1,720,972 research outputs found
Solid lipid nanoparticle as a tool to deliver mTOR inhibitors
No full textRecently, the use of mammalian target of rapamycin (mTOR) inhibitors, in particular rapamycin (Rp), has been suggested to improve the treatment of neurodegenerative diseases.
However, as Rp is a strong immunosuppressant, specific delivery to the brain has been postulated to avoid systemic exposure. In this work, Rp loaded solid lipid nanoparticles (Rp-SLN) stabilized with polysorbate 80 (PS80) were prepared comparing two different methods and lipids.
The formulations were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), wide angle X-ray scattering (WAXS), cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and particle tracking. In vitro release and short-term stability were assessed. Biological behavior of Rp-SLN was tested in SH-SY5Y neuroblastoma cells. The inhibition of mTOR complex 1 (mTORC1) was evaluated over time by a pulse-chase study compared to free Rp and Rp nanocrystals.
Compritol Rp-SLN resulted more stable and possessed proper size and surface properties with respect to cetyl palmitate Rp-SLN. Rapamycin was entrapped in an amorphous form in the solid lipid matrix that showed partial crystallinity with stable Lbeta, sub-Lalfa and Lbeta’ arrangements. PS80 was stably anchored on particle surface.
The SEM and AFM imaging and shape-modeling by the combined DLS-SANS analysis revealed that Rp-SLN with a hydrodynamic radius of ∼46 nm preserve a platelet-like or flat ellipsoidal structure with a thickness of 8–9 nm. These dimensions correlate with a single lipid bilayer, organized in a triclinic Lbeta polymorph, and covered with a 1–2-nm P80 shell. Consistently, FT-IR spectra acquired in the range 52–75◦C, confirmed that the Rp incorporation within the lipid matrix decreases the point of the gel-liquid crystal (Lbeta-Lalfa) phase transition.
No drug release was observed over 24 h and Rp-SLN had a higher cell uptake and a more sustained effect over a week. The mTORC1 inhibition was increased with Rp-SLN. Overall, compritol Rp-SLN show suitable characteristics and short-term stability to be considered for further investigation as Rp brain delivery system
Rapamycin-loaded solid lipid nanoparticles for brain targeting
No full textNeurodegenerative diseases are very debilitating conditions with
an increasing impact on the world population and as yet without
an effective remedy. Therefore, the development of new strategies
for early diagnosis and treatment of these diseases is becoming a
priority. The selectivity of the blood-brain barrier (BBB) strictly
limits the number of therapeutic substances able to reach the
brain and therefore, in recent years, many studies have been directed
to the development of systems that facilitate the passage of
drugs to the central nervous system (CNS). One of the most crucial
protein complexes, that regulates vital processes within signal
transduction, proliferation and autophagy pathways, is the mammalian
target of rapamycin (Rp) complex (mTOR). Specific inhibition
of mTOR by Rp in-feed administration has been recently
demonstrated to ameliorate the cognitive behavior in an Alzheimer’s
mice model [1]. Rp is an immunosuppressive drug that can
pass the BBB, but its systemic administration produces a number
of side effects that may impair its therapeutic efficacy [2].
Nanoparticles represent one of the most innovative and noninvasive
approaches for drug targeting. In particular, due to an
average size below 100 nm and lipophilic properties, the use of
P80-coated solid lipid nanoparticles (SLNs) can overcome the
BBB and allow accumulation of drugs directly into the brain tissue,
through the apolipoprotein blood-to-brain pathway. Here,
we report the development of a novel formulation of Rp loaded
SLNs and the investigation of the effect upon treatment of SHSY5Y
neuroblastoma cells. Our results show that Rp loaded
SLNs are able to inhibit mTOR activity over a longer period of
time compared to free Rp. This prolonged action is rather evident
even at concentrations as low as 2 nM and it is consistent
with a longer retention of Rp due to a slower release from the
SLNs. On the basis of the data obtained, we will perform experiments
to assay in vivo the ability of Rp-SLNs to deliver Rp therapeutic
doses to the CNS, limiting systemic exposure to the drug
side effects
pNiPAM nanoparticles suspensions as crowded complex model systems: synthesis, characterization and properties
Get PDFImprovements in controlled polymer synthesis and characterization methods have lead scientists to investigate new materials that would not only improve old techniques, but also open way for new approaches in several industrial and bio-medical applications. Poly-N-isopropylacrylamide (pNiPAM) is one example among this new class of materials. Being respondent to variations in temperature this ‘intelligent’ polymer is considered as a model system that is a candidate for biomaterials, drug delivery systems, biosensors, bioanalytical devices or bio-scaffolds for cell cultures. Wide range of potential applications arises mostly from nanometric size and tunable properties. Various types of pNiPAM nanoparticles with its lower critical solution temperature (LCST), around natural human body temperature (at 33oC) were synthesized and characterized in terms of size and morphology. Additionally mechanical properties of pNiPAM microgel with oscillation rheology in the absence and in the presence of linear pNiPAM chains additives was studied. Next an efficient way for chemical labeling of the polymeric nanoparticles with a fluorescent dye was established. PNiPAM nanoparticles were suitable for fluorescent techniques which allowed using them as model systems to study diffusion process and micro/macro viscosity effect in crowded complex systems. A correction procedure to study the size of relatively large, uniformly labeled nanoparticles in FCS experiment was proposed. Finally, conducted cytotoxicity studies, not only proved the lack of toxic effect but additionally demonstrated a bioscaffold based growth promotion effect on cell cultures.Postęp w stosowaniu polimerowych materiałów koncentruje uwagę naukowców na polimerach wykazujących właściwości konkurencyjne w stosunku do tradycyjnych materiałów. Polimery tworzące struktury w skali nano stanowią obiecujące narzędzie o szerokim spektrum zastosowań jako biomateriały, biosensory, systemy dostarczania leków czy bio-podłoża do hodowli komórkowych. Jednym z takich polimerów jest pNiPAM (poly-N-isoporpylacrylamid), który dzięki temperaturze przejścia fazowego około naturalnej temperatury ciała ludzkiego (33oC) zasługuje na szczególna uwagę. Syntetyzowano różnego rodzaju nanocząsteki polimeru pNiPAM oraz scharakteryzowano pod katem rozmiaru i morfologii. Dodatkowo w celu określenia właściwości mechanicznych przeprowadzono oscylacyjne badania reologiczne samego mikrożelu i w obecności liniowych łańcuchów polimeru pNiPAM. Funkcjonalizacja nanocząstek za pomocą chemicznego wprowadzenia fluorescencyjnie barwnika w strukturę nanocząstek pNiPAM, umożliwiła ich zastosowanie w technikach fluorescencyjnych. Umożliwiło to użycie nanocząstek pNiPAM jako modelowego systemu do badania dyfuzji w gęstych kładach złożonych oraz do badań nad micro/macro lepkością. Zaproponowano także poprawkę do procedury pomiaru wielkości, relatywnie dużych, jednolicie wyznakowanych nanocząstek przy użyciu techniki FCS. Dodatkowo ze względu szeroką gammę zastosowań w biologii i biotechnologii przeprowadzono badania nad cytotoksycznością otrzymanych nanocząstek. Stwierdzono brak efektu cytotoksyczności i ponadto zaobserwowano przyspieszenie wzrostu komórek w obecności nanocząstek pNiPAM.This work was supported by the International PhD Projects Program (”The PhD in Nanoscience and Nanotechnology”) Foundation for polish Science operated within the Innovative Economy Operational Programme (IE OP) 2007-2013 within European Regional Fund
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Synthesis and characterization of selected nanoparticles with potential medical application
No full textZakład Biofizyki Molekularnej, Centrum NanoBioMedyczne UAMRozwój nanotechnologii daje możliwości projektowania, kształtowania i wytwarzania struktur o pożądanych właściwościach fizykochemicznych do aplikacji medycznych.
W pracy przedstawiono informacje na temat leków, substancji do diagnostyki, nanoukładów oraz emulsji, w tym Pickeringa, do aplikacji medycznych. Zsyntetyzowano wybrane rodzaje nanocząstek, o potencjalnych zastosowaniach w medycynie: fluorescencyjną krzemionkę, polimerowe cząstki heptafluoro-n-butyl metakrylatu (HFBA) cechujące się niskim współczynniku załamania światła oraz magnetyczny tlenek żelaza z powłoką biopolimerową. Nanoukłady scharakteryzowano za pomocą skaningowej i transmisyjnej mikroskopii elektronowej, NTA (nanoparticle tracking analysis – analiza ruchu cząstek), techniką dynamicznego rozpraszani światła i spektroskopii korelacji fluorescencji oraz laserowego mikroskopu skaningowego (LSM). Przeprowadzono walidację i analizę techniki NTA względem DLS za pomocą cząstek standaryzowanych i zsyntetyzowanych. Zbadano układ emulsyjny typu Pickeringa złożony z dekstranu i żelatyny. Jako stabilizatora użyto m.in. cząstki HFBA, które skupiają się w dekstranie.
Wyniki i hipotezy badawcze, stanowią bazę do opracowania i szczegółowej charakterystyki kolejnych układów modelowych, przydatnych do badania specyficznych oddziaływań in vitro i w żywej komórce i projektowania leków oraz substancji do diagnostyki medycznej.Development of nanotechnology provides opportunities for design and manufacturing of structures with desirable physicochemical properties for medical applications.
In the introduction information on drugs, diagnostic substances, nanosystems and emulsions, including Pickering emulsion system, for medical applications is presented.
Synthesis of selected types of nanoparticles, with potential uses in medicine, such as: fluorescent silica, polymeric particles of heptfluoro-n-butyl methacryle (HFBA) with a low refractive index and a magnetic iron oxide coated by biopolymer layer were made. Nanosystems were characterized by scanning and transmission electron microscopy, NTA (nanoparticle tracking analysis), dynamic light scattering and fluorescence correlation spectroscopy techniques and laser scanning microscope (LSM).
NTA versus DLS technique was validated using standardized nanoparticles and synthesized nanostructures.
Pickering emulsion based on biopolymers such as dextran and gelatin were studied. As a stabilizer HFBA particles were used. It was found that HFBA preferred the dextran phase.
Presented results and hypotheses are the next miles stones for development and subsequent detailed characterization of model systems useful to examine specific interactions in vitro and in living cell. They are interesting for the design of drugs and substances for medical diagnosis
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Preparation and in vitro characteristics of rapamycin-loaded solid lipid nanoparticles for medical application
No full textWydział FizykiW ostatnim czasie stałe nanocząstki lipidowe na bazie Compritol® 888 ATO, stabilizowane polisorbatem 80, stały się powszechnym nośnikiem, mającym na celu dostarczenie, ochronę i kontrolowane uwalnianie leku w miejscu przeznaczenia. Dane eksperymentalne wskazują, że taka enkapsulacja w odpowiednio przyrządzonych nośnikach zwiększa biodostępność leków w terapii celowanej. W pracy doktorskiej nanocząstki SLN przyrządzono w celu zwiększenia efektu cytostatycznego rapamycyny (Rap), czyli znanego i trudno rozpuszczalnego inhibitora kinazy mTOR w modelowej linii komórkowej. Rap-SLN wytworzono metodą homogenizacji wysoko-ciśnieniowej, a skład analizowano spektroskopią UV-Vis i Ramana. Rozmiary nanocząstek zmierzono metodami DLS i PT, natomiast ich morfologię technikami AFM, EM i SANS. Strukturę wewnętrzną SLN badano za pomocą 1HNMR i XRD, a pomiary FT-IR i DSC wykazały zjawiska przemian fazowych w układach lamelarnych pod wpływem temperatury. Efekt terapeutyczny Rap-SLN analizowano w komórkach neuroblastomy SH SY5Y, czyli modelu eksperymentalnego chorób neurodegeneracyjnych. Stabilność rapamycyny w pożywce zmierzono techniką HPLC, a funkcjonalność Rap-SLN w SH SY5Y badano poprzez analizę cytotoksyczności i wpływu na aktywność enzymatyczną mTOR. Pobór Rap-SLN przez komórki analizowano poprzez uprzednie wyznakowanie fluorescencyjne nanocząstek.Recently the Compritol® 888 ATO solid lipid nanoparticles (SLN)-based drug-delivery systems, stabilized with polysorbate 80, have been studied in terms of the preservation and controlled release of pharmaceuticals in site-targeted therapies. Much data indicates the enhancement of the drug bioavailability in the encapsulated form. In this thesis, SLN were loaded with rapamycin (Rap SLN), a water-insoluble, anti-proliferative agent, to enhance its inhibitory properties towards the mTOR kinase in the model cell line. Rap SLN was formulated by cold high-pressure homogenization. The drug content was established by UV Vis and Raman spectroscopy. The stability of Rap-SLN was evaluated by measuring the ZP value, whilst DLS and PT enabled the acquisition of a size distribution. The morphology was investigated by AFM, EM and SANS. The 1HNMR and XRD measurements yielded the details of the internal structure, whereas FT-IR and DSC revealed the events of phase transitions within the lipid matrix. The therapeutic effect of Rap SLN was investigated in the SH SY5Y neuroblastoma cell line, which is an experimental model of neurodegenerative disorders. HPLC was exploited to measure the stability of the drug in a cell medium over time. The cytotoxicity and the mTOR activity assay were performed to study the impact of the drug on the cells, while the cellular uptake was visualized fluorescently
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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