Exosomes have recently emerged as a promising drug delivery system with low immunogenicity, high biocompatibility, and high efficacy of delivery. We demonstrated earlier that macrophage-derived ...exosomes (exo) loaded with a potent anticancer agent paclitaxel (PTX) represent a novel nanoformulation (exoPTX) that shows high anticancer efficacy in a mouse model of pulmonary metastases. We now report the manufacture of targeted exosome-based formulations with superior structure and therapeutic indices for systemic administration. Herein, we developed and optimized a formulation of PTX-loaded exosomes with incorporated aminoethylanisamide-polyethylene glycol (AA-PEG) vector moiety to target the sigma receptor, which is overexpressed by lung cancer cells. The AA-PEG-vectorized exosomes loaded with PTX (AA-PEG-exoPTX) possessed a high loading capacity, profound ability to accumulate in cancer cells upon systemic administration, and improved therapeutic outcomes. The combination of targeting ability with the biocompatibility of exosome-based drug formulations offers a powerful and novel delivery platform for anticancer therapy.
Exosomes released by autologous macrophages were loaded with paclitaxel (PTX) and vectorized with anisamide-polyethylene glycol (AA-PEG) moiety to target the sigma receptor, which is overexpressed by lung cancer cells. The obtained formulation (AA-exoPTX) showed a high loading capacity and profound ability to accumulate in cancer cells upon systemic administration, and improved therapeutic outcomes. Display omitted
SUMMARY
Recent developments of distributed acoustic sensing (DAS) techniques and rotational seismometers enable us to record strain and rotational seismograms. This prompts us to adapt the methods ...used for traditional translational seismograms to strain and rotational seismograms. Recently, we extended the formulation of the spatial autocorrelation (SPAC) method to strain, rotation and tilt records. According to seismic interferometry for translation seismograms, cross correlations have clear connections to Green's functions under the isotropy and equipartition of noise wavefields. In this study, we clarify similar connections for strain and rotation seismograms. Because we extend the formulation in the frequency domain, we actually study the connection between the cross-spectral matrix of strain and rotation at two receivers and the Green's tensor. First, we provide a proof under a general framework by simply extending the proof for translation to that for strain and rotation. The proof shows the following results: (1) The cross-spectral matrix of (i, j)-component strains at two receivers is found to be proportional to the strain Green's tensor at one receiver for the sum of (i, j)- and (j, i)-components of the moment tensor source at the other receiver. (2) The cross-spectral matrix of (i, j)-component rotations at two receivers is found to be proportional to the rotation Green's tensor at one receiver for the difference of (i, j)- and (j, i)-components of the moment tensor source at the other receiver. Necessary assumptions for the proof are the isotropy and equipartition of the wavefield. We then check this proof with specific calculations for surface waves observed on the free surface. The proof is confirmed for the isotropic incidence of random-phase surface waves with a specific ratio between Rayleigh and Love wave energies. Seismic interferometry for strain and rotation was already studied. However, the connection of cross correlations to the Green's function for strain and rotation seismograms is discovered by this study for the first time. A specific proof for body waves that is assured by the general proof will be our next study.
Exosomes are naturally occurring nanosized vesicles that have attracted considerable attention as drug delivery vehicles in the past few years. Exosomes are comprised of natural lipid bilayers with ...the abundance of adhesive proteins that readily interact with cellular membranes. We posit that exosomes secreted by monocytes and macrophages can provide an unprecedented opportunity to avoid entrapment in mononuclear phagocytes (as a part of the host immune system), and at the same time enhance delivery of incorporated drugs to target cells ultimately increasing drug therapeutic efficacy. In light of this, we developed a new exosomal-based delivery system for a potent antioxidant, catalase, to treat Parkinson's disease (PD). Catalase was loaded into exosomes ex vivo using different methods: the incubation at room temperature, permeabilization with saponin, freeze–thaw cycles, sonication, or extrusion. The size of the obtained catalase-loaded exosomes (exoCAT) was in the range of 100–200nm. A reformation of exosomes upon sonication and extrusion, or permeabilization with saponin resulted in high loading efficiency, sustained release, and catalase preservation against proteases degradation. Exosomes were readily taken up by neuronal cells in vitro. A considerable amount of exosomes was detected in PD mouse brain following intranasal administration. ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD. Overall, exosome-based catalase formulations have a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders.
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Abstract Exosomes have recently come into focus as “natural nanoparticles” for use as drug delivery vehicles. Our objective was to assess the feasibility of an exosome-based drug delivery platform ...for a potent chemotherapeutic agent, paclitaxel (PTX), to treat MDR cancer. Herein, we developed and compared different methods of loading exosomes released by macrophages with PTX (exoPTX), and characterized their size, stability, drug release, and in vitro antitumor efficacy. Reformation of the exosomal membrane upon sonication resulted in high loading efficiency and sustained drug release. Importantly, incorporation of PTX into exosomes increased cytotoxicity more than 50 times in drug resistant MDCKMDR1 (Pgp +) cells. Next, our studies demonstrated a nearly complete co-localization of airway-delivered exosomes with cancer cells in a model of murine Lewis lung carcinoma pulmonary metastases, and a potent anticancer effect in this mouse model. We conclude that exoPTX holds significant potential for the delivery of various chemotherapeutics to treat drug resistant cancers.
Backprojection of volcanic tremor Haney, Matthew M.
Geophysical research letters,
28 March 2014, Letnik:
41, Številka:
6
Journal Article
Recenzirano
Backprojection has become a powerful tool for imaging the rupture process of global earthquakes. We demonstrate the ability of backprojection to illuminate and track volcanic sources as well. We ...apply the method to the seismic network from Okmok Volcano, Alaska, at the time of an escalation in tremor during the 2008 eruption. Although we are able to focus the wavefield close to the location of the active cone, the network array response lacks sufficient resolution to reveal kilometer‐scale changes in tremor location. By deconvolving the response in successive backprojection images, we enhance resolution and find that the tremor source moved toward an intracaldera lake prior to its escalation. The increased tremor therefore resulted from magma‐water interaction, in agreement with the overall phreatomagmatic character of the eruption. Imaging of eruption tremor shows that time reversal methods, such as backprojection, can provide new insights into the temporal evolution of volcanic sources.
Key Points
First application of backprojection for tracking changing volcanic tremor
Array deconvolution needed to resolve kilometer‐scale changes in tremor location
Tremor imaging reveals escalation due to a shift toward an intracaldera lake
The 15 January 2022 climactic eruption of Hunga volcano, Tonga, produced an explosion in the atmosphere of a size that has not been documented in the modern geophysical record. The event generated a ...broad range of atmospheric waves observed globally by various ground-based and spaceborne instrumentation networks. Most prominent is the surface-guided Lamb wave (Formula: see text0.01 Hz), which we observed propagating for four (+three antipodal) passages around the Earth over six days. Based on Lamb wave amplitudes, the climactic Hunga explosion was comparable in size to that of the 1883 Krakatau eruption. The Hunga eruption produced remarkable globally-detected infrasound (0.01-20 Hz), long-range (~10,000 km) audible sound, and ionospheric perturbations. Seismometers worldwide recorded pure seismic and air-to-ground coupled waves. Air-to-sea coupling likely contributed to fast-arriving tsunamis. We highlight exceptional observations of the atmospheric waves.
The pathobiology of Parkinson's disease (PD) is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) projecting to the striatum. Currently, there are no ...treatments that can halt or reverse the course of PD; only palliative therapies, such as replacement strategies for missing neurotransmitters, exist. Thus, the successful brain delivery of neurotrophic factors that promote neuronal survival and reverse the disease progression is crucial. We demonstrated earlier systemically administered autologous macrophages can deliver nanoformulated antioxidant, catalase, to the SNpc providing potent anti-inflammatory effects in PD mouse models. Here we evaluated genetically-modified macrophages for active targeted brain delivery of glial cell-line derived neurotropic factor (GDNF). To capitalize on the beneficial properties afforded by alternatively activated macrophages, transfected with GDNF-encoded pDNA cells were further differentiated toward regenerative M2 phenotype. A systemic administration of GDNF-expressing macrophages significantly ameliorated neurodegeneration and neuroinflammation in PD mice. Behavioral studies confirmed neuroprotective effects of the macrophage-based drug delivery system. One of the suggested mechanisms of therapeutic effects is the release of exosomes containing the expressed neurotropic factor followed by the efficient GDNF transfer to target neurons. Such formulations can serve as a new technology based on cell-mediated active delivery of therapeutic proteins that attenuate and reverse progression of PD, and ultimately provide hope for those patients who are already significantly disabled by the disease.
In December 2016, the unmonitored Bogoslof volcano unexpectedly began erupting, producing at least 70 explosions over the next 8.5 months. Roughly half of the explosions were preceded by observable ...short-term precursory activity, defined here as seismic activity ending within 30 min of the explosion onset or an earthquake swarm ending within a few hours before the explosion onset. Five different types of precursors were noted during the Bogoslof eruption: non-swarm earthquakes, earthquake swarms, rapid rate events, tremor, and chromatic tremor. Most of the precursors that were detectable by the nearby seismic networks (> 45 km away) occurred during the first 3 months of the eruption, with nearly all precursory earthquake swarms occurring during this period. A hydrophone deployed ~ 7 km northeast of the summit for the last 3 months of the eruption detected weaker activity that was not recorded by the more distant seismic networks. We describe the observed precursors and discuss their inter-relations. Overall, the precursors seem indicative of processes occurring throughout the volcanic system and suggest possible changes in the system during the eruption. We then compare the short-term precursors with explosion parameters, such as plume height, duration, and occurrence of lightning, to look for relations that may provide more insight into the eruption dynamics and subsurface processes and help to further improve forecasting. We find no obvious relations between any of the precursor or explosion parameters, suggesting that their use in forecasting eruption characteristics at Bogoslof is limited.
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