antimicrobial peptide (AMP) assembly. A tripeptide with glycyl-l-histidyl-l-lysine (GHK) capable of Gd3+ chelation was attached to short AMPs containing pyrazole amino acids that spontaneously assembled as a function of the number of hydrophobic amino acid residues and the peptide length of AMPs. Aqueous coassembly of GHK with tumor-targeting, cyclic arginine-glycine-aspartic acid (cRGD)-tagged AMPs resulted in the formation of micelles, fibrils, vesicles, sheets, and planar networks. Interestingly, the two-dimensional planar network nanostructure showed less antibacterial activity and tumor cell cytotoxicity but greater drug loading/delivery and magnetic resonance signaling than micelles because of its intrinsic structural characteristics. This study can provide a rational approach for the design and fabrication of clinically useful nanoagents.

Heading toward Macromolecular and Nanosized Bioresponsive MRI Probes for Successful Functional Imaging.

The quest for bioresponsive or smart contrast agents (SCAs) in molecular imaging, in particular magnetic resonance imaging (MRI), is progressively increasing since they allow for the monitoring of essential biological processes on molecular and cellular levels in a dynamic fashion. These are offshoot molecules of common contrast agents that are sensitive to biochemical changes in their environment, capable of reporting on such changes by inducing MRI signal alteration. Various mechanistic approaches and different types of SCAs have been developed in order to visualize desired processes, using diverse imaging protocols and methods. To date, the most frequently exploited probes are paramagnetic molecules that change longitudinal or transverse relaxation at proton frequency, or so-called T1- and T2-weighted probes, respectively. Moreover, SCAs operating by the chemical exchange saturation transfer mechanism, suitable for 19F MRI or possessing hyperpolarized nuclei have also appeared in the past decade, slowly finding their role in functional imaging studies. Following these mechanistic principles, a large number of SCAs suitable for diverse targets have been reported to date. This Account condenses this exciting progress, particularly focusing on probes designed for abundant targets that are suitable for practical, in vivo utilization. To date, the greatest advancements have been certainly made in the preparation of pH sensitive probes, which usually contain protonable groups that interact with paramagnetic centers, or take advantage of supramolecular (dis)assembling to induce the MRI signal change, thereupon enabling pH mapping in vivo. In a complementary approach, a combination of metal chelating ligands for Ca2+ or Zn2+ with MR reporting units results in a wide variety of SCAs that operate with different contrast mechanisms and can be used for initial functional experiments. Finally, the first examples of molecular sensing by creating host-guest complexes to track neurotransmitter flux have also been recently reported, allowing the study of brain function in an unprecedented manner. Nevertheless, wider SCA utilization in vivo has not yet been achieved. There are a few reasons for this disparity between their nominal potential and practical usage, with one of the major reasons being the low sensitivity of the MRI technique. Subsequently, the production of detectable signal change can be achieved using higher concentrations of the bioresponsive probe; however, the biocompatibility of these probes then starts to play an important role. An elegant solution to these practical challenges has been found with the integration of multiple small-sized SCAs into macromolecular and nanosized probes. In such case, the multivalent SCAs are able to circumvent the sensitivity issue, thus enhancing the MR signal and desired contrast changes. Moreover, they prolong the probe tissue retention time, while often reducing their toxicity. Finally, with altered size and properties, they allow for exploitation of mechanisms that induce the contrast change which is not possible with small-sized SCAs. To this end, this Account also discusses the current approaches that aim to develop macromolecular and nanosized SCAs suitable for practical MRI applications. With these, further progress of this exciting field is affirmed, with remarkable results expected in the near future on both the probe preparation and their utilization in functional molecular imaging.

Theranostic poly(lactic-co-glycolic acid) nanoparticle for magnetic resonance/infrared fluorescence bimodal imaging and efficient siRNA delivery to macrophages and its evaluation in a kidney injury model

In this work, a theranostic nanoparticle was developed for multimodal imaging and siRNA delivery. The core of the nanoparticles (NP) was formed by encapsulation of superparamagnetic iron oxides and indocyanine green in a PLGA matrix to serve as a multimodal probe for near-infrared (NIFR) and magnetic resonance (MR) imaging. The surface of the particle was coated with polyethylenimine (PEI) for siRNA delivery. Macrophages efficiently took up the nanoparticles and emitted strong NIFR and MR contrast. When transfected with siRNA targeting the pro-inflammatory enzyme cyclooxygenase-2 (COX-2), significant down-regulation of COX-2 was achieved in activated macrophages. Furthermore, after injection into a unilateral ureteral obstruction (UUO)-induced kidney injury model, NIFR and MRI imaging revealed accumulation of nanoparticles in the injury kidney. In addition, in vivo silencing of COX-2 was achieved by NP/PEI/siCOX-2, which further attenuated kidney injury. Our theranostic platform represents a promising approach for simultaneous diagnosis and treatment of inflammatory diseases.

Europium doping of superparamagnetic iron oxide nanoparticles enables their detection by fluorescence microscopy and for quantitative analytics.

Pharmacokinetic studies and histological detection of superparamagnetic iron oxide nanoparticles (SPIO) in biomedical research are limited due to a high iron background especially in pathological tissues. The suitability of doping the iron oxide cores of SPIO with europium (Eu) was tested for improved histologic detection and for quantitative analysis without changing their properties as probes for magnetic resonance imaging (MRI). A special variant of SPIO, so called very small superparamagnetic iron oxide nanoparticles (VSOP), was used for this approach. VSOP, stabilized by a citrate coating, were synthesized with and without addition of Eu (Eu-VSOP and VSOP, respectively). MR signal enhancing effects of Eu-VSOP and VSOP were studied in vitro. Cellular uptake of Eu-VSOP and VSOP was examined in RAW264.7 cells. For Eu-VSOP, fluorescence microscopy and spectrophotometry were used. Eu fluorescence was enhanced by means of an antenna system. For VSOP, Prussian blue staining and photometry using the phenanthroline method were applied. Results for both VSOP variants were compared. Eu-VSOP and VSOP did not differ with respect to MR signal enhancing effects nor to uptake characteristics in the RAW264.7 cell experiments. Fluorescence microscopy detects Eu-VSOP with higher sensitivity compared to light microscopy using Prussian blue staining. In microscopy as well as in the analytical quantification using fluorescence, detection of Eu-VSOP is not contaminated by Fe background. Doping the VSOP with Eu allows for their improved detection by fluorescence microscopy and quantitative analysis without changing their cellular uptake characteristics or their MR signal enhancing effects and thus would allow for a multimodal approach for studying their pharmacokinetics and biodistribution in experimental research.

Magnetic Resonance Imaging-Guided Multi-Drug Chemotherapy and Photothermal Synergistic Therapy with pH and NIR-Stimulation Release.

The combination of multidrug chemotherapy and photothermal therapy (PTT) enhances cancer therapeutic efficacy. Herein, we develop a simple and smart pH/NIR dual-stimulus-responsive degradable mesoporous CoFe2O4@PDA@ZIF-8 sandwich nanocomposite. The mesoporous CoFe2O4 core acts as T2-weighted magnetic resonance (MR) imaging probe, PTT agent, and loading platform of hydrophilic doxorubicin (DOX). A polydopamine (PDA) layer is used to avoid the premature leakage of DOX before arriving at tumor site, enhance PTT efficiency, and facilitate the integration of ZIF-8 (a kind of metal-organic framework). The ZIF-8 shell serves to encapsulate hydrophobic camptothecin (CPT) and as the switch for the pH and NIR stimulation-responsive release of the two drugs. Therefore, T2-weighted MR imaging-guided multidrug chemotherapy and PTT synergistic treatment is achieved. Two kinds of anticancer drugs, hydrophilic DOX and hydrophobic CPT, are successfully loaded in CoFe2O4 and ZIF-8, respectively, so no mutual interference between the two drugs exists. A unique two-stage stepwise release process is exhibited for CPT and DOX with an interval of 12 h to improve the anticancer efficacy under the acidic microenvironment of tumor tissue. NIR irradiation achieves the burst drug-release and PTT after laser stimulation, simultaneously. With this smart design, high drug concentration is achieved at the tumor site by quick release, especially for the therapeutic drugs that show nonlinear pharmacokinetics, and PTT is integrated efficiently. Furthermore, negligible biotoxicity and a remarkable synergic antitumor effect of the hybrid nanocomposites are validated by HepG2 cells and tumor-bearing mice as models. Our multidrug delivery-releasing composite improves tumor therapeutic efficiency significantly compared with a single-drug chemotherapy system. The simple multifunctional composite system can be applied as an effective platform for personal nanomedicine with diagnosis, smart drug delivery, and cancer treatment through its remarkable photothermal property and controllable multidrug release.