Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy

Efficient targeted delivery of anticancer agents to TNBC cells remains one of the greatest challenges to developing therapies. The lack of tumor-specific markers, aggressive nature of the tumor, and unique propensity to recur and metastasize make TNBC tumors more difficult to treat than other subtypes. We propose to exploit natural ability of macrophages to target cancer cells by means of extracellular vesicles (EVs) as drug delivery vehicles for chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (Dox). We demonstrated earlier that macrophage-derived EVs loaded with PTX (EV-PTX) and Dox (EV-Dox) target cancer cells and exhibited high anticancer efficacy in a mouse model of pulmonary metastases. Herein, we report a manufacture and characterization of novel EV-based drug formulations using different loading procedures that were optimized by varying pH, temperature, and sonication conditions. Selected EV-based formulations showed a high drug loading, efficient accumulation in TNBC cells in vitro, and pronounced anti-proliferation effect. Drug-loaded EVs target TNBC in vivo, including the orthotopic mouse T11 tumors in immune competent BALB/C mice, and human MDA-MB-231 tumors in athymic nu/nu mice, and abolished tumor growth. Overall, EV-based formulations can provide a novel solution to a currently unmet clinical need and reduce the morbidity and mortality of TNBC patients

Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells

Background: Our laboratories forged the concept of macrophage delivery of protein antioxidants to attenuate neuroinflammation and nigrostriatal neurodegeneration in Parkinsons disease. Notably, the delivery of the redox enzyme, catalase, incorporated into a polyion complex micelle ('nanozyme) by bone marrow-derived macrophages protected nigrostriatum against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication. Nonetheless, how macrophage delivery of nanozyme increases the efficacy of catalase remains unknown. Methods: In this study, we examined the transfer of nanozyme from macrophages to brain microvessel endothelial cells, neurons and astrocytes. Results: Facilitated transport of the nanozyme from macrophages to endothelial, neuronal and glial target cells occurred through endocytosis-independent mechanisms that involved fusion of cellular membranes, macrophage bridging conduits and nanozyme lipid coatings. Nanozyme transfer was operative across an artificial blood-brain barrier and showed efficient reactive oxygen species decomposition. Conclusion: This is the first demonstration, to our knowledge, that drug-loaded macrophages discharge particles to contiguous target cells for therapeutic brain enzyme delivery. The data shown are of potential value for the treatment of neurodegenerative disorders and notably, Parkinsons disease

Polyelectrolyte complex optimization for macrophage delivery of redox enzyme nanoparticles

Background: We posit that cell-mediated drug delivery can improve transport of therapeutic enzymes to the brain and decrease inflammation and neurodegeneration seen during Parkinsons disease. Our prior works demonstrated that macrophages loaded with nanoformulated catalase ('nanozyme) then parenterally injected protect the nigrostriatum in a murine model of Parkinsons disease. Packaging of catalase into block ionomer complex with a synthetic polyelectrolyte block copolymer precludes enzyme degradation in macrophages. Methods: We examined relationships between the composition and structure of block ionomer complexes with a range of block copolymers, their physicochemical characteristics, and loading, release and catalase enzymatic activity in bone marrow-derived macrophages. Results: Formation of block ionomer complexes resulted in improved aggregation stability. Block ionomer complexes with -polylysine and poly(L-glutamic acid)-poly(ethylene glycol) demonstrated the least cytotoxicity and high loading and release rates. However, these formulations did not efficiently protect catalase inside macrophages. Conclusion: Nanozymes with polyethyleneimine- and poly(L-lysine) 10-poly(ethylene glycol) provided the best protection of enzymatic activity for cell-mediated drug delivery

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

A search for resonances decaying into a Higgs boson and a new particle X in the XH → qqbb final state with the ATLAS detector

A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb−1 of proton–proton collision data at collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle X is assumed to decay to a pair of light quarks, and the fully hadronic final state is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the resonance

Search for dark matter produced in association with a hadronically decaying vector boson in pp collisions at sqrt (s) = 13 TeV with the ATLAS detector

A search is presented for dark matter produced in association with a hadronically decaying W or Z boson using 3.2 fb−1 of pp collisions at View the MathML sources=13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Events with a hadronic jet compatible with a W or Z boson and with large missing transverse momentum are analysed. The data are consistent with the Standard Model predictions and are interpreted in terms of both an effective field theory and a simplified model containing dark matter

Search for TeV-scale gravity signatures in high-mass final states with leptons and jets with the ATLAS detector at sqrt [ s ] = 13TeV

A search for physics beyond the Standard Model, in final states with at least one high transverse momentum charged lepton (electron or muon) and two additional high transverse momentum leptons or jets, is performed using 3.2 fb−1 of proton–proton collision data recorded by the ATLAS detector at the Large Hadron Collider in 2015 at √s = 13 TeV. The upper end of the distribution of the scalar sum of the transverse momenta of leptons and jets is sensitive to the production of high-mass objects. No excess of events beyond Standard Model predictions is observed. Exclusion limits are set for models of microscopic black holes with two to six extra dimensions