Tracking mesenchymal stem cells with Ir(III) complex-encapsulated nanospheres in cranium defect with postmenopausal osteoporosis.

Osteoporosis (OP) is a significant public health problem with associated fragility fractures, thereby causing large bone defects and difficulty in self-repair. The introduction of human mesenchymal stem cells (hMSCs) is the most promising platform in bone tissue engineering for OP therapy, which induces less side effects than conventional medication. However, the safety and efficiency of the cell-based OP therapy requires the ability to monitor the cell's outcome and biodistribution after cell transplantation. Therefore, we designed an in vivo system to track hMSCs in real time and simultaneously attempted to obtain a significant therapeutic effect during the bone repair process. In this study, we synthesized Ir(III) complex, followed by encapsulation with biodegradable methoxy-poly(ethylene glycol) poly(lactic-co-glycolic acid) nanospheres through double emulsions strategy. The Ir(III) complex nanospheres did not affect hMSC proliferation, stemness, and differentiation and realized highly efficient and long-term cellular labeling for at least 25 days in vivo. The optimal transplantation conditions were also determined first by injecting a gradient number of labeled hMSCs percutaneously into the cranial defect of the nude mouse model. Next, we applied this method to ovariectomy-induced OP mice. Results showed long-term optical imaging with high fluorescence intensity and computed tomography (CT) scanning with significantly increased bone formation between the osteoporotic and sham-operated bones. During the tracking process, two mice from each group were sacrificed at two representative time points to examine the bony defect bridging via micro-CT morphometric analyses. Our data showed remarkable promise for efficient hMSC tracking and encouraging treatment in bioimaging-guided OP stem cell therapy.

Light-Addressable Nanoclusters of Ultrasmall Iron Oxide Nanoparticles for Enhanced and Dynamic Magnetic Resonance Imaging of Arthritis.

Design of novel nanoplatforms with single imaging elements for dynamic and enhanced T 1/T 2-weighted magnetic resonance (MR) imaging of diseases still remains significantly challenging. Here, a facile strategy to synthesize light-addressable ultrasmall Fe3O4 nanoparticles (NPs) that can form nanoclusters (NCs) under laser irradiation for enhanced and dynamic T 1/T 2-weighted MR imaging of inflammatory arthritis is reported. Citric acid-stabilized ultrasmall Fe3O4 NPs synthesized via a solvothermal approach are linked with both the arthritis targeting ligand folic acid (FA) and light-addressable unit diazirine (DA) via polyethylene glycol (PEG) spacer. The formed ultrasmall Fe3O4-PEG-(DA)-FA NPs are cytocompatible, display FA-mediated targeting specificity to arthritis-associated macrophage cells, and can form NCs upon laser irradiation to have tunable r 1 and r 2 relaxivities by varying the laser irradiation duration. With these properties owned, the designed Fe3O4-PEG-(DA)-FA NPs can be used for T 1-weighted MR imaging of arthritis without lasers and enhanced dual-mode T 1/T 2-weighted MR imaging of arthritis under laser irradiation due to the formation of NCs that have extended accumulation within the arthritis region and limited intravasation back to the blood circulation. The designed light-addressable Fe3O4-PEG-(DA)-FA NPs may be used as a promising platform for dynamic and precision T 1/T 2-weighted MR imaging of other diseases.

Targeted tumor dual mode CT/MR imaging using multifunctional polyethylenimine-entrapped gold nanoparticles loaded with gadolinium.

We report the construction and characterization of polyethylenimine (PEI)-entrapped gold nanoparticles (AuNPs) chelated with gadolinium (Gd) ions for targeted dual mode tumor CT/MR imaging in vivo. In this work, polyethylene glycol (PEG) monomethyl ether-modified PEI was sequentially modified with Gd chelator and folic acid (FA)-linked PEG (FA-PEG) was used as a template to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining PEI surface amines. The formed FA-targeted PEI-entrapped AuNPs loaded with Gd (FA-Gd-Au PENPs) were well characterized in terms of structure, composition, morphology, and size distribution. We show that the FA-Gd-Au PENPs with an Au core size of 3.0 nm are water dispersible, colloidally stable, and noncytotoxic in a given concentration range. Thanks to the coexistence of Au and Gd elements within one nanoparticulate system, the FA-Gd-Au PENPs display a better X-ray attenuation property than clinical iodinated contrast agent (e.g. Omnipaque) and reasonable r1 relaxivity (1.1 mM-1s-1). These properties allow the FA-targeted particles to be used as an efficient nanoprobe for dual mode CT/MR imaging of tumors with excellent FA-mediated targeting specificity. With the demonstrated organ biocompatibility, the designed FA-Gd-Au PENPs may hold a great promise to be used as a nanoprobe for CT/MR dual mode imaging of different FA receptor-overexpressing tumors.

Quantitative Evaluation of the Compressed L5 and S1 Nerve Roots in Unilateral Lumbar Disc Herniation by Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: Nerve root compression by lumbar disc herniation (LDH) induces a series of clinical symptoms, seriously affecting the patient's life and work. The purpose of this study is to investigate microstructural changes and fiber bundle abnormalities of the compressed L5 and S1 nerve roots in young patients with unilateral LDH by using diffusion tensor imaging (DTI). METHODS: Forty young patients with unilateral LDH and 17 healthy volunteers participated in the study, and 33 patients received follow-up DTI examination after one month of conservative treatment. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and trace weight (TraceW) values of the L5 and S1 nerve roots were measured on FA maps. RESULTS: The mean FA, ADC and TraceW values of the affected nerve roots were 0.259 ± 0.047, 1.79 ± 0.252 and 0.076 ± 0.025, respectively. Compared to the contralateral side and volunteers, the affected nerve roots showed a decreased FA (P < 0.01), an increased ADC (P < 0.01) and TraceW (P < 0.05). The compression severity had a moderately negative correlation with FA (r = -0.646, P < 0.01) and positive correlation with ADC (r = 0.408, P < 0.01) but not with TraceW (r = 0.298, P = 0.06). For 33 patients with follow-up study after conservative treatment, FA (0.286 ± 0.06) and ADC (1.630 ± 0.046) in the affected nerve roots showed an increasing and a decreasing trend, respectively. Moreover, FA values (14 cases; 0.246 ± 0.015, P = 0.213) in the severe compression group had no significant changes between initial and follow-up data. CONCLUSIONS: DTI is able to assess microstructural abnormalities of the compressed nerve roots and has potentially practical value for prognostic evaluation after treatment in patients with LDH.

Comparison of semi-quantitative and quantitative dynamic contrast-enhanced MRI evaluations of vertebral marrow perfusion in a rat osteoporosis model.

BACKGROUND: This study aims to investigate the technical feasibility of semi-quantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the assessment of longitudinal changes of marrow perfusion in a rat osteoporosis model, using bone mineral density (BMD) measured by micro-computed tomography (micro-CT) and histopathology as the gold standards. METHODS: Fifty rats were randomly assigned to the control group (n=25) and ovariectomy (OVX) group whose bilateral ovaries were excised (n=25). Semi-quantitative and quantitative DCE-MRI, micro-CT, and histopathological examinations were performed on lumbar vertebrae at baseline and 3, 6, 9, and 12 weeks after operation. The differences between the two groups in terms of semi-quantitative DCE-MRI parameter (maximum enhancement, Emax), quantitative DCE-MRI parameters (volume transfer constant, Ktrans; interstitial volume, Ve; and efflux rate constant, Kep), micro-CT parameter (BMD), and histopathological parameter (microvessel density, MVD) were compared at each of the time points using an independent-sample t test. The differences in these parameters between baseline and other time points in each group were assessed via Bonferroni's multiple comparison test. A Pearson correlation analysis was applied to assess the relationships between DCE-MRI, micro-CT, and histopathological parameters. RESULTS: In the OVX group, the Emax values decreased significantly compared with those of the control group at weeks 6 and 9 (p=0.003 and 0.004, respectively). The Ktrans values decreased significantly compared with those of the control group from week 3 (p<0.05). However, the Ve values decreased significantly only at week 9 (p=0.032), and no difference in the Kep was found between two groups. The BMD values of the OVX group decreased significantly compared with those of the control group from week 3 (p<0.05). Transmission electron microscopy showed tighter gaps between vascular endothelial cells with swollen mitochondria in the OVX group from week 3. The MVD values of the OVX group decreased significantly compared with those of the control group only at week 12 (p=0.023). A weak positive correlation of Emax and a strong positive correlation of Ktrans with MVD were found. CONCLUSIONS: Compared with semi-quantitative DCE-MRI, the quantitative DCE-MRI parameter Ktrans is a more sensitive and accurate index for detecting early reduced perfusion in osteoporotic bone.

Reduction of Longitudinal Vertebral Blood Perfusion and Its Likely Causes: A Quantitative Dynamic Contrast-enhanced MR Imaging Study of a Rat Osteoporosis Model.

Purpose To determine the longitudinal relationships among lumbar vertebral blood perfusion, bone mass, and marrow adipose tissue in a rat osteoporosis model after ovariectomy by using quantitative dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging, microcomputed tomography (micro-CT), and proton MR spectroscopy. Materials and Methods In this animal review committee-approved study, lumbar vertebrae were evaluated through MR spectroscopy, quantitative DCE MR imaging, micro-CT, and histopathologic analysis, and blood was examined at 0, 2, 6, 10, 14, 18, and 24 weeks after ovariectomy consisting of exposure of the ovaries but no excision (n = 35) or sham operation, defined as exposure of the ovaries but no excision (n = 35). Differences in the parameters of these examinations between two groups at the same time point were analyzed by an independent-sample t test. Results Significantly reduced volume transfer constant (Ktrans) and volume of extravascular extracellular space per unit volume of tissue (week 2 and 10, respectively; P = .036 and P = .014, respectively), decreased bone mineral density (week 2; P = .014), and increased fat fraction (week 6; P = .036) in the ovariectomy group were observed, compared with those in the sham group. Vascular endothelial growth factor and microvessel density values of the ovariectomy group decreased significantly compared with those of the sham group from weeks 18 (P = .005) and 14 (P = .018), respectively. Transmission electron microscopy revealed tighter gaps among vascular endothelial cells and more marrow fibrosis in the ovariectomy group. Conclusion Quantitative DCE MR imaging can directly reflect marrow perfusion. Ktrans is a promising parameter to demonstrate early reduced marrow perfusion. Enhanced vasoconstriction and tightened gaps among vascular endothelial cells may be the likely causes in the initial stage of osteoporosis. Increased marrow adipose tissue, decreased microvessel density, and increased marrow fibrosis may aggravate marrow ischemia in the late stage of osteoporosis. © RSNA, 2016 Online supplemental material is available for this article.

(99m)Tc-Labeled Multifunctional Low-Generation Dendrimer-Entrapped Gold Nanoparticles for Targeted SPECT/CT Dual-Mode Imaging of Tumors.

Development of cost-effective and highly efficient nanoprobes for targeted tumor single-photon emission computed tomography (SPECT)/computed tomography (CT) dual-mode imaging remains a challenging task. Here, multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) modified with folic acid (FA) and labeled with (99m)Tc were synthesized for targeted dual-mode SPECT/CT imaging of tumors. Generation 2 (G2) poly(amidoamine) (PAMAM) dendrimers (G2-NH2) conjugated with cyclic diethylenetriamine pentaacetic anhydride (cDTPAA) via an amide linkage and FA via a spacer of polyethylene glycol (PEG) were used for templated synthesis of Au core NPs, followed by labeling of (99m)Tc via chelation. The thus created multifunctional Au DENPs were well-characterized. It is shown that particles with an average Au core diameter of 1.6 nm can be dispersed in water, display stability under different conditions, and are cytocompatible in the studied concentration range. Further results demonstrate that the multifunctional nanoprobe is able to be utilized for targeted SPECT/CT dual-mode imaging of cancer cells having FA receptor (FAR)-overexpression in vitro and the established subcutaneous tumor model in vivo within a time frame up to 4 h. The formed multifunctional Au DENPs synthesized using dendrimers of low-generation may be employed as an effective and economic nanoprobe for SPECT/CT imaging of different types of FAR-expressing tumors.

PEGylated polyethylenimine-entrapped gold nanoparticles loaded with gadolinium for dual-mode CT/MR imaging applications.

AIM: To synthesize and characterize cost-efficient polyethylenimine-entrapped gold nanoparticles loaded with gadolinium (Gd@Au PENPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging applications. MATERIALS & METHODS: PEGylated PEI modified with gadolinium (Gd) chelator (DOTA) was used as a template to synthesize the Gd@Au PENPs and the particles were well characterized in terms of their physicochemical properties, cytotoxicity and performances in CT and MR imaging in vitro and in vivo. RESULTS: The formed Gd@Au PENPs with low cytotoxicity can be used as a highly efficient contrast agent for dual-mode CT/MR imaging of blood pool and major organs of animals. CONCLUSION: The designed Gd@Au PENPs may be used as a versatile nanoplatform for dual-mode CT/MR imaging of different biological systems.