Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity

In the past decade, mesoporous silica nanoparticles (MSNs) have attracted more and more attention for their potential biomedical applications. With their tailored mesoporous structure and high surface area, MSNs as drug delivery systems (DDSs) show significant advantages over traditional drug nanocarriers. In this review, we overview the recent progress in the synthesis of MSNs for drug delivery applications. First, we provide an overview of synthesis strategies for fabricating ordered MSNs and hollow/rattle-type MSNs. Then, the in vitro and in vivo biocompatibility and biotranslocation of MSNs are discussed in relation to their chemophysical properties including particle size, surface properties, shape, and structure. The review also highlights the significant achievements in drug delivery using mesoporous silica nanoparticles and their multifunctional counterparts as drug carriers. In particular, the biological barriers for nano-based targeted cancer therapy and MSN-based targeting strategies are discussed. We conclude with our personal perspectives on the directions in which future work in this field might be focused.

Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery

Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle. Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye molecules and coated with hydrophilic groups to prevent aggregation. Water-insoluble anticancer drugs were delivered into human cancer cells; surface conjugation with cancer-specific targeting agents increased the uptake into cancer cells relative to that in non-cancerous fibroblasts. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications.

/pdf/multifunctional-inorganic-nanoparticles-for-imaging-32xbo3we7g.pdf

Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery

Recent advancements in morphology control and surface functionalization of mesoporous silica nanoparticles (MSNs) have enhanced the biocompatibility of these materials with high surface areas and pore volumes. Several recent reports have demonstrated that the MSNs can be efficiently internalized by animal and plant cells. The functionalization of MSNs with organic moieties or other nanostructures brings controlled release and molecular recognition capabilities to these mesoporous materials for drug/gene delivery and sensing applications, respectively. Herein, we review recent research progress on the design of functional MSN materials with various mechanisms of controlled release, along with the ability to achieve zero release in the absence of stimuli, and the introduction of new characteristics to enable the use of nonselective molecules as screens for the construction of highly selective sensor systems.

Mesoporous silica nanoparticles for drug delivery and biosensing applications

We demonstrate a strategy for the synthesis of multifunctional mesoporous silica nanoparticles. These uniform tumblerlike nanocomposites, which simultaneously possess magnetic, luminescent, and porous properties, have great potential in biomedical applications.

Multifunctional composite nanoparticles: Magnetic, luminescent, and mesoporous

High-contrast paramagnetic fluorescent mesoporous silica nanorods as a multifunctional cell-imaging probe

The unique properties of mesoporous silica nanoparticles (MSNs), such as high surface areas, uniform pore size, easy modification, and biocompatibility, make them highly suitable for biological applications. In previous reports, MSNs have been demonstrated to function as cell markers and as gene transfection and drug delivery agents. Although these cell-level studies are attractive, some important issues, such as the cellular uptake efficiency, toxicity, and circulation behavior of MSNs in living animals, still have to be addressed for further practical animal-level applications. Superparamagnetic nanoparticles (i.e. , magnetite) with diameters of less than 20 nm exhibit effective magnetic resonance imaging (MRI) contrast enhancement behavior. Because MRI is a noninvasive imaging method, it is a powerful tool with which to track the migration of cells and to investigate the distribution of nanoparticles in the living body. The main drawbacks of the MRI technique, however, are low sensitivity and resolution, which make it unable to provide detailed biological information. In previous reports, magnetic–optical bifunctional nanoparticles have been fabricated for imaging applications. However, they are nonporous hybrid magnetic composites. To offset the shortcomings and to expand the bioimaging/delivery ACHTUNGTRENNUNGapplications, simultaneous attachment of a fluorescent probe (subcellular imaging) and a MRI probe (noninvasive imaging) to MSN is an important task. Recently, we adopted a strategy involving the simultaneous fusion of amorphous silica shells of Fe3O4@SiO2 nanoparticles with MSNs that are attached to fluorescein isothiocyanate (FITC). These nanoparticles with multifunctionalities—fluorescent, magnetic, and porous (MagDye@MSNs)—can simultaneously serve as bimodal imaging probes and drug reservoirs. Thus, we believe that MagDye@MSNs would be a suitable material with which to study the cellular uptake efficiency, toxicity, and accumulative behavior of MSNs in living animals. To the best of our knowledge, this is the first report of direct injection of mesoporous silica nanoparticles (MSNs) into mice and of in vivo visualization of the localization of MSNs by MRI. Mag-Dye@MSNs were synthesized according to the method we previously developed (the detailed synthetic method is described in the Experimental Section). A transmission electron microscopy (TEM) image of the Mag-Dye@MSNs (Figure 1)

Multifunctional mesoporous silica nanoparticles for intracellular labeling and animal magnetic resonance imaging studies.

PURPOSE Some cases of hemichorea-hemiballism (HCHB) are associated with a hyperintense putamen on T1-weighted MR images, the cause of which remains unclear. Our purpose was to determine the cause and significance of these MR signal changes. METHODS We analyzed the clinical and neuroimaging findings in 10 patients with HCHB, focusing on locations of the hyperintense lesions on T1-weighted images, comparing them with those on CT scans, and evaluating their changes after years of follow-up. A biopsy was performed in one patient. RESULTS Seven patients had hyperglycemia and two had cortical infarcts. HCHB recurred in four patients. A hyperintense putamen preceded the occurrence of HCHB in two patients. T1-weighted MR images revealed hyperintense lesions limited to the ventral striatum in six patients. Hyperintense lesions extended to the level of the midbrain in one patient and persisted for as long as 6 years in another patient. T2-weighted MR images revealed slit-shaped cystic lesions in the lateral part of the putamina 2 to 6 years after the onset of symptoms in two patients. A biopsy specimen from the hyperintense putamen in one patient revealed a fragment of gliotic brain tissue with abundant gemistocytes. Proton MR spectroscopy of the specimen showed an increase in lactic acid, acetate, and lipids, and a decrease in N-acetylaspartate and creatine, suggesting the presence of pronounced energy depletion and neuronal dysfunction. CONCLUSION Gemistocytes are sufficient to explain the shortening of T1 relaxation time. Our investigation suggests that neurons in the ventral striatum and striatonigral pathway may play a critical role in generating ballism.

http://www.ajnr.org/content/ajnr/19/5/863.full.pdf

Hemichorea-hemiballism: an explanation for MR signal changes.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A(2A) adenosine receptor (A(2A)-R)-selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D-microMRI analysis revealed that CGS reversed the enlarged ventricle-to-brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. (1)H-MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin-positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5'AMP-activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2005.03029.x

Chen Chang

Papers

Multifunctional composite nanoparticles: Magnetic, luminescent, and mesoporous

High-contrast paramagnetic fluorescent mesoporous silica nanorods as a multifunctional cell-imaging probe

Multifunctional mesoporous silica nanoparticles for intracellular labeling and animal magnetic resonance imaging studies.

Hemichorea-hemiballism: an explanation for MR signal changes.

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model.