A stable USPIO capable for MR lymphography with ultra-low effective dosage.

Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles appear to be promising tools for MR lymphography due to their unique magnetic properties. In clinical diagnosis, the effectiveness of USPIO will greatly affect the clinician's judgment to the enhanced MR images. In this study, we evaluated the effectiveness of CS015, a PAA-coated USPIO, with subcutaneous and intravenous administration. It appeared that subcutaneously injected particles had much higher efficiency to reach lymph nodes, and even worked at a very small dose 0.075 µmol/kg. Further, we compared CS015 with ferumoxytol and ferumoxtran-10 in MR lymphography and found that CS015 had the best performance. And the lymph node metastases in New Zealand rabbits were successfully detected using CS015 with one single dose. These merits of CS015 make it a promising MR lymphography contrast agent with potential applications in cancer therapy.

Effect of region of interest on ADC and interobserver variability in thyroid nodules.

BACKGROUND: To determine the effect of region of interest (ROI) on tumor's apparent diffusion coefficient (ADC) and interobserver variability in thyroid nodules. METHODS: Thirty-three individuals with 45 pathologically-confirmed thyroid nodules were assessed by preoperative diffusion-weighted imaging (DWI) with b values of 0 and 400 s/mm2, respectively. Two readers evaluated the ADC values of lesions based on three ROI techniques: whole-volume, single-slice and small solid-sample groups. Interobserver variability was analyzed for all ROI techniques, and the mean ADCs of benign and cancerous thyroid nodules were compared. RESULTS: For the mean ADCs of non-cancerous thyroid nodules, average differences and limits of agreement (LOAs) between readers were 0.00 [- 0.17-0.17] × 10- 3 mm2/s for whole-volume ROI (ICC = 0.967), 0.00 [- 0.26-0.26] × 10- 3 mm2/s for single-slice ROI (ICC = 0.932) and - 0.02 [- 0.38-0.41] × 10- 3 mm2/s for small solid-sample ROI (ICC = 0.823). For the mean ADCs of cancerous thyroid nodules, average differences and LOAs between readers were - 0.05 [- 0.23-0.13] × 10- 3 mm2/s (ICC = 0.885), 0.01 [- 0.23-0.25] × 10- 3 mm2/s (ICC = 0.839) and - 0.07 [- 0.52-0.39] × 10- 3 mm2/s (ICC = 0.579) for the three ROI methods, respectively. The mean ADC values were more scattered in the small solid-sample ROI group in comparison with the whole-volume and single-slice groups, in noncancerous and cancerous specimens. Of all three ROI techniques, whole-volume ROI-determined ADC had the highest combined sensitivity (80.0%), specificity (88.3%) and Youden index (0.683), with a cut-off of 1.84 × 10- 3 mm2/s. CONCLUSIONS: The ROI method overtly affects ADC measurements in benign and cancerous thyroid nodules. Small solid-sample ROI yielded the worst interobserver variability of average ADC measurements.

A T1/T2 dual functional iron oxide MRI contrast agent with super stability and low hypersensitivity benefited by ultrahigh carboxyl group density.

Clinically acceptable safety and efficacy are the most important issues for the design and synthesis of iron oxide MRI contrast agents. In order to meet the practical requirements, a kind of low molecular weight PAA-coated Fe3O4 nanoparticle (CS015) with super colloidal stability and low hypersensitivity benefitting from an ultrahigh carboxyl group density was developed in this study. The composition and physicochemical properties of the particles were characterized by TEM, XRD, FTIR and TGA. The ultrahigh density of COOH on the particles (33 COOH per nm2) was verified while a core size of 5.1 nm and a dynamic diameter of 41 nm with a narrow distribution were also achieved. The particles still showed excellent dispersity and stability even after a spray-drying or freeze-drying process, exposure to high temperature sterilized conditions and long-term storage. The nanoparticles could quickly capture iron ions in bulk solution which was confirmed by ITC results, and the bioactive iron concentration of CS015 was greatly decreased (0.54 ± 0.05 mg L-1) compared to that of commercially available ferumoxytol, iron sucrose and VSOP. Free iron ion release was 1120 times lower than the toxic concentration of iron. An excellent biocompatibility of CS015 with no obvious cytotoxicity and low risk of hypersensitivity has been manifested by cytotoxicity experiments and a passive cutaneous anaphylaxis test. The T1 and T2-weighted MRI contrast effects both in vitro and in vivo have also been verified which made CS015 a potential dual MRI contrast agent. Furthermore, theoretically calculated conformation was speculated and all the advantages mentioned above were benefited from the three dimensional brush-like texture of CS015. Therefore, these merits make the CS015 nanoplatform highly suitable in diagnostic applications as a MRI contrast agent.

cRGD-Conjugated Fe3O4@PDA-DOX Multifunctional Nanocomposites for MRI and Antitumor Chemo-Photothermal Therapy.

BACKGROUND: Photothermal therapy (PTT) has great potential in the clinical treatment of tumors. However, most photothermal materials are difficult to apply due to their insufficient photothermal conversion efficiencies (PCEs), poor photostabilities and short circulation times. Furthermore, tumor recurrence is likely to occur using PTT only. In the present study, we prepared cyclo (Arg-Gly-Asp-d-Phe-Cys) [c(RGD)] conjugated doxorubicin (DOX)-loaded Fe3O4@polydopamine (PDA) nanoparticles to develop a multifunctional-targeted nanocomplex for integrated tumor diagnosis and treatment. MATERIALS AND METHODS: Cytotoxicity of Fe3O4@PDA-PEG-cRGD-DOX against HCT-116 cells was determined by cck-8 assay. Cellular uptake was measured by confocal laser scanning microscope (CLSM). Pharmacokinetic performance of DOX was evaluated to compare the differences between free DOX and DOX in nanocarrier. Performance in magnetic resonance imaging (MRI) and antitumor activity of complex nanoparticles were evaluated in tumor-bearing nude mice. RESULTS: Fe3O4@PDA-PEG-cRGD-DOX has a particle size of 200-300 nm and a zeta potential of 22.7 mV. Further studies in vitro and in vivo demonstrated their excellent capacity to target tumor cells and promote drug internalization, and significantly higher cytotoxicity with respect to that seen in a control group was shown for the nanoparticles. In addition, they have good thermal stability, photothermal conversion efficiencies (PCEs) and pH responsiveness, releasing more DOX in a mildly acidic environment, which is very conducive to their chemotherapeutic effectiveness in the tumor microenvironment. Fe3O4@PDA-PEG-cRGD-DOX NPs were used in a subcutaneous xenograft tumor model of nude mouse HCT-116 cells showed clear signal contrast in T2-weighted images and effective anti-tumor chemo-photothermal therapy under NIR irradiation. CONCLUSION: According to our results, Fe3O4@PDA-PEG-cRGD-DOX had a satisfactory antitumor effect on colon cancer in nude mice and could be further developed as a potential integrated platform for the diagnosis and treatment of cancer to improve its antitumor activity against colon cancer.

Strategy to prevent cardiac toxicity induced by polyacrylic acid decorated iron MRI contrast agent and investigation of its mechanism.

Polyelectrolyte modified iron oxide nanoparticles have great potential applications for clinical magnetic resonance imaging (MRI) and anemia treatments, however, possible associated heart toxicity is rarely reported. Here, polyacrylic acid (PAA)-coated Fe3O4 nanoparticles (PION) were synthesized and lethal reactions appeared when it was applied in vivo. The investigation of underlying mechanism showed that PION could break electrolyte balance and further resulted in serious heart failure, which was observed under color doppler ultrasound and dynamic vector blood flow technique. The results demonstrated that PION had a strong absorption tendency for divalent ions and the maximum tolerated dose (MTD) was lower than 100 mg/kg. From electrocardiography (ECG), PION presented an obvious impact on CaV1.2 ion channel, which leading to fatal arrhythmia. An appropriate solution for preventing this deadly effect was pre-chelation Ca2+ (n (Ca): n (COOH) = 3: 8) to PION (PION-Ca), which displayed much higher cardiac and electrophysiological safety when sealing the binding point of divalent cation ions with PAA. The injection in Beagle dogs further confirmed the safety of PION-Ca. This study explored the mechanism and offered a solution for cardiac toxicity induced by PAA-coated nanoparticles, which guides for enhancing the safety of such polyelectrolyte decorated nanoparticles and provides assurance for clinical applications.

[Functional MRI in chronic liver disease of hepatitis B patients].

OBJECTIVE: To estimate the correlations between functional MRI (fMRI) parameters and the severity of chronic liver lesions of hepatitis B patients. METHODS: 47 hepatitis B patients [6 with chronic hepatitis, 41 with cirrhosis (14 with Child-Pugh class A cirrhosis; 12 with class B cirrhosis; and 15 with class C cirrhosis)] and 10 normal volunteers, referred for measurements of apparent diffusion coefficient (ADC) values of the liver, perfusion imaging parameters, portal flow parameters and serum markers of hepatic fibrosis were included in the study. Diffusion-weighted imaging (DWI) with different b values and b value remainder was performed. Time to peak (TP), maximum slope of increase (MSI) and distribution volume (DV) were measured with dynamic contrast material-enhanced MR imaging. Portal velocity and portal flow with phase contrast (PC) were measured. The patients' serum hepatic fibrosis markers, including hyaluronic acid (HA), type-III-procollagen (PC III), laminin (LN) and type-IV-collagen (C IV), were measured and analyzed together with the fMRI results. RESULTS: (1) The mean ADC3 in Child A, B, C cirrhosis patients was significantly lower than that in the controls (P < 0.05 in Child A, and P < 0.05 in Child B). (2) There was a significant increase of time to peak and a decrease of maximum slope of increase (P < 0.01) in the Child A, B, C patients than in the normal controls. (3) There was a significant decrease in portal velocity in cirrhotic patients as compared to that of the controls and chronic hepatitis patients (P < 0.01). (4) The mean HA in Child A, B, C cirrhosis patients was significantly higher than that in chronic hepatitis patients and in the controls (P < 0.01); The mean LN in Child A, B, C cirrhosis was also significantly higher than that in chronic hepatitis patients and in normal controls (P < 0.01); The mean PC III in Child A, B, C cirrhosis was significantly higher than that in the normal controls (P < 0.01). CONCLUSION: fMRI parameters can reflect some changes of the livers, therefore fMRI parameters are of value in clinical diagnosis and treatment of chronic hepatitis B patients.

Ultrasound-triggered BSA/SPION hybrid nanoclusters for liver-specific magnetic resonance imaging.

Nanoclusters of superparamagnetic iron oxide nanoparticles (SPION) are developed for liver-specific magnetic resonance imaging (MRI) by a unique synthesis route. The process is efficient, environmentally benign, and straight forward within five minutes. The clustering effect is triggered in the presence of bovine serum albumin (BSA) aqueous phase under ultrasonication condition. The hydrophobic SPION are densely self-assembled into BSA/SPION hybrid nanoclusters with a uniform size of ~86 nm. The as-prepared BSA/SPION hybrid nanoclusters are found to be biocompatible and stable. They exhibit high transverse relaxivity and longitudinal relaxivity in water (r(2) and r(1) values are 600.8 and 4.3 s(-1) per mM of Fe(3+), respectively). In vivo T(2)-weighted MRI shows excellent enhancement in liver with an imaging time-window up to 48 h. In vivo biodistribution study indicates a gradual excretion of the nanoclusters via hepatobiliary (HB) processing. No toxicity is observed in the in vivo and ex vivo experiments. The BSA/SPION hybrid nanoclusters present great potential in MRI as the liver-specific contrast agents (CAs).