Chunchao Xia

Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging

Iron oxide nanoparticles are effective contrast agents for enhancement of magnetic resonance imaging at tissue, cellular or even molecular levels. In this study, manganese doped superparamagnetic iron oxide (Mn-SPIO) nanoparticles were used to form ultrasensitive MRI contrast agents for liver imaging. Hydrophobic Mn-SPIO nanoparticles are synthesized in organic phase and then transferred into water with the help of block copolymer mPEG-b-PCL. These Mn-SPIO nanoparticles are self-assembled into small clusters (mean diameter approximately 80nm) inside micelles as revealed by transmission electron microscopy. Mn-SPIO nanoparticles inside micelles decrease PCL crystallization temperatures, as verified from differential scanning calorimetry and Fourier transform infrared spectroscopy. The Mn-SPIO based nanocomposites are superparamagnetic at room temperature. At the magnetic field of 1.5T, Mn-SPIO nanoparticle clustering micelles have a T(2) relaxivity of 270 (Mn+Fe)mM(-1)s(-1), which is much higher than single Mn-SPIO nanoparticle containing lipid-PEG micelles. This clustered nanocomposite has brought significant liver contrast with signal intensity changes of -80% at 5min after intravenous administration. The time window for enhanced-MRI can last about 36h with obvious contrast on liver images. This sensitive MRI contrast agent may find applications in identification of small liver lesions, evaluation of the degree of liver cirrhosis, and differential diagnosis of other liver diseases.

Low molecular weight alkyl-polycation wrapped magnetite nanoparticle clusters as MRI probes for stem cell labeling and in vivo imaging.

Superparamagnetic iron oxide (SPIO) nanoparticles are potential probes for noninvasive cell tracking, but the design of safe probes coupled with high labeling efficiency is still an important objective for such application. In this study, an efficient SPIO probe has been developed for mesenchymal stem cells (MSCs) labeling and tracking. Different from many other systems involving high molecular polycations, we chose low molecular weight amphiphilic PEI2k to form stable nanocomplexes with SPIO nanoparticles. The probe can hold multiple SPIO nanoparticles with a controlled clustering structure, leading to much higher T(2) relaxivities compared to single SPIO nanoparticles. Labeled MSCs are unaffected in their viability, proliferation, or differentiation capacity. The iron uptake process in MSCs displays a time- and dose-dependent behavior. Transmission electron microscopy reveals that the nanoprobes are internalized into the cytoplasm of MSCs. Subcutaneous injection of the labeled MSCs dispersed in a collagen type I hydrogel showed strong image contrast against unlabeled cells under a clinical 3T magnetic resonance imaging (MRI) scanner up to 19 days post-transplantation. This study provides an important alternative to label MSCs at optimized low dosages with high efficiency, and the probe may be useful to label other biologically important cells for imaging studies.

Amphiphilic starlike dextran wrapped superparamagnetic iron oxide nanoparticle clsuters as effective magnetic resonance imaging probes

Starlike polymers have been widely used in various fields, such as tissue engineering, imaging, gene and drug delivery because of their unique structures and properties. Dextran has long been used as a temporary plasma substitute because of its excellent biocompatibility. In this study, starlike polysaccharide with multiple dextran arms was designed and developed by attaching dextran to a β-cyclodextrin core through click chemistry. Next, starlike dextran was modified with aliphatic chains and these amphiphilic polymers can self-assemble into nanoscale micelles in water, and their critical micelle concentration values (3.7 × 10(-8) M) are much lower comparing to its linear analogs (1.7 × 10(-7) M), resulting in more stable nanostructures in aqueous environment. These micelles can encapsulate multiple superparamagnetic iron oxide nanoparticles and forming clustering particle nanostructures in water, and the resulting nanocomposites have a high T(2) relaxivity of 436.8 Fe mm(-1) s(-1) under a 1.5T clinical magnetic resonance imaging (MRI) scanner. Further, dual functional probes were developed by loading both superparamagnetic iron oxide nanoparticles and small molecule anticancer drug doxorubicin into polymeric micelles. Multidrug-resistant breast cancer cells MCF-7/Adr treated with these probes can be characterized under MRI.

Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells

Multidrug resistance (MDR) is one of the major barriers in cancer chemotherapy. P-glycoprotein (P-gp), a cell membrane protein in MDR, also a member of ATP-Binding cassette (ABC) transporter, can increase the efflux of various hydrophobic anticancer drugs. In this study, polycation/iron oxide nanocomposites, were chosen as small interfering RNA (siRNA) carriers to overcome MDR through silencing of the target messenger RNA and subsequently reducing the expression of P-gp. Amphiphilic low molecular weight polyethylenimine was designed with different alkylation groups and alkylation degree to form various nanocarriers with clustered iron oxide nanoparticles inside and carrying siRNA through electrostatic interaction. A few optimized formulations can form stable nanocomplexes with siRNA and protect them from degradation during delivery, and lead to effective silencing effect that comparable to a commercial golden standard transfection agent, Lipofectamine 2000. Human breast cancer MCF-7/ADR cells can be vulnerable to doxorubicin treatment after the strong downregulation of P-gp through siRNA tranfection. Once transfected with these nanocomplexes, the cells displayed significant contrast enhancement against non-transfected cells under a 3T clinical MRI scanner. These nanocomposites also demonstrated their downregulation efficacy of P-gp in a MCF-7/ADR orthotopic tumor model in mice.

Magnetic resonance imaging probes for labeling of chondrocyte cells

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 MRI probes for in vivo tracking of dendritic cell migration with a clinical 3 T scanner

Dendritic cell (DC) based vaccines have shown promising results in the immunotherapy of cancers and other diseases. How to track the in vivo fate of DC vaccines will provide important insights to the final therapeutic results. In this study, we chose magnetic resonance imaging (MRI) to track murine DCs migration to the draining lymph node under a clinical 3 T scanner. Different from labeling immature DCs usually reported in literature, this study instead labeled matured DC with superparamagnetic iron oxide (SPIO) nanoparticle based imaging probes. The labeling process did not show negative impacts on cell viability, morphology, and surface biomarker expression. To overcome the imaging challenges brought by the limitations of the scanner, the size of lymph node, and the number of labeled cell, we optimized MRI pulse sequences. As a result, the signal reduction, caused either by gelatin phantoms containing as low as 12 SPIO-laden cells in each voxel or by the homing SPIO-laden DCs within the draining nodes after footpad injection of only 1 × 10(5) cells, can be clearly depicted under a 3 T MR scanner. Overall, the MRI labeling probes offer a low-toxic and high-efficient MR imaging platform for the assessment of DC-based immunotherapies.

Multivalent manganese complex decorated amphiphilic dextran micelles as sensitive MRI probes

T1 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).

Native T1 mapping for characterization of acute and chronic myocardial infarction in swine: Comparison with contrast-enhanced MRI

Both acute and chronic myocardial infarction (AMI and CMI, respectively) exhibit delayed enhancement; however, clinical decision‐making processes frequently require the differentiation of these two types of myocardial injury.

Micro PET imaging of 18F-Fluoromisonidazole in an MDA-MB-231 triple negative human breast cancer xenograft model

Background: While 18 F-Fluoromisonidazole ( 18 F-FMISO) is the most frequently used positron emission tomography (PET) tracer for detecting hypoxia, it has not been studied in a metastatic triple-negative [lack expression of estrogen receptor (ER), progesterone receptor (PR) and human EGF receptor 2 (HER2)] human breast cancer cell xenografts model to our best knowledge. This study focuses on whether 18 F-FMISO can detect the hypoxic status of triple-negative human breast cancer (TNBC). Methods: The TNBC cells MDA-MB-231 were successfully inoculated in right forelimb of nude mice. Nude mice models with TNBC xenografts were assessed by micro-PET imaging with 18 F-FMISO, and hypoxic status of the TNBC xenografts was determined by immunohistochemistry. We also compared 18 F-FDG uptake, the most commonly used PET tracer in clinical practice, with 18 F-FMISO uptake to find out its correlation in MDA-MB-231 xenografts. Results: For 18 F-FMISO, intestines and liver as well as bladder could be seen in micro-PET images. 18 F-FDG showed physiologically high uptake in brain, heart, bladder and intestinal tracts. The quantitative radioactivity of 18 F-FMISO and 18 F-FDG in tumor were 2.18±0.15 and 3.84±0.54 %ID/g, respectively. The quantitative radioactivity of 18 F-FMISO and 18 F-FDG in muscle were 1.23±0.08 and 0.59±0.09 %ID/g, respectively. The tumor-to-muscle ratios were 1.79±0.015 and 7.11±2.84 for 18 F-FMISO and 18 F-FDG, respectively. Immunofluorescent images from MDA-MB-231 cryosections showed significant hypoxia. Conclusions: 18 F-FMISO PET may be used for detection of hypoxia in tumor microenvironment of triple negative human breast cancer.

MANGANESE CHELATE-ENHANCED MAGNETIC RESONANCE IMAGING OF MYOCARDIAL INFARCTION IN A RABBIT ISCHEMIA MODEL: COMPARISON WITH GADOLINIUM-ENHANCED MAGNETIC RESONANCE IMAGING

Gadolinium-based delayed enhancement magnetic resonance imaging (DEMRI) quantitatively identifies myocardial infarction (MI) but is nonspecific. Manganese (Mn)-enhanced MRI (MEMRI) can specifically detect cardiomyocyte viability. We developed a rigid Mn(II) chelate as MRI contrast agent to