In contrast to the classical world, an unknown quantum state cannot be cloned ideally, as stated by the no-cloning theorem. However, it is expected that approximate or probabilistic quantum cloning will be necessary for different applications, and thus various quantum cloning machines have been designed. Phase quantum cloning is of particular interest because it can be used to attack the Bennett-Brassard 1984 (BB84) states used in quantum key distribution for secure communications. Here, we report the first room-temperature implementation of quantum phase cloning with a controllable phase in a solid-state system: the nitrogen-vacancy centre of a nanodiamond. The phase cloner works well for all qubits located on the equator of the Bloch sphere. The phase is controlled and can be measured with high accuracy, and the experimental results are consistent with theoretical expectations. This experiment provides a basis for phase-controllable quantum information devices.
The mechanisms by which the exposure of mice to Cl2 decreases vectorial Na+ transport and fluid clearance across their distal lung spaces have not been elucidated. We examined the biophysical, biochemical, and physiological changes of rodent lung epithelial Na+ channels (ENaCs) after exposure to Cl2, and identified the mechanisms involved. We measured amiloride-sensitive short-circuit currents (Iamil) across isolated alveolar Type II (ATII) cell monolayers and ENaC single-channel properties by patching ATII and ATI cells in situ. α-ENaC, γ-ENaC, total and phosphorylated extracellular signal-related kinase (ERK)1/2, and advanced products of lipid peroxidation in ATII cells were measured by Western blot analysis. Concentrations of reactive intermediates were assessed by electron spin resonance (ESR). Amiloride-sensitive Na+ channels with conductances of 4.5 and 18 pS were evident in ATI and ATII cells in situ of air-breathing mice. At 1 hour and 24 hours after exposure to Cl2, the open probabilities of these two channels decreased. This effect was prevented by incubating lung slices with inhibitors of ERK1/2 or of proteasomes and lysosomes. The exposure of ATII cell monolayers to Cl2 increased concentrations of reactive intermediates, leading to ERK1/2 phosphorylation and decreased Iamil and α-ENaC concentrations at 1 hour and 24 hours after exposure. The administration of antioxidants to ATII cells before and after exposure to Cl2 decreased concentrations of reactive intermediates and ERK1/2 activation, which mitigated the decrease in Iamil and ENaC concentrations. The reactive intermediates formed during and after exposure to Cl2 activated ERK1/2 in ATII cells in vitro and in vivo, leading to decreased ENaC concentrations and activity.
lung slices; patch clamp; radicals
We examined gene expression in the lumbar spinal cord and the specific response of motoneurons, intermediate gray and proprioceptive sensory neurons after spinal cord injury and exercise of hindlimbs to identify potential molecular processes involved in activity dependent plasticity. Adult female rats received a low thoracic transection and passive cycling exercise for 1 or 4 weeks. Gene expression analysis focused on the neurotrophic factors; brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and their receptors because of their potential roles in neural plasticity. We also examined expression of genes involved in the cellular response to injury; heat shock proteins (HSP) -27 and -70, glial fibrillary acidic protein (GFAP) and caspases -3, -7, and -9. In lumbar cord samples, injury increased the expression of mRNA for TrkB, all three caspases and the HSPs. Acute and prolonged exercise increased expression of mRNA for the neurotrophic factors BDNF and GDNF, but not their receptors. It also increased HSP expression and decreased caspase-7 expression, with changes in protein levels complimentary to these changes in mRNA expression.
Motoneurons and intermediate grey displayed little change in mRNA expression following injury, but acute and prolonged exercise increased levels of mRNA for BDNF, GDNF and NT-4. In large DRG neurons, mRNA for neurotrophic factors and their receptors were largely unaffected by either injury or exercise. However, caspase mRNA expression was increased by injury and decreased by exercise. Our results demonstrate that exercise affects expression of genes involved in plasticity and apoptosis in a cell specific manner and that these change with increased post-injury intervals and/or prolonged periods of exercise.
Spinal cord; transection; exercise; neuroplasticity; brain-derived neurotrophic factor; glial cell-line derived neurotrophic factor
AZ465 is a novel selective transient receptor potential cation channel, member A1 (TRPA1) antagonist identified during a focused drug discovery effort. In vitro, AZ465 fully inhibits activation by zinc, O-chlorobenzylidene malononitrile (CS), or cinnamaldehyde of the human TRPA1 channel heterologously expressed in human embryonic kidney cells. Our data using patch-clamp recordings and mouse/human TRPA1 chimeras suggest that AZ465 binds reversibly in the pore region of the human TRPA1 channel. Finally, in an ex vivo model measuring TRPA1 agonist-stimulated release of neuropeptides from human dental pulp biopsies, AZD465 was able to block 50%–60% of CS-induced calcitonin gene-related peptide release, confirming that AZ465 inhibits the native human TRPA1 channel in neuronal tissue.
pain; pharmacology; antagonist; chimeric proteins; dental pulp; inflammation; neuropeptide; calcitonin gene-related peptide; CGRP
Reversible assembly and disassembly of nanostructures has important function in controllable construction of nanodevices. There are several methods to achieve reversible assembly/disassembly, such as pH, temperature, DNA hybridization and so on. Among these methods, pH driven reversible assembly presents superiority due to its ease-of-use and no waste produced. Herein we report a novel design that use two single-stranded (ss) DNAs wrapped single walled carbon nanotubes (SWCNTs) for the pH controlled assembly of SWCNTs without generation of waste.
Both of the two DNAs with a same wrapping sequence of d(GT)20 and different free terminals showed a very high tendency to wrap around carbon nanotubes. The assembly was driven by the hybridization between the two free terminals of wrapped DNAs on the neighboring SWCNTs: i-motif (four-stranded C-quadruplex) and its complemental stranded G-quadruplex which would form tight tetraplexes and break the hybridization under slightly acidic conditions. Thus the assembly and disassembly are reversibly controlled by pH. And this assembly/disassembly process can be easily distinguished by naked eyes. Gel electrophoresis and Atomic Force Microscope are used to demonstrate the assembly and disassembly of SWCNTs at different pH.
A novel pH induced reversible assembly and disassembly of SWCNTs was realized which may have potential applications in the area of controlled assembly of nanostructures.
pH controlled reversible assembly; Single walled carbon nanotubes (SWCNTs); i-motif; G-quadruplex
Transforming growth factor-β1 (TGF-β1) has been implicated in the pathogenesis of Peyronie’s disease (PD) and also plays a role in collagen and elastin metabolism. Pentoxifylline (PTX) antagonizes the effects of TGF-β1 and has been utilized in our clinic for the management of PD.
We studied the effects of TGF-β1 and PTX on collagen metabolism and elastogenesis in tunica albuginea-derived fibroblasts (TADFs).
TADFs from men with and without PD were cultured and treated with TGF-β1 and PTX as monotherapy at differing concentrations and time points. Combination treatment (TGF-β1 followed by PTX and vice versa) was also investigated.
Main Outcome Measures
Cell proliferation assay, enzyme-linked immunosorbent assay, and immunohistochemistry were utilized to assess the impact of TGF-β1 and PTX on TADF with respect to elastin and collagen I metabolism.
PTX inhibited fibroblast proliferation at doses of 100 μM. TGF-β1 stimulated elastogenesis and collagen I fiber deposition in TADF in a dose- and time-dependent fashion. Pretreatment with PTX dramatically attenuated TGF-β1-mediated elastogenesis and collagen fiber deposition in TADF from men with and without PD. Interestingly, production of collagen I was higher in untreated Peyronie’s tunica (PT) cells relative to normal tunica (NT) cells; furthermore, PTX attenuated collagen production to levels similar to untreated control TADF in PT cells but not in NT cells, suggesting important intrinsic differences between PT and NT cells.
Both elastin and collagen are upregulated by TGF-β1 in TADF. This likely contributes to the PD phenotype. Pretreatment with PTX attenuates both collagen fiber deposition and elastogenesis in TADF exposed to TGF-β1; these effects suggest a useful role for PTX in the management of PD.
TGF-Beta; Pentoxifylline; Peyronie’s Disease; Elastin; Tunica Albuginea; Fibroblasts
We investigated microRNAs (miRs) associated with PTEN/mTOR signaling after spinal cord injury (SCI) and after hind limb exercise (Ex), a therapy implicated in promoting spinal cord plasticity. After spinalization, rats received cycling Ex 5 days/week. The expression of miRs, their target genes and downstream effectors were probed in spinal cord tissue at 10 and 31 days post injury. Ex elevated expression of miR21 and decreased expression of miR 199a-3p correlating with significant change in the expression of their respective target genes: PTEN mRNA decreased and mTOR mRNA increased. Western blotting confirmed comparable changes in protein levels. An increase in phosphorylated-S6 (a downstream effector of mTOR) within intermediate grey neurons in Ex rats was blocked by Rapamycin treatment. It thus appears possible that activity-dependent plasticity in the injured spinal cord is modulated in part through miRs that regulate PTEN and mTOR signaling and may indicate an increase in the regenerative potential of neurons affected by a SCI.
Objectives: Most chemotherapy agents cause tumor cell death primarily by the induction of apoptosis. The ability to noninvasively image apoptosis in vivo could dramatically benefit pre-clinical and clinical evaluation of chemotherapeutics targeting the apoptotic pathway. This study aims to visualize the dynamics of apoptotic process with temporal bioluminescence imaging (BLI) using an apoptosis specific bioluminescence reporter gene. Methods: Both UM-SCC-22B human head and neck squamous carcinoma cells and 4T1 murine breast cancer cells were genetically modified with a caspase-3 specific cyclic firefly luciferase reporter gene (pcFluc-DEVD). Apoptosis induced by different concentrations of doxorubicin in the transfected cells was evaluated by both annexin V staining and BLI. Longitudinal BLI was performed in xenografted tumor models at different time points after doxorubicin or Doxil treatment, to evaluate apoptosis. After imaging, DNA fragmentation in apoptotic cells was assessed in frozen tumor sections using TUNEL staining. Results: Dose- and time-dependent apoptosis induced by doxorubicin in pcFluc-DEVD transfected UM-SCC-22B and 4T1 cells was visualized and quantified by BLI. Caspase-3 activation was confirmed by both caspase activity assay and GloTM luciferase assay. One dose of doxorubicin treatment induced a dramatic increase in BLI intensity as early as 24 h after treatment in 22B-pcFluc-DEVD xenografted tumors. Sustained signal increase was observed for the first 3 days and the fluorescent signal from ex vivo TUNEL staining was consistent with BLI imaging results. Long-term imaging revealed that BLI signal consistently increased and reached a maximum at around day 12 after the treatment with one dose of Doxil. Conclusions: BLI of apoptosis with pcFluc-DEVD as a reporter gene facilitates the determination of kinetics of the apoptotic process in a real-time manner, which provides a unique tool for drug development and therapy response monitoring.
apoptosis; cyclic firefly luciferase; bioluminescence imaging; doxorubicin; caspase-3.
Recent studies have shown that copy number variation (CNV) in mammalian genomes contributes to phenotypic diversity, including health and disease status. In domestic pigs, CNV has been catalogued by several reports, but the extent of CNV and the phenotypic effects are far from clear. The goal of this study was to identify CNV regions (CNVRs) in pigs based on array comparative genome hybridization (aCGH).
Here a custom-made tiling oligo-nucleotide array was used with a median probe spacing of 2506 bp for screening 12 pigs including 3 Chinese native pigs (one Chinese Erhualian, one Tongcheng and one Yangxin pig), 5 European pigs (one Large White, one Pietrain, one White Duroc and two Landrace pigs), 2 synthetic pigs (Chinese new line DIV pigs) and 2 crossbred pigs (Landrace × DIV pigs) with a Duroc pig as the reference. Two hundred and fifty-nine CNVRs across chromosomes 1–18 and X were identified, with an average size of 65.07 kb and a median size of 98.74 kb, covering 16.85 Mb or 0.74% of the whole genome. Concerning copy number status, 93 (35.91%) CNVRs were called as gains, 140 (54.05%) were called as losses and the remaining 26 (10.04%) were called as both gains and losses. Of all detected CNVRs, 171 (66.02%) and 34 (13.13%) CNVRs directly overlapped with Sus scrofa duplicated sequences and pig QTLs, respectively. The CNVRs encompassed 372 full length Ensembl transcripts. Two CNVRs identified by aCGH were validated using real-time quantitative PCR (qPCR).
Using 720 K array CGH (aCGH) we described a map of porcine CNVs which facilitated the identification of structural variations for important phenotypes and the assessment of the genetic diversity of pigs.
In mammals, R-spondin (Rspo), an activator of the Wnt/β-catenin signaling pathway, has been shown to be involved in ovarian differentiation. However, the role of the Rspo/Wnt/β-catenin signaling pathway in fish gonads is still unknown.
In the present study, full-length cDNAs of Rspo1, 2 and 3 were cloned from the gonads of medaka (Oryzias latipes). The deduced amino acid sequences of mRspo1-3 were shown to have a similar structural organization. Phylogenetic analysis showed that Rspo1, 2 and 3 were specifically clustered into three distinct clads. Tissue distribution revealed that three Rspo genes were abundantly expressed in the brain and ovary. Real-time PCR analysis around hatching (S33-5dah) demonstrated that three Rspo genes were specifically enhanced in female gonads from S38. In situ hybridization (ISH) analysis demonstrated that three Rspo genes were expressed in the germ cell in ovary, but not in testis. Fluorescence multi-color ISH showed that Rspo1 was expressed in both somatic cells and germ cells at 10dah. Exposure to ethinylestradiol (EE2) in XY individuals for one week dramatically enhanced the expression of three Rspo genes both at 0dah and in adulthood.
These results suggest that the Rspo-activating signaling pathway is involved in the ovarian differentiation and maintenance in medaka.
Rspo1, 2, 3; Molecular cloning; Expression profiles; Ovarian differentiation
Herein we demonstrate for the first time that a fluorogenic probe can be used as an in vivo imaging agent for visualizing activities of membrane-tethered, membrane-type matrix metalloproteinases (MT-MMPs). An MT-MMP fluorogenic probe that consisted of an MT1-MMP (MMP-14) substrate and near-infrared (NIR) dye-quencher pair exhibited rapid, efficient boosts in fluorescence upon cleavage by MT1-MMP in tumor-bearing mice. In particular, unlike similar fluorogenic probes designed to target extracellular, soluble-type MMPs (EC-MMPs)--which can be cleared from the blood stream after activation--the fluorescence signals activated by MT1-MMP enable clear visualization of MT1-MMP-positive tumors in animal models for up to 24 hours. The results indicate that a simple form of a fluorogenic probe that is less effective in EC-MMP imaging is an effective probe for imaging MT-MMP activities in vivo. These findings can be widely applied to designing probes and to applications targeting various membrane-anchored proteases in vivo.
activatable probe; fluorogenic probe; membrane-type matrix metalloproteinase; optical imaging; protease
Existing two-phase solvent systems for high-speed countercurrent chromatography cover the separation of hydrophobic to moderately polar compounds, but often fail to provide suitable partition coefficient values for highly polar compounds such as sulfonic acids, catecholamines and zwitter ions. The present paper introduces a new solvent series which can be applied for the separation of these polar compounds. It is composed of 1-butanol, ethanol, saturated ammonium sulfate and water at various volume ratios and consists of a series of 10 steps which are arranged according to the polarity of the solvent system so that the two-phase solvent system with suitable K values for the target compound(s) can be found in a few steps. Each solvent system gives proper volume ratio and high density difference between the two phases to provide a satisfactory level of retention of the stationary phase in the spiral column assembly. The method is validated by partition coefficient measurement of four typical polar compounds including methyl green (basic dye), tartrazine (sulfonic acid), tyrosine (zwitter ion) and epinephrine (a catecholamine), all of which show low partition coefficient values in the polar 1-butanol-water system. The capability of the method is demonstrated by separation of three catecholamines.
Organic-high ionic aqueous two-phase solvent systems; high-speed counter-current chromatography (HSCCC); flat-twisted spiral column; sulfonic acids; zwitter ions; catecholamines
There is a growing use of bioinformatics based methods in the field of Glycobiology. These have been used largely to curate glycan structures, organize array-based experimental data and display existing knowledge of glycosylation-related pathways in silico. Although the cataloging of vast amounts of data is beneficial, it is often a challenge to gain meaningful mechanistic insight from this exercise alone. The development of specific analysis tools to query the database is necessary. If these queries can integrate existing knowledge of glycobiology, new insights may be gained. Such queries that couple biochemical knowledge and mathematics have been developed in the field of Systems Biology. The current review summarizes the current state of the art in the application of computational modeling in the field of Glycobiology. It provides (i) an overview of experimental and online resources that can be used to construct glycosylation reaction networks, (ii) mathematical methods to formulate the problem including a description of ordinary differential equation and logic-based reaction networks, (iii) optimization techniques that can be applied to fit experimental data for the purpose of model reconstruction and for evaluating unknown model parameters, (iv) post-simulation analysis methods that yield experimentally testable hypotheses and (v) a summary of available software tools that can be used by non-specialists to perform many of the above functions.
in silico simulation; leukocyte–endothelium interaction; O-glycans; optimization; systems biology
Nanostructures containing 2,4-Dinitrophenyl (DNP) as antigen were designed and produced to investigate antibody-mediated activation of mast cells. The design consists of nanogrids of DNP termini inlaid in alkanethiol self-assembled monolayers (SAMs). Using scanning probe-based nanografting, nanometer precision was attained for designed geometry, size and periodicity. Rat basophilic leukemia (RBL) cells exhibited high sensitivity to the geometry and local environment of DNP presented on these nanostructures. The impact included cellular adherence, spreading, membrane morphology, cytoskeleton structure, and activation. The highest level of spreading and activation was induced by nanogrids of 17 nm line width and 40 nm periodicity, with DNP haptens 1.4 nm above the surroundings. The high efficacy is attributed to two main factors. First, DNP sites in the nanostructure are highly accessible by anti-DNP-IgE during recognition. Second, the arrangement or geometry of DNP termini in nanostructures promotes clustering of FcεRI receptors that are pre-linked to IgE. The clustering effectively initiates Lyn-mediated signaling cascades, ultimately leading to the degranulation of RBL cells. This work demonstrates an important concept, that nanostructures of ligands provide new and effective cues for directing cellular signaling processes.
atomic force microscopy; engineered nanostructures; self-assembled monolayers; mast cells; antibody-mediated activation; nanografting
Invasive plants are often confronted with heterogeneous environments and various stress factors during their secondary phase of invasion into more stressful habitats. A high tolerance to stress factors may allow exotics to successfully invade stressful environments. Ipomoea cairica, a vigorous invader in South China, has recently been expanding into salt marshes.
To examine why this liana species is able to invade a stressful saline environment, we utilized I. cairica and 3 non-invasive species for a greenhouse experiment. The plants were subjected to three levels of salinity (i.e., watered with 0, 4 and 8 g L−1 NaCl solutions) and simulated herbivory (0, 25 and 50% of the leaf area excised) treatments. The relative growth rate (RGR) of I. cairica was significantly higher than the RGR of non-invasive species under both stress treatments. The growth performance of I. cairica was not significantly affected by either stress factor, while that of the non-invasive species was significantly inhibited. The leaf condensed tannin content was generally lower in I. cairica than in the non-invasive I. triloba and Paederia foetida. Ipomoea cairica exhibited a relatively low resistance to herbivory, however, its tolerance to stress factors was significantly higher than either of the non-invasive species.
This is the first study examining the expansion of I. cairica to salt marshes in its introduced range. Our results suggest that the high tolerance of I. cairica to key stress factors (e.g., salinity and herbivory) contributes to its invasion into salt marshes. For I. cairica, a trade-off in resource reallocation may allow increased resources to be allocated to tolerance and growth. This may contribute to a secondary invasion into stressful habitats. Finally, we suggest that I. cairica could spread further and successfully occupy salt marshes, and countermeasures based on herbivory could be ineffective for controlling this invasion.
High mobility group box 1 (HMGB1) is a highly conserved protein with multiple intracellular and extracellular functions, including transcriptional regulation as well as modulation of inflammation, cell migration, and ingestion of apoptotic cells. In the present experiments, we examined a potential role for intracellular HMGB1 in modulating phagocytosis. We found that phagocytosis of apoptotic cells resulted in translocation of HMGB1 into the cytoplasm and extracellular space. Transient or stable inhibition of HMGB1 expression in bone marrow derived macrophages resulted in increased phagocytosis of apoptotic thymocytes and apoptotic neutrophils. Knockdown of HMGB1 was associated with enhanced activation of Rac-1 as well as cytoskeletal rearrangement. Intracellular events involved in phagocytosis and upstream of Rac-1 activation, such as phosphorylation of ERK and FAK, were increased after knockdown of HMGB1. Inhibition of Src kinase activity prevented the increase in phosphorylation of FAK and ERK present during phagocytosis in HMGB1 knockdown cells, and also abrogated the enhancement in phagocytosis associated with HMGB1 knockdown. Interaction between Src and FAK in the cytoplasm of HMGB1 knockdown fibroblasts was enhanced compared with that present in control fibroblasts. Under in vitro conditions, the presence of HMGB1 diminished interactions between purified FAK and Src. The present studies demonstrate a novel role for HMGB1 in the regulation of phagocytosis. In particular, these experiments show that intracellular HMGB1, through associating with Src kinase and inhibiting interactions between Src and FAK, diminishes the phagocytic ability of macrophages and other cell populations.
Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP) because of Fmr1 gene silencing. Serotonin (5-HT) is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR) is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5-HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca2+ concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation.
The aim of this study was to investigate the efficacy of combined debridement, bone graft and articular cavity sealing using synovium in the treatment of metaphyseal osteomyelitis involving the knee joint. Eleven patients with metaphyseal osteomyelitis, which involved femurs in 4 patients and tibiae in 7, were included. The patients received a novel treatment, which combined debridement, bone graft and articular cavity sealing using the synovium. Of the 11 patients, 4 patients with knee joint instability received a structural allograft and 7 with a stable knee joint underwent a particulate bone graft. The 11 patients underwent regular clinical and radiological evaluation; the average follow-up was 74 months (range, 58–96). Infection recurrence in the joint and bone graft area was not observed in 10 of the 11 cases. In one patient, who underwent a lateral granular cancellous bone allograft in the right tibial plateau, the infection recurred 2 weeks later in the graft area. The infection was arrested 3 months after re-debridement and a bilateral ilium bone graft to eliminate the dead space. Combined debridement, bone graft and articular cavity sealing using the synovium may be a feasible treatment for metaphyseal osteomyelitis involving the knee joint.
osteomyelitis; knee joint; synovium sealing; bone graft
Enormous efforts have been made toward translating nanotechnology into medical practice, including cancer management. The approaches have generally been classifiable into two categories--those for diagnosis and those for therapy. The targets for diagnostic probes and therapy are often the same, however, and separate approaches to develop diagnostic and therapeutic agents can miss opportunities to improve the efficiency and effectiveness of both. A close and continuous linkage between therapy and diagnosis is also important, because a patient’s diagnosis/prognosis will evolve during treatment.
The unique physical properties of nanomaterials enable them to serve as 1) bases for superior imaging probes to locate and report cancerous lesions, and 2) vehicles to deliver therapeutics preferentially to those lesions. These technologies for probes and vehicles have converged in the current efforts to develop nano-theranostics—that is, nanoplatforms with both imaging and therapeutic functionalities. These latest multimodal platforms are highly versatile and valuable components of the emerging beneficial trend toward personalized medicine, which emphasizes tailoring practices to individual needs so as to optimize outcomes. Unlike conventional methods, imaging and therapeutic functions are seamlessly unified in nano-theranostics, thereby permitting updates to diagnosis/prognosis along with treatment, and enabling opportunities to switch to alternative, possibly more suitable, regimens.
Magnetic nanoparticles, especially superparamagnetic iron oxide nanoparticles (hereafter referred to as IONPs), have long been studied as contrast agents for magnetic resonance imaging (MRI). Owing to recent progress in synthesis and surface modification, many new avenues have opened, though, for this class of biomaterials. The idea is to conceptualize the nanoparticles not as merely tiny magnetic crystals, but rather as platforms with large surface-to-volume ratios. By taking advantage of the well developed surface chemistry of these materials, one can load a wide range of functionalities, such as targeting, imaging and therapeutic features, onto their surfaces. This makes magnetic nanoparticles excellent scaffolds to construct theranostic agents and has attracted many efforts toward this goal.
In this account we will summarize the progress made in our recent studies. We will introduce the surface engineering techniques that we and others have developed, with an emphasis on how the techniques affect the role of nanoparticles as imaging or therapeutic agents.
An ongoing effort in the field of nanomedicine is to develop nanoplatforms with both imaging and therapeutic functions, the “nano-theranostics”. We have previously developed a human serum albumin (HSA) coated iron oxide nanoparticle (HINP) formula and used multiple imaging modalities to validate its tumor targeting attributes. In the current study, we sought to impart doxorubicin (Dox) onto the HINPs and to assess the potential of the conjugates as theranostic agents. In a typical preparation, we found that about 0.5 mg of Dox and 1 mg of iron oxide nanoparticles (IONPs, Fe content) could be loaded into 10 mg of HSA matrices. The resulting D-HINPs (Dox loaded HINPs) have a hydrodynamic size of 50 nm and are able to release Dox in a sustained fashion. More impressively, the HINPs can assist the translocation of Dox across cell membrane and even its accumulation in the nucleus. In vivo, D-HINPs retained a tumor targeting capability of HINPs, as manifested by both in vivo MRI and ex vivo immunostaining results. In a follow-up therapeutic study on a 4T1 murine breast cancer xenograft model, D-HINPs showed a striking tumor suppression effect that was comparable to Doxil and greatly outperformed free Dox. Such a strategy can be readily extended to load other types of small molecules, making HINP a promising theranostic nanoplatform.
Iron oxide nanoparticle; theranostic nanomedicine; magnetic resonance imaging; doxorubicin; drug delivery; breast cancer
Stro-1 is the best-known mesenchymal stem cell marker. However, despite its bone marrow origin, its localization in bone marrow has never been demonstrated. By immunofluorescence staining, we show here that ∼0.74% of nucleated bone morrow cells expressed Stro-1. We also found that ∼8.7% of CD34-expressing cells expressed Stro-1, and more than 20% of Stro-1-expressing cells did not express CD34. In adipose tissue Stro-1 expression was identified in the endothelium of arterioles and capillaries. Stro-1 was also localized in the endothelium of some but not all adipose tissue veins. Endothelial expression of Stro-1 was also identified in blood vessels in penis and in leg muscles, but not in other tested tissues. In these other tissues, Stro-1 was scantly expressed near but not in blood vessels. These variable and endothelial expression patterns of Stro-1 point to a need to re-examine published data that relied on Stro-1 as a mesenchymal stem cell marker.