1,720,966 research outputs found
Towards the development of new strategies for targeted and controlled drug delivery
No full textIn this contribution the design and development on new approaches for targeted or controlled drug delivery is proposed. The selected starting material for the synthesis of these drug delivery systems (DDSs) was pullulan. Pullulan is a natural and linear polysaccharide that possesses excellent water solubility, biocompatibility and biodegradability. In virtues of the presence of multiple anchoring points along its chain, pullulan represents also an ideal carrier to build up colloidal drug delivery systems.
Initially, pullulan oxidation was performed and deeply investigated as a convenient method for its functionalization. This strategy allowed the synthesis of a polymer therapeutic suitable for the treatment of the hepatocellular carcinoma (HCC). According to statistics, HCC is the third cause of cancer related death and the problems regarding its treatment are mainly caused by the considerable consequences of the first-pass effect and the lack of selectivity towards cancer cells. Thus, we aimed at developing a pullulan based DDS with higher selectivity for liver cancer cells. In literature a peptide sequence called preS121-47, portion of a protein located in the envelope of the Hepatitis B virus, was reported to be responsible for hepatocytes recognition, interaction and virus internalization. Moreover, the proposed receptor for this peptide, named SERPINB3, has been found overexpressed in HCC, thus representing a favourable target. Pullulan was modified with the introduction of seven peptide preS121-47 molecules and the selectivity towards cells overexpressing SERPINB3 (HepG2/SERPINB3) was proved to be 2 times higher when compared with both control cells not overexpressing SERPINB3 (HepG2/EMPTY) and control polymer without targeting agent. Then, the introduction of doxorubicin, linked to pullulan through an hydrazone pH-sensitive cleavable bond, lead to the formation of a complete polymer therapeutic which showed improved efficacy on hepatocellular carcinoma cells.
Intending to explore other protocols for pullulan functionalization, its activation with p-toluenesulfonyl chloride and subsequent substitution with propargylammine was carried out. The display of alkyl groups along the polysaccharide chain permits the introduction of linking groups through copper-catalyzed azide-alkyne click chemistry reaction (CuAAC). Two rhodamine labelled polymers containing labile linking groups, i.e. hydrazone and ester, were synthesized. The stability of these conjugates in response to the
pH was tested in comparison with a control polymers including only covalent bonds. Pullulan functionalized with the ester bond showed less stability that what expected, while sufficient retention of rhodamine, used as fluorescent drug model, was observed for the hydrazone bond. The potential use of these products as carrier for the sustained drug release in the vitreous of the eye was then evaluated. The flexible and highly biocompatible pullulan-based products demonstrated ex vivo to move slowly into the vitreous of an intact porcine eye. In vitro tests confirmed the safeness and high internalization levels of such bioconjugates on retina epithelium cells (ARPE-19).
Furthermore, considering the peculiar features of the anatomy of the eye, we hypothesized to investigate the potential use of cell penetrating enhancer (CPE) decorated liposomes for improved entrance to the retinal cells after the administration through intravitreal injection. Taking advantage of the expertize on polysaccharide functionalization, the synthesis of an innovative CPE molecule starting from a maltotriose core was accomplished in our laboratory. This non-peptidic and polycationic TAT-like system was used in the present work for the decoration of liposomes. Different combinations of TAT and PEG2kDa-DSPE were evaluated and tested, but the formulation containing equal amount of these two decorating agents showed the most favourable characteristic for ophthalmic applications. Indeed, the diffusion coefficient calculation performed ex vivo on porcine eyes highlighted the possibility to tune liposomes mobility in vitreous by tuning their superficial properties. The surface decoration of liposomes with PEG2kDa-DSPE endowed liposomes with slipping properties, improving their vitreous mobility, while the presence of TAT molecule conferred enhanced uptake and penetration ability towards retina cells. Indeed, in vitro cell studies on ARPE-19 confirmed the low toxic effects and excellent level of uptake achieved with the co-decoration with PEG and TAT
Design, synthesis, and photophysical properties of pyrroloquinoline-based compounds showing strong blue fluorescence as potential dyes for biomedical applications
No full textA small library of 3-ethylpyrrolo[3,2-f]quinoline derivatives was synthesized to identify a novel class of dyes for use in biological studies. According to the spectroscopic analyses performed to evaluate the fluorimetric parameters of quantum yield and brightness, 7-methyl- and 6,7-dimethylpyrroloquinolin(9)one derivatives were found to be the best blue luminescent dyes for biological applications. To enhance the luminescence profiles and to obtain probes that could be conjugated to functional groups of supramolecular drug delivery systems, these compounds were further modified at position3 to obtain 3-heptanoic acid and 3-aminohexylpyrroloquinolin(9)one methylated derivatives. The most brilliant 6,7-dimethyl-3-aminohexylpyrroloquinolinone hydrochloride was conjugated to pullulan, a biocompatible polysaccharide used to produce colloidal systems for drug delivery. Comparative studies showed that this compound can be properly exploited as a blue fluorescent label in biological investigations, namely cell trafficking and pharmacokinetics/biodistribution studies. These molecules possess higher fluorescence efficiency than commercial dyes in biological media, making them suitable alternatives to commercially available products in current use
A novel soluble supramolecular system for sustained rh-GH delivery
No full textMethoxy-poly(ethylene glycol)s bearing a terminal cholanic moiety (mPEG5kDa-cholane, mPEG10kDa-cholane and mPEG20kDa-cholane) were physically combined with recombinant human growth hormone (rh-GH) to obtain supramolecular assemblies for sustained hormone delivery. The association constants (Ka) calculated by Scatchard analysis of size exclusion chromatography (SEC) data were in the order of 10(5)M(-1). The complete rh-GH association with mPEG5kDa-cholane, mPEG10kDa-cholane and mPEG20kDa-cholane was achieved with 7.5±1.1, 3.9±0.4 and 2.6±0.4 w/w% rh-GH/mPEG-cholane, respectively. Isothermal titration calorimetry (ITC) yielded association constants similar to that calculated by SEC and showed that rh-GH has 21-25 binding sites for mPEG-cholane, regardless the polymer molecular weight. Dialysis studies showed that the mPEG-cholane association strongly delays the protein release; 80-90% of the associated rh-GH was released in 200h. However, during the first 8h the protein formulations obtained with mPEG10kDa-cholane and mPEG20kDa-cholane showed a burst release of 8 and 28%, respectively. Circular dichroism (CD) analyses showed that the mPEG5kDa-cholane association does not alter the secondary structure of the protein. Furthermore, mPEG5kDa-cholane was found to enhance both the enzymatic and physical stability of rh-GH. In vivo pharmacokinetic and pharmacodynamic studies were performed by subcutaneous administration of rh-GH and rh-GH/mPEG5kDa-cholane to normal and hypophysectomised rats. The study showed that mPEG5kDa-cholane decreases the maximal concentration in the blood but prolongs the body exposure of the protein, which resulted in 55% bioavailability increase. Finally, rh-GH formulated with mPEG5kDa-cholane yielded prolonged weight increase of hypophysectomised rats as compared to rh-GH in buffer or formulated with mPEG5kDa-OH. After the second administration the weight of the animals treated with rh-GH formulated with mPEG5kDa-cholane was about 2 times higher than that obtained with equal dose of non-formulated rh-GH
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
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
New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma
Get PDFHepatocellular carcinoma, the most frequent solid tumor of the liver, has a very poor prognosis, being the second most common cause of death from cancer worldwide. The incidence and mortality of this liver tumor are increasing in most areas of the world as a consequence of aging and the emerging of new risk factors such as the metabolic syndrome, beside the recognized role of hepatitis B and C viral infections and alcohol abuse. Despite the increasing knowledge on the molecular mechanisms underlying hepatic carcinogenesis, effective therapeutic strategies are still an unmet clinical need. Efforts have been made to develop selective drugs as well as effective targeted drug delivery systems. The development of novel drug carriers for therapeutic molecules can indeed offer a valuable strategy to ameliorate the efficacy of HCC treatment. In this review, we discuss recent drug delivery strategies for HCC treatment based on the exploitation of targeted nanoparticles (NPs). Indeed, a few of these platforms have achieved an advanced stage of preclinical development. Here, we review the most promising drug nanovehicles based on both synthetic and natural polymers, including polysaccharides that have emerged for their biocompatibility and biodegradability. To maximize site-selectivity and therapeutic efficacy, drug delivery systems should be functionalized with ligands which can specifically recognize and bind targets expressed by HCC, namely cell membrane associated antigens, receptors or biotransporters. Cell surface and intracellular molecular targets are exploited either to selectively deliver drug-loaded nanovehicles or to design novel selective therapeutics. In conclusion, the combination of novel and safe drug delivery strategies based on site-specific targeted drug nanovehicles with therapeutic molecular targets may significantly improve the pharmacological efficacy for the treatment of HCC
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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