Jinbao Qin

Photothermal Theragnosis Synergistic Therapy Based on Bimetal Sulphide Nanocrystals Rather Than Nanocomposites

A new generation of photothermal theranostic agents is developed based on Cu3BiS3 nanocrystals. A computed tomography imaging response and photothermal effect, as well as near-infrared fluorescence emission, can be simultaneously achieved through Cu3BiS3 nanocrystals rather than frequently used nanocomposites. These results provide some insight into the synergistic effect from bimetal sulphide semiconductor compounds for photothermal theragnosis therapy.

Targeted tumor CT imaging using folic acid-modified PEGylated dendrimer-entrapped gold nanoparticles

The development of multifunctional nanoprobes with a targeting capability for efficient molecular imaging of tumors still remains a great challenge. Herein, we report the synthesis and characterization of folic acid (FA)-modified dendrimer-entrapped gold nanoparticles (Au DENPs) via a facile polyethylene glycol (PEG) linking strategy for in vivo targeted tumor computed tomography (CT) imaging applications. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) sequentially modified by two types of PEG moieties (PEG monomethyl ether with one end of carboxyl group (mPEG-COOH), and FA-modified PEG with one end of carboxyl group (FA-PEG-COOH)) were used as templates to synthesize AuNPs within the dendrimer interiors, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. Cell viability assay, flow cytometric analysis of the cell cycles, and hemolysis assay were used to assess the cytotoxicity and hemocompatibility of the particles. We show that the formed multifunctional Au DENPs are stable at different pH and temperature conditions and in different aqueous media, cytocompatible and hemocompatible in the given Au concentration range, and display much higher X-ray attenuation intensity than Omnipaque (an iodine-based CT contrast agent) under similar concentrations of the active element (Au or iodine). Moreover, the developed Au DENPs enable targeted CT imaging of the model cancer cells with high FA receptor expression in vitro and the corresponding xenografted tumor model in vivo. These findings suggest that the designed Au DENPs may be used as promising contrast agents for targeted CT imaging of tumors.

Dendrimer-stabilized bismuth sulfide nanoparticles: synthesis, characterization, and potential computed tomography imaging applications

We report here a general approach to synthesizing dendrimer-stabilized bismuth sulfide nanoparticles (Bi2S3 DSNPs) for potential computed tomography (CT) imaging applications. In this study, ethylenediamine core glycidol hydroxyl-terminated generation 4 poly(amidoamine) dendrimers (G4.NGlyOH) were used as stabilizers to first complex the Bi(III) ions, followed by reaction with hydrogen sulfide to generate Bi2S3 DSNPs. By varying the molar ratio of Bi atom to dendrimer, stable Bi2S3 DSNPs with an average size range of 5.2-5.7 nm were formed. The formed Bi2S3 DSNPs were characterized via different techniques. X-ray absorption coefficient measurements show that the attenuation of Bi2S3 DSNPs is much higher than that of iodine-based CT contrast agent at the same molar concentration of the active element (Bi versus iodine). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay and hemolysis assay reveal that the formed Bi2S3 DSNPs are noncytotoxic and have a negligible hemolysis effect in the studied concentration range. Furthermore, we show that cells incubated with the Bi2S3 DSNPs are able to be imaged using CT, a prominent enhancement at the point of rabbit injected subcutaneously with the Bi2S3 DSNPs is able to be visualized via CT scanning, and the mouses pulmonary vein can be visualized via CT after intravenous injection of the Bi2S3 DSNPs. With the good biocompatibility, enhanced X-ray attenuation property, and tunable dendrimer chemistry, the designed Bi2S3 DSNPs should be able to be further functionalized, allowing them to be used as a highly efficient contrast agent for CT imaging of different biological systems.

Systematic review and meta-analysis of balloon angioplasty versus primary stenting in the infrapopliteal disease.

Objectives: We performed a systematic review and meta-analysis of comparing balloon angioplasty and primary stenting for symptomatic infrapopliteal disease to evaluate the clinical value of primary stenting in treating infrapopliteal diseases. Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. PubMed (1984-present), ScienceDirect (1980-present), Embase (1990-present), and CBM (1988-present) databases were searched for relevant articles. Finally, 16 studies (published between 2001 and 2013) satisfying the inclusion criteria were identified. The outcome parameters were immediate technical success, 1-year primary patency rate, 1-year limb salvage rate, and 1-year target vessel revascularization (TVR)-free rate. Comparisons were made with balloon angioplasty and primary stenting, and based on the different types of stents, we divided the primary stent group into the bare metal stent (BMS) group and drug-eluting stent (DES) group. Results: A total of 3789 patients and 4339 limbs constituted our final study population. The technical success rate of balloon angioplasty was 92.29% (95% confidence interval [CI] 88.75%-94.78%). Only 2 study reported the technical failure rates as 4% and 5.2% in the primary stent group. The pooled estimates of 1-year primary patency and TVR-free rate were similarly low in the balloon angioplasty group and BMS group (primary patency: 57.65%, 95% CI 53.54%-61.67% vs 60.95%, 95% CI 48.31%-72.28%, P = .38; TVR-free rate: 73.41%, 95% CI 66.51%-80.08% vs 73.66%, 95% CI 63.58%-81.75%, P = .91). The pooled estimates of 1-year primary patency and TVR-free rate in DES group were 81.10% (95% CI 75.48%-85.67%) and 90.30% (95% CI 85.30%-93.73%), respectively, which were better than those of the BMS and balloon angioplasty groups (P < .001 for both). The pooled estimate of 1-year limb salvage in the balloon angioplasty, BMS, and DES groups was 88.61% (95% CI 85.01%-91.43%), 94.41% (95% CI 89.52%-97.1%), and 95.20% (95% CI 86.97%-98.33%), respectively (P < .001). The BMS and DES groups had higher limb salvage rates than the balloon angioplasty group (P < .001 for both comparisons). The rates of severe complications were low both in the balloon angioplasty and in the primary stent groups. Conclusion: Primary BMS implantation had no advantage over balloon angioplasty in reducing restenosis or revascularization for infrapopliteal disease. Primary DES implantation seems to be a promising treatment for focal infrapopliteal lesions. Publication bias could not be ruled out, and the results should be treated with caution.

Long-term MRI tracking of dual-labeled adipose-derived stem cells homing into mouse carotid artery injury

Background Stem cell therapy has shown great promise for regenerative repair of injured or diseased tissues. Adipose-derived stem cells (ADSCs) have become increasingly attractive candidates for cellular therapy. Magnetic resonance imaging has been proven to be effective in tracking magnetic-labeled cells and evaluating their clinical relevance after cell transplantation. This study investigated the feasibility of imaging green fluorescent protein-expressing ADSCs (GFP-ADSCs) labeled with superparamagnetic iron oxide particles, and tracked them in vivo with noninvasive magnetic resonance imaging after cell transplantation in a model of mouse carotid artery injury. Methods GFP-ADSCs were isolated from the adipose tissues of GFP mice and labeled with superparamagnetic iron oxide particles. Intracellular stability, proliferation, and viability of the labeled cells were evaluated in vitro. Next, the cells were transplanted into a mouse carotid artery injury model. Clinical 3 T magnetic resonance imaging was performed immediately before and 1, 3, 7, 14, 21, and 30 days after cell transplantation. Prussian blue staining and histological analysis were performed 7 and 30 days after transplantation. Results GFP-ADSCs were found to be efficiently labeled with superparamagnetic iron oxide particles, with no effect on viability and proliferation. Homing of the labeled cells into the injured carotid artery tissue could be monitored by magnetic resonance imaging. Conclusion Magnetically labeled ADSCs with expression of GFP can home into sites of vascular injury, and may provide new insights into understanding of cell-based therapy for cardiovascular lesions.

Noninvasive detection of macrophages in atherosclerotic lesions by computed tomography enhanced with PEGylated gold nanoparticles

Macrophages are becoming increasingly significant in the progression of atherosclerosis (AS). Molecular imaging of macrophages may improve the detection and characterization of AS. In this study, dendrimer-entrapped gold nanoparticles (Au DENPs) with polyethylene glycol (PEG) and fluorescein isothiocyanate (FI) coatings were designed, tested, and applied as contrast agents for the enhanced computed tomography (CT) imaging of macrophages in atherosclerotic lesions. Cell counting kit-8 assay, fluorescence microscopy, silver staining, and transmission electron microscopy revealed that the FI-functionalized Au DENPs are noncytotoxic at high concentrations (3.0 μM) and can be efficiently taken up by murine macrophages in vitro. These nanoparticles were administered to apolipoprotein E knockout mice as AS models, which demonstrated that the macrophage burden in atherosclerotic areas can be tracked noninvasively and dynamically three-dimensionally in live animals using micro-CT. Our findings suggest that the designed PEGylated gold nanoparticles are promising biocompatible nanoprobes for the CT imaging of macrophages in atherosclerotic lesions and will provide new insights into the pathophysiology of AS and other concerned inflammatory diseases.

MRI of iron oxide nanoparticle-labeled ADSCs in a model of hindlimb ischemia.

Adipose-derived stem cells (ADSCs) exhibit tremendous potential for repair of ischemic diseases. However, studies on the fate, migration, differentiation, and body distribution of the labeled ADSCs are rarely reported. In this study, magnetic iron oxide nanoparticles were designed, synthesized, and coated with meso-2,3-dimercaptosuccinic acid (DMSA) to produce DMSA nanoparticles (DMSA-NPs). The properties, size distribution, and characterization of DMSA-NPs were evaluated. Green fluorescent protein expressing ADSCs (GFP-ADSCs) were obtained and labeled with DMSA-NPs. The viability, cytotoxicity and multi-differentiation capacity of labeled GFP-ADSCs were evaluated in vitro. Labeled and non-labeled GFP-ADSCs were injected into a mouse model of hindlimb ischemia, and 3T magnetic resonance imaging (MRI) was acquired. The synthesized DMSA-NPs efficiently labeled the GFP-ADSCs in vitro and in vivo without affecting cell viability, proliferation, cell cycle, and multi-differentiation capacity. The MRI showed hypointense spots in the labeled GFP-ADSCs that lasted up to 8 weeks. Prussian blue staining and immunofluorescence assay at 4 and 8 weeks indicated that the labeled GFP-ADSCs were in and around the ischemic sites and some differentiated into capillaries. This observation is identical to that seen for transplants of unlabeled cells. Labeled cells were also identified mainly in the liver and spleen, with significantly smaller amounts in the lungs, intestines, heart, and kidney. Developed DMSA-NPs were shown to exhibit a considerable potential for use as nanoprobes for MRI of stem cells, which will enhance our understanding of cell-based therapeutic strategies for ischemic diseases.

In vivo MRI tracking of iron oxide nanoparticle-labeled human mesenchymal stem cells in limb ischemia.

Background Stem cell transplantation has been investigated for repairing damaged tissues in various injury models. Monitoring the safety and fate of transplanted cells using noninvasive methods is important to advance this technique into clinical applications. Methods In this study, lower-limb ischemia models were generated in nude mice by femoral artery ligation. As negative-contrast agents, positively charged magnetic iron oxide nanoparticles (aminopropyltriethoxysilane-coated Fe2O3) were investigated in terms of in vitro labeling efficiency, effects on human mesenchymal stromal cell (hMSC) proliferation, and in vivo magnetic resonance imaging (MRI) visualization. Ultimately, the mice were sacrificed for histological analysis three weeks after transplantation. Results With efficient labeling, aminopropyltriethoxysilane-modified magnetic iron oxide nanoparticles (APTS-MNPs) did not significantly affect hMSC proliferation. In vivo, APTS-MNP-labeled hMSCs could be monitored by clinical 3 Tesla MRI for at least three weeks. Histological examination detected numerous migrated Prussian blue-positive cells, which was consistent with the magnetic resonance images. Some migrated Prussian blue-positive cells were positive for mature endothelial cell markers of von Willebrand factor and anti-human proliferating cell nuclear antigen. In the test groups, Prussian blue-positive nanoparticles, which could not be found in other organs, were detected in the spleen. Conclusion APTS-MNPs could efficiently label hMSCs, and clinical 3 Tesla MRI could monitor the labeled stem cells in vivo, which may provide a new approach for the in vivo monitoring of implanted cells.

Periostin enhances adipose-derived stem cell adhesion, migration, and therapeutic efficiency in Apo E deficient mice with hind limb ischemia.

IntroductionTherapeutic angiogenesis by transplantation of autologous/allogeneic adipose-derived stem cells (ADSCs) is a potential approach for severe ischemic diseases. However, poor viability, adhesion, migration and differentiation limit the therapeutic efficiency after the cells were transplanted into the targeted area. Periostin, an extracellular matrix protein, exhibits a critical role in wound repair as well as promotes cell adhesion, survival, and angiogenesis.MethodADSCs were obtained and genetically engineered with periostin gene (P-ADSCs). The viability, proliferation, migration, and apoptosis of P-ADSCs under hypoxia were analyzed. Moreover, P-ADSCs were implanted into Apo E deficient mice with hind limb ischemia. The Laser Doppler perfusion index, immunofluorescence, and histological pathology assay were tested to evaluate the therapeutic effects. The associated molecular mechanism of periostin on the proliferation, adhesion, migration, and differentiation of ADSCs was also analyzed.ResultsThe in vitro studies have shown that periostin-transfected ADSCs (P-ADSCs) promoted viability, proliferation, and migration of ADSCs. Apoptosis of ADSCs was inhibited under hypoxic conditions. The Laser Doppler perfusion index was significantly higher in the P-ADSCs group compared with that in the ADSC and control groups after 4 weeks. Immunofluorescence and histological pathology assay showed that the P-ADSCs were in and around the ischemic sites, and some cells differentiated into capillaries and endothelium. Microvessel densities were significantly improved in P-ADSCs group compared with those in the control group. The molecular mechanisms that provide the beneficial effects of periostin were connected with the upregulated expression of integrinβ1/FAK/PI3K/Akt/eNOS signal pathway and the increased secretion of growth factors.ConclusionOverexpression of periostin by gene transfection on ADSCs promotes survival, migration, and therapeutic efficiency, which will bring new insights into the treatment of critical limb ischemia.

Glyoxalase-1 Overexpression Reverses Defective Proangiogenic Function of Diabetic Adipose-Derived Stem Cells in Streptozotocin-Induced Diabetic Mice Model of Critical Limb Ischemia

Adipose‐derived stem cell (ADSC)‐based therapy is promising for critical limb ischemia (CLI) treatment, especially in patients with diabetes. However, the therapeutic effects of diabetic ADSCs (D‐ADSCs) are impaired by the diabetes, possibly through intracellular reactive oxygen species (ROS) accumulation. The objective of the present study was to detect whether overexpression of methylglyoxal‐metabolizing enzyme glyoxalase‐1 (GLO1), which reduces ROS in D‐ADSCs, can restore their proangiogenic function in a streptozotocin‐induced diabetic mice model of CLI. GLO1 overexpression in D‐ADSCs (G‐D‐ADSCs) was achieved using the lentivirus method. G‐D‐ADSCs showed a significant decrease in intracellular ROS accumulation, increase in cell viability, and resistance to apoptosis under high‐glucose conditions compared with D‐ADSCs. G‐D‐ADSCs also performed better in terms of migration, differentiation, and proangiogenic capacity than D‐ADSCs in a high‐glucose environment. Notably, these properties were restored to the same level as that of nondiabetic ADSCs under high‐glucose conditions. G‐D‐ADSC transplantation induced improved reperfusion and an increased limb salvage rate compared D‐ADSCs in a diabetic mice model of CLI. Histological analysis revealed higher microvessel densities and more G‐D‐ADSC‐incorporated microvessels in the G‐D‐ADSC group than in the D‐ADSC group, which was comparable to the nondiabetic ADSC group. Higher expression of vascular endothelial growth factor A and stromal cell‐derived factor‐1α and lower expression of hypoxia‐induced factor‐1α were also detected in the ischemic muscles from the G‐D‐ADSC group than that of the D‐ADSC group. The results of the present study have demonstrated that protection from ROS accumulation by GLO1 overexpression is effective in reversing the impaired biological function of D‐ADSCs in promoting neovascularization of diabetic CLI mice model and warrants the future clinical application of D‐ADSC‐based therapy in diabetic patients. Stem Cells Translational Medicine 2017;6:261–271