Emerging methods in therapeutics using multifunctional nanoparticles

Clinical translation of nanoparticle‐based drug delivery systems is hindered by an array of challenges including poor circulation time and limited targeting. Novel approaches including designing multifunctional particles, cell‐mediated delivery systems, and fabrications of protein‐based nanoparticles have gained attention to provide new perspectives to current drug delivery obstacles in the interdisciplinary field of nanomedicine. Collectively, these nanoparticle devices are currently being investigated for applications spanning from drug delivery and cancer therapy to medical imaging and immunotherapy. Here, we review the current state of the field, highlight opportunities, identify challenges, and present the future directions of the next generation of multifunctional nanoparticle drug delivery platforms.This article is categorized under:Biology‐Inspired Nanomaterials > Protein and Virus‐Based StructuresNanotechnology Approaches to Biology > Nanoscale Systems in BiologyNovel approaches in designing nanoparticles to overcome challenges faced by traditional nanoparticle‐based drug delivery systems.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155963/1/wnan1625.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155963/2/wnan1625_am.pd

Spatial Analysis of Metal-PLGA Hybrid Microstructures Using 3D SERS Imaging

The incorporation of gold nanoparticles in biodegradable polymeric nanostructures with controlled shape and size is of interest toward different applications in nanomedicine. Properties of the polymer such as drug loading and antibody functionalization can be combined with the plasmonic properties of gold nanoparticles, to yield advanced hybrid materials. This study presents a new way to synthesize multicompartmental microgels, fibers, or cylinders, with embedded anisotropic gold nanoparticles. Gold nanoparticles dispersed in an organic solvent can be embedded within the poly(lactic‐co‐glycolic acid) (PLGA) matrix of polymeric microstructures, when prepared via electrohydrodynamic co‐jetting. Prior functionalization of the plasmonic nanoparticles with Raman active molecules allows for imaging of the nanocomposites by surface‐enhanced Raman scattering (SERS) microscopy, thereby revealing nanoparticle distribution and photostability. These exceptionally stable hybrid materials, when used in combination with 3D SERS microscopy, offer new opportunities for bioimaging, in particular when long‐term monitoring is required

Biocompatible, Multiresponsive Nanogel Composites for Codelivery of Antiangiogenic and Chemotherapeutic Agents

Single therapy approaches are usually insufficient to treat certain diseases, due to genetic differences between patients or disease resistance. Therefore, such approaches are gradually replaced by combination therapies comprising two or more drugs. In oncology, these include BRAF inhibitors and cytotoxic, antiangiogenic, or immunomodulatory agents, among others. We propose herein the use of multiresponsive nanogel composites for the codelivery of a DNA intercalator (doxorubicin) and an antiangiogenic and immunomodulatory agent (pomalidomide). We introduce a surfactant-free synthetic protocol to decorate biocompatible poly(ethylene glycol)methacrylate nanogels (PEGMA) with evenly distributed gold nanoparticles and explore their ability to deliver drugs upon stimulation by various triggers such as heat, light, and reducing agents present in the intracellular environment. We further demonstrate that an additional polymer coating on the nanogel surface can decrease uncontrolled drug leakage and modulate cellular uptake and the drug release profile

Mechanism of PP2A-mediated IKKβ dephosphorylation: a systems biological approach

BACKGROUND: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NF kappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NF kappaB, involving a lack of inhibitor of kappaB (I kappaB alpha) protein reappearance. Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha. RESULTS: To investigate the mechanism underlying the general PP2A-mediated tuning of IKK beta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKK beta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKK beta phosphorylation thus allowing for I kappaB alpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKK beta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of I kappaB alpha reappearance, is not a direct UVB action but requires instrumentality. CONCLUSION: The model developed here can be used as a reliable building block of larger NF kappa B models and offers comprehensive simplification potential for future modeling of NF kappa B signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NF kappa B, which is crucial for the development of new anti-cancer strategies

Context specificity of post-error and post-conflict cognitive control adjustments

There has been accumulating evidence that cognitive control can be adaptively regulated by monitoring for processing conflict as an index of online control demands. However, it is not yet known whether top-down control mechanisms respond to processing conflict in a manner specific to the operative task context or confer a more generalized benefit. While previous studies have examined the taskset-specificity of conflict adaptation effects, yielding inconsistent results, controlrelated performance adjustments following errors have been largely overlooked. This gap in the literature underscores recent debate as to whether post-error performance represents a strategic, control-mediated mechanism or a nonstrategic consequence of attentional orienting. In the present study, evidence of generalized control following both high conflict correct trials and errors was explored in a task-switching paradigm. Conflict adaptation effects were not found to generalize across tasksets, despite a shared response set. In contrast, post-error slowing effects were found to extend to the inactive taskset and were predictive of enhanced post-error accuracy. In addition, post-error performance adjustments were found to persist for several trials and across multiple task switches, a finding inconsistent with attentional orienting accounts of post-error slowing. These findings indicate that error-related control adjustments confer a generalized performance benefit and suggest dissociable mechanisms of post-conflict and post-error control. © 2014 Forster, Cho

The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

The NF-κB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-κB functions in response to different cellular stimuli. Using rela(−/−) mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-κB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration–associated genes such as WAVE3 and α-actinin 4. We also define a new component of cisplatin-induced, RelA T505–dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-κB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration

Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer’s dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer’s Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer’s dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were ‘amyloid positive’ (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were ‘amyloid negative’ (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan–Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer’s disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer’s disease co-existent with other pathologies

Amyloid and tau cerebrospinal fluid biomarkers in HIV infection

<p>Abstract</p> <p>Background</p> <p>Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.</p> <p>Methods</p> <p>In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ), amyloid beta fragment 1-42 (Aβ_1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.</p> <p>Results</p> <p>CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ_1-42in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.</p> <p>Conclusions</p> <p>Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.</p