Nuclear magnetic resonance relaxometry and diffusometry study of bulk and confined complex liquids

The nuclear magnetic resonance (NMR) was used as a core method to tackle the molecular dynamic problems of complex liquids: ionic liquids and crude oil compounds. The NMR relaxation studies at the large range of magnetic field strengths covering from the proton Larmor frequency of \SI{\sim10}{kHz} to \SI{300}{MHz} enable the identification of dynamics of molecules at a large timescale. Thermal and NMR studies of five ionic liquids were considered in this investigation: Emim Tf2N and Bmim Tf2N; Emim Br, Bmim Br, and Hmim Br. The focus has been on the supercooled temperature regimes where the motion of ions become slower. The nano-meter geometrical restriction effects were studied by preparing Bmim Tf2N inside a porous glass of \SI{4}{nm} pore-size. A comparative study of crude oils were done to identify and determine the maltene-asphaltene interactions. Differential scanning calorimetry method provided the supercooled temperature regimes for each ionic liquid. The frequency dependent \Tone~relaxation times were measured at supercooled temperatures for bulk ionic liquids. A relaxation model assuming rotational and translational dynamics for the ions was employed and the corresponding correlation times were quantified. Different fitting procedures based on the relaxation model were considered and the outcome of each procedure was discussed. The temperature dependence of translational dynamics showed generally non-Arrhenius behaviours while the rotational dynamics followed Arrhenius trends for the measured temperature ranges. Independent pulsed field gradient NMR self-diffusion measurements confirmed the relaxation model. A unique property was observed for the ionic liquids approaching their glass transition temperatures that the temperature dependence trends were deviated at a certain temperature around $1.2\,T_\text{g}$. This temperature was identified as the crossover temperature \Tc~which had been reported to be a unique feature of glass forming molecular liquids. The observation of such a transition for some of the ionic liquids in this study has not been reported to date. Furthermore, degrees of cooperativity of the ionic translational motions were quantified from the frequency dependent relaxation studies.Mittels Kernspinresonanz (NMR) als grundlegender Messmethode wurden molekulardynamische Fragestellungen für zwei komplexe, flüssige Systeme untersucht: Ionische Flüssigkeiten und Rohölproben. Ein Schwerpunkt lag hierbei auf der Untersuchung von Kernspin-Relaxationsprozessen über einen breiten Bereich magnetischer Feldstärken, welcher Kernspin-Larmorfrequenzen von etwa \SI{10}{kHz} bis \SI{300}{MHz} abdeckt. Dies ermöglicht Aussagen über molekulardynamische Prozesse über eine große Spanne verschiedener Zeitskalen. Für fünf ionische Flüssigkeiten wurden außerdem NMR- mit kalorimetrischen Messungen kombiniert: Emim Tf2N und Bmim Tf2N, Emim Br, Bmim Br und Hmim Br. Hierbei lag das Hauptaugenmerk auf einem Temperaturbereich, bei dem ein unterkühlter Zustand mit deutlich verringerter Ionenmobilität vorliegt. Darüber hinaus wurden für Bmim Tf2N Effekte nanoskaliger, geometrischer Begrenzungen in porösem Glas mit \SI{4}{nm} Porengröße untersucht. Weiterhin wurden auf Grundlage einer vergleichenden Studie mit mehreren Rohölproben Malten-Asphalten-Wechselwirkungen untersucht. Für jede ionische Flüssigkeit wurde der Temperaturbereich, bei dem ein unterkühlter Zustand vorliegt, mittels dynamische Differenzkalorimetrie (DSC) bestimmt. In diesem Temperaturbereich wurde daraufhin die Frequenzabhängigkeit der Tone-Relaxationszeiten für alle ionische Flüssigkeiten ohne Begrenzungen (Bulk-Proben) gemessen. Ein Relaxationsmodell, welches Beiträge von Rotations- und Translationsdynamik beinhaltet, wurde an die Daten angepasst und daraus entsprechende Korrelationszeiten bestimmt. Hierbei wurden verschiedene Regressionsmethoden getestet und bewertet. Während die Temperaturabhängigkeit der Translationsdynamik kein Arrhenius-Verhalten zeigte, konnte die Temperaturabhängigkeit der Rotationsdynamik im untersuchten Bereich mit einem Arrhenius-Modell beschrieben werden

Neurofeedback Therapy for Enhancing Visual Attention: State-of-the-Art and Challenges

We have witnessed a rapid development of brain-computer interfaces (BCIs) linking the brain to external devices. BCIs can be utilized to treat neurological conditions and even to augment brain functions. BCIs offer a promising treatment for mental disorders, including disorders of attention. Here we review the current state of the art and challenges of attention-based BCIs, with a focus on visual attention. Attention-based BCIs utilize electroencephalograms (EEGs) or other recording techniques to generate neurofeedback, which patients use to improve their attention, a complex cognitive function. Although progress has been made in the studies of neural mechanisms of attention, extraction of attention-related neural signals needed for BCI operations is a difficult problem. To attain good BCI performance, it is important to select the features of neural activity that represent attentional signals. BCI decoding of attention-related activity may be hindered by the presence of different neural signals. Therefore, BCI accuracy can be improved by signal processing algorithms that dissociate signals of interest from irrelevant activities. Notwithstanding recent progress, optimal processing of attentional neural signals remains a fundamental challenge for the development of efficient therapies for disorders of attention

Nanodelivery of Mycophenolate Mofetil to the Organ Improves Transplant Vasculopathy.

Inflammation occurring within the transplanted organ from the time of harvest is an important stimulus of early alloimmune reactivity and promotes chronic allograft rejection. Chronic immune-mediated injury remains the primary obstacle to the long-term success of organ transplantation. However, organ transplantation represents a rare clinical setting in which the organ is accessible ex vivo, providing an opportunity to use nanotechnology to deliver therapeutics directly to the graft. This approach facilitates the directed delivery of immunosuppressive agents (ISA) to target local pathogenic immune responses prior to the transplantation. Here, we have developed a system of direct delivery and sustained release of mycophenolate mofetil (MMF) to treat the donor organ prior to transplantation. Perfusion of a donor mouse heart with MMF-loaded PEG-PLGA nanoparticles (MMF-NPs) prior to transplantation abrogated cardiac transplant vasculopathy by suppressing intragraft pro-inflammatory cytokines and chemokines. Our findings demonstrate that ex vivo delivery of an ISA to donor organs using a nanocarrier can serve as a clinically feasible approach to reduce transplant immunity

Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery.

BACKGROUND: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79. METHODS: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC. FINDINGS: The trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was more robust than non-conjugated NPs. Treatment with MECA79-Taxol-NPs augmented the delivery of Paclitaxel (Taxol) to the tumor site and significantly reduced the tumor size. This effect was associated with a higher apoptosis rate of PDAC cells and reduced vascularization within the tumor. INTERPRETATION: Targeting the HEVs of PDAC using MECA79-NPs could lay the ground for the localized delivery of a wide variety of drugs including chemotherapeutic agents. FUND: National Institutes of Health (NIH) grants: T32-EB016652 (B·B.), NIH Cancer Core Grant CA034196 (L.D.S.), National Institute of Allergy and Infectious Diseases grants R01-AI126596 and R01-HL141815 (R.A.)

Drug Delivery Approaches for the Treatment of Cervical Cancer

Cervical cancer is a highly prevalent cancer that affects women around the world. With the availability of new technologies, researchers have increased their efforts to develop new drug delivery systems in cervical cancer chemotherapy. In this review, we summarized some of the recent research in systematic and localized drug delivery systems and compared the advantages and disadvantages of these methods

Injectable gellan gum-based nanoparticles-loaded system for the local delivery of vancomycin in osteomyelitis treatment

Infection spreading in the skeletal system leading to osteomyelitis can be prevented by the prolonged administration of antibiotics in high doses. However systemic antibiotherapy, besides its inconvenience and often low efficacy, provokes numerous side effects. Thus, we formulated a new injectable nanoparticle-loaded system for the local delivery of vancomycin (Vanc) applied in a minimally-invasive way. Vanc was encapsulated in poly(Llactide- co-glycolide) nanoparticles (NPs) by double-emulsification. The size (258 ± 11 nm), polydispersity index (0.240 ± 0.003) and surface potential (-25.9 ± 0.2 mV) of NPs were determined by dynamic light scattering and capillary electrophoresis measurements. They have a spherical morphology and a smooth topography as observed using atomic force microscopy. Vanc loading and encapsulation efficiencies were 8.8 ± 0.1 and 55.2 ± 0.5 %, respectively, based on fluorescence spectroscopy assays. In order to ensure injectability, NPs were suspended in gellan gum and cross-linked with $Ca^{2+}$; also a portion of dissolved antibiotic was added to the system. The resulting system was found to be injectable (extrusion force 11.3 ± 1.1 N), reassembled its structure after breaking as shown by rheology tests and ensured required burst release followed by sustained Vanc delivery. The system was cytocompatible with osteoblast-like MG-63 cells (no significant impact on cells’ viability was detected). Growth of Staphylococcus spp. reference strains and also those isolated from osteomyelitic joints was inhibited in contact with the injectable system. As a result we obtained a biocompatible system displaying ease of application (low extrusion force), self-healing ability after disruption, adjustable drug release and antimicrobial properties

A modular approach toward producing nanotherapeutics targeting the innate immune system.

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1-based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.This work was supported by NIH grants R01 CA220234, R01 HL144072, P01 HL131478, and NWO/ZonMW Vici 91818622 (to W.J.M.M.); R01 HL143814 and P01HL131478 (to Z.A.F.); R01 AI139623 (to J.O.); and P30 CA008748 (to T.R.). M.M.T.v.L. was supported by the American Heart Association (grant 19PRE34380423). M.G.N. was supported by a Spinoza grant from the Netherlands Organization for Scientific Research and an ERC Advanced Grant (no. 833247); L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587).S