16 results on '"Novoa Carballal R"'
Search Results
2. Antithrombotic and hemocompatible properties of nanostructured coatings assembled from block copolymers
- Author
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Fontelo, R., Soares da Costa, D., Reis, R.L., Novoa-Carballal, R., and Pashkuleva, I.
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- 2022
- Full Text
- View/download PDF
3. Bactericidal nanopatterns generated by block copolymer self-assembly
- Author
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Fontelo, R., primary, Soares da Costa, D., additional, Reis, R.L., additional, Novoa-Carballal, R., additional, and Pashkuleva, I., additional
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- 2020
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4. Biomedical potential of fucoidan, a seaweed sulfated polysaccharide: from a anticancer agent to a building block of cell encapsulating systems for regenerative medicine
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Silva, Tiago José Quinteiros Lopes Henriques, Oliveira, Catarina, Reys, Lara Priscila Lopes, Costa, Diana Pereira Soares, Novoa-Carballal, R., Oliveira, Nuno M., Ferreira, Andreia S., Nunes, Cláudia, Silva, Simone Santos, Martins, Albino, Coimbra, Manuel A., Mano, J. F., Neves, N. M., Reis, R. L., and Universidade do Minho
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Biomacromolecule ,Biomimetic ,Tissue engineering ,Biomaterial - Abstract
Marine macroalgae or seaweeds synthesize a wide variety of polymers and smaller compounds with several bioactivities, among which the sulfated polysaccharides acquire greater relevance not only due to the reported antioxidant, antiviral and anticancer[1]Â activities, but also to the resemblance of extracellular matrix glycosaminoglycans found in the human body[2]. In this study, the potential of fucoidan (Fu) isolated from brown seaweed Fucus vesiculosus for therapeutical use has been evaluated, focusing in its performance as antitumoral agent (bioactive role) or as building block of cell encapsulating systems (structural role). Materials and Methods:Â The anticancer activity of Fu extracts was assessed by evaluating the cytotoxic behavior over two human breast cancer cell lines (MCF-7 and MDA-MB-231) in in-vitro culture, using human fibroblasts and endothelial cells (HPMEC-ST1 and MRC-5, respectively) as reference. Regarding the structural role, Fu was modified by methacrylation reaction (MFu) using methacrylic acid and further crosslinked using visible radiation and triethanolamine and eosin-y as photoinitiators. The photocrosslinking was performed on MFu solution droplets placed in a silica-based superhydrophobic surface[3], allowing the formation of particles[4]Â (since natural Fu is highly soluble in water and ion gelation is not effective). Biological performance of the developed particles was assessed by in vitro culture of fibroblasts and pancreatic cells (L929 and 1.1B4, respectively) in contact with MFu particles, up to 7 days. The ability of the developed materials to support adhesion and proliferation of cells was evaluated for both types of cells. Results and Discussion:Â The tested anticancer activity is not ubiquitous on Fu extracts, being dependent on its chemical features, with molecular weight (Mw) representing a particular role. Specifically, Mw values around 60 kDa exhibited cytotoxic effects to human breast cancer cell lines, while not affecting normal fibroblasts or endothelial cells (which represent the cells of the healthy tissue that would be closer to the tumor in a real situation). A concentration range of 0.2 to 0.3 mg mL-1 from the selected Fu extract could be considered as the therapeutic window for further studies. Regarding fucoidanâ s role on innovative biomaterials, the developed MFu particles could support the proliferation of fibroblasts (L929), but also of human pancreatic beta cells (1.1B4), which tend to form pseudo-islets after 7 days in culture (Fig. 1). This pancreatic cells could be also successfully encapsulated, opening a new route for a diabetes mellitus type 1 therapeutic approach. Fig. 1:Â Confocal microscopy images of 1.1B4 cells cultured in the presence of fucoidan-based particles and organized in pseudo-islets (red â actin; blue â nuclei). Conclusion:Â The present work establishes fucoidan as a high performance building block for the development of advanced therapies for cancer (targeted therapy) or tissue and organ regeneration. It shed light on the relation between chemical structure and biological activity towards anti-cancer effect and proposes novel beta cell laden particles as injectable insulin producing systems to tackle diabetes., Funding from projects 0687_NOVOMAR_1_P (co-funded by INTERREG 2007-2013 / POCTEP), CarbPol_u_Algae (EXPL/MAR-BIO/0165/2013, funded by the Portuguese Foundation for Science and Technology, FCT), POLARIS (FP7-REGPOT-CT2012-316331) and ComplexiTE (ERC-2012-ADG 20120216-321266), funded by the European Union’s Seventh Framework Programme for Research and Development is acknowledged. ASF, SSS, NMO and DSC are also thankful to FCT for their individual fellowships.
- Published
- 2016
5. An aquaporin 4 antisense oligonucleotide loaded, brain targeted nanoparticulate system design
- Author
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Kozlu S, Caban S, Yerlikaya F, Fernandez-Megia E, Novoa-Carballal R, Riguera R, Yemisci M, Gursoy-Ozdemir Y, Dalkara T, COUVREUR Patrick, Capan Y, Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, and Universidade de Santiago de Compostela. Departamento de Química Orgánica
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Aquaporin 4 ,Chitosan ,Drug Delivery Systems ,Surface Properties ,Chemistry, Pharmaceutical ,Drug Compounding ,Drug Design ,Electrochemistry ,Brain ,Nanoparticles ,Brain Edema ,Oligonucleotides, Antisense ,Particle Size - Abstract
Aquaporins (AQPs), members of the water-channel protein family, are highly expressed in brain tissue especially in astrocytic end-feet. They are important players for water hemostasis during development of cytotoxic as well as vasogenic edema. Increased expression of AQPs is important in pathophysiology of neurological diseases such as neuroinflammation and ischemia. Unfortunately, there are a few pharmacological inhibitors of AQP4 with several side effects limiting their translation as a drug for use in clinical conditions. Another therapeutic approach is using antisense oligonucleotides (ASOs) to block AQP4 activity. These are short, synthetic, modified nucleic acids that bind RNA to modulate its function. However, they cannot pass the blood brain barrier (BBB). To overcome this obstacle we designed a nanoparticulate system made up of chitosan nanoparticles surface modified with PEG and conjugated with monoclonal anti transferrin receptor-1 antibody via streptavidin-biotin binding. The nanocarrier system could be targeted to the transferrin receptor-1 at the brain endothelial capillaries through monoclonal antibodies. It is hypothesized that the nanoparticles could pass the BBB via receptor mediated transcytosis and reach brain parenchyma. Particle size, zeta potential, loading capacity and release profiles of nanoparticles were investigated. It was observed that all types of chitosau (CS) nanoparticles had positive zeta potential values and nanoparticle particle size distribution varied between 100 and 800 nm. The association efficiency of ASOs into the nanoparticles was between 80–97% and the release profiles of the nanoparticles exhibited an initial burst effect followed by a controlled release. The results showed that the designed chitosan based nanocarriers could be a promising carrier system to transport nucleic acid based drugs to brain parenchyma This study is supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project Number: 110S460) SI
- Published
- 2014
6. Nanocarriers based on interpolyelectrolyte complexation of Sulphated polysaccharide-b- PEG diblock copolymers and PLL
- Author
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Novoa-Carballal, R., Reis, R. L., Pashkuleva, I., and Universidade do Minho
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Hyaluronic acid ,education ,Chondroitin sulphate ,health care economics and organizations ,humanities - Abstract
Publicado em "Journal of Tissue Engeneering and Regenerative Medicine", vol. 7, supp. 1 (2013), Glycosaminoglycans (GAGs) are integral part of the closest cellular environment: they can be found on the cells surface and in the extracellular matrix, where they interact with different proteins acting as local regulator of their activity. The use of GAGs in the preparation of protein delivery nanosystems is, therefore, prominent but so far, underexploited mainly because of the heterogeneity (composition and molecular weights) of natural glycans and the multistep procedures needed to obtain GAGs’ synthetic analogues and diblock copolymers.1 Recently, we have shown that oxime click reaction can be applied as a straightforward methodology for the synthesis of poly(ethylene glycol) (PEG)- hyaluronic acid (HA) diblock copolymers.2 These copolymers formed nanosized interpolyelectrolyte complexes (45 to 150 nm) by interaction with poly- L -lysine (PLL).3 Unfortunately, these complexes are not stable at physiological ionic strength. Herein, we describe a strategy to overcome this drawback; chondroitin sulphate-b-PEG diblock copolymers (CS-b-PEG) were obtained using the same oxime click reaction. The stronger negative charge of sulphate groups (versus the carboxilic groups present in HA) resulted in the complexes with higher stability: interpolyelectrolyte complexes between PLL and (CS-b-PEG) are stable up to 260 mM ionic strenght. Because carbohydrates do not activate Tcells, we believe that the reported herein complexes have an enormous potential in both drug delivery and vaccination fields.
- Published
- 2013
7. Preparation and evaluation of alpha-phenyl-n-tert-butyl nitrone (PBN)-encapsulated chitosan and PEGylated chitosan nanoparticles
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Pinarbasli O, Aktas Y, Dalkara T, Andrieux K, Maria Jose Alonso, Fernandez-Megia E, Novoa-Carballal R, Riguera R, Couvreur P, and Capan Y
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Cyclic N-Oxides ,Excipients ,Chitosan ,Chemistry, Pharmaceutical ,Drug Compounding ,Electrochemistry ,Nanoparticles ,Free Radical Scavengers ,Particle Size ,Polyethylene Glycols - Abstract
Alpha-phenyl-n-tert-butyl nitrone (PBN) shows its major effect by scavenging free radicals formed in the ischemia and it has the ability to penetrate through the blood brain barrier easily. The in vivo stability of PBN is very low and when administered systemically, it has a mean plasma half life of about three hours. Therefore, formulations which are able to prolong the plasma residence time of PBN are of major interest, because oxygen radicals are usually continuously formed under pathological conditions. In this study, PBN, a nitrone compound having neuroprotective properties, was encapsulated in chitosan (CS) and chitosan-poly(ethylene glycol) (CS-PEG) nanoparticles for treatment of diseases such as stroke, in which sustained free radical production is reported. The nanoparticles were characterized through particle size determination, zeta potential, encapsulation efficiency, surface morphology determinations and in vitro release studies. The surface morphologies were evaluated by transmission electron microscopy (TEM) and nanoparticles having spherical shapes were characterized. The particle size distribution was between approximately 97 nm and approximately 322 nm; and the zeta potentials varied between approximately 9 mV and approximately 33 mV. Size of the nanoparticle formulations was important for the release of PBN from nanoparticles. The quantitative determination of PBN has been evaluated by a validated analytical HPLC method. The presented chitosan-based nanotechnology opens new perspectives for testing antioxidant activity in vivo.
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- 2009
8. Isolation and Characterization of Polysaccharides from the Ascidian Styela clava .
- Author
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Valcarcel J, Vázquez JA, Varela UR, Reis RL, and Novoa-Carballal R
- Abstract
Styela clava is an edible sea squirt farmed in Korea that has gradually invaded other seas, negatively impacting the ecology and economy of coastal areas. Extracts from S. clava have shown wide bioactivities, and ascidians have the unique capability among animals of biosynthesizing cellulose. Thus, S. clava is a relevant candidate for valorization. Herein, we aimed at surveying and characterizing polysaccharides in both tunic and flesh of this ascidian. To this end, we enzymatically hydrolyzed both tissues, recovering crystalline cellulose from the tunic with high aspect ratios, based on results from microscopy, X-ray diffraction, and infrared spectroscopy analyses. Alkaline hydroalcoholic precipitation was applied to isolate the polysaccharide fraction that was characterized by gel permeation chromatography (with light scattering detection) and NMR. These techniques allowed the identification of glycogen in the flesh with an estimated Mw of 7 MDa. Tunic polysaccharides consisted of two fractions of different Mw. Application of Diffusion-Ordered NMR allowed spectroscopically separating the low-molecular-weight fraction to analyze the major component of an estimated Mw of 40-66 kDa. We identified six different sugar residues, although its complexity prevented the determination of the complete structure and connectivities of the residues. The two more abundant residues were N-acetylated and possibly components of the glycosaminoglycan-like (GAG-like) family, showing the remaining similarities to sulfated galactans. Therefore, Styela clava appears as a source of nanocrystalline cellulose and GAG-like polysaccharides.
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- 2021
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9. [Differential clinic in children infected by SARS-CoV-2, traceability of contacts and cost-effectiveness of diagnostic tests: Cross-sectional observational study].
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Fiel-Ozores A, González-Durán ML, Novoa-Carballal R, Portugués-de la Red MDM, Fernández-Pinilla I, Cabrera-Alvargonzález JJ, Martínez-Reglero C, Rey-Cao S, and Concheiro-Guisán A
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- Adolescent, Age Factors, COVID-19 virology, Child, Child, Preschool, Contact Tracing, Cost-Benefit Analysis, Cross-Sectional Studies, Female, Fever epidemiology, Fever virology, Humans, Infant, Infant, Newborn, Male, Predictive Value of Tests, SARS-CoV-2 immunology, Sensitivity and Specificity, COVID-19 diagnosis, COVID-19 Testing methods, Reverse Transcriptase Polymerase Chain Reaction methods, SARS-CoV-2 isolation & purification
- Abstract
Introduction: Given the possible coexistence of infection by the SARS-CoV-2 with other seasonal infections, the aim is to identify differential symptoms. There has been studied the role of children in intrafamily contagion and the sensitivity of reverse transcriptase polymerase chain reaction (RT-PCR) in an area with low community transmission., Material and Methods: Cross-sectional observational study. Patients between 0-15 years studied by RT-PCR technique due to clinical suspicion of infection by SARS-CoV-2 virus in the months of March-May 2020. Survey on symptoms and contacts. Determination of Anti-SARS-CoV-2 antibodies at least 21 days after the RT-PCR test., Results: 126 patients were included, 33 with confirmed infection and mean age 8.4 years (95% CI 6.8-10,5), age higher than not infected. Fever was the most common symptom and with greater sensitivity. The differences found were a greater frequency of anosmia (P=0.029) and headache (P=.009) among children infected with a specificity of 96.7% and 81.5% respectively. There were no differences in the duration of the symptoms. 81.8% of those infected were probably infected in the family nucleus, 85.2% by a parent who worked outside the home. The sensitivity of RT-PCR was 70.9% and its negative predictive value 91.1%., Conclusions: The clinical picture is nonspecific and the more specific symptoms difficult to detect in younger children. Children had a reduced role in the intrafamily transmission. The sensitivity of RT-PCR could be related to a less contagiousness in children after one week of infection., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)
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- 2021
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10. [Urethral prolapse: Diagnostic image of a rare pathology].
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Novoa-Carballal R, Cantero Rey R, García García I, and Valenzuela Besada O
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- Child, Female, Humans, Prolapse, Urethral Diseases pathology, Urethral Diseases diagnosis
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- 2019
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11. Minimalistic supramolecular proteoglycan mimics by co-assembly of aromatic peptide and carbohydrate amphiphiles.
- Author
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Brito A, Abul-Haija YM, da Costa DS, Novoa-Carballal R, Reis RL, Ulijn RV, Pires RA, and Pashkuleva I
- Abstract
We report the co-assembly of aromatic carbohydrate and dipeptide amphiphiles under physiological conditions as a strategy to generate minimalistic proteoglycan mimics. The resulting nanofibers present a structural, fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) core and a functional carbohydrate (Fmoc-glucosamine-6-sulfate or -phosphate) shell. The size, degree of bundling and mechanical properties of the assembled structures depend on the chemical nature of the carbohydrate amphiphile used. In cell culture medium, these nanofibers can further organize into supramolecular hydrogels. We demonstrate that, similar to proteoglycans, the assembled gels prolong the stability of growth factors and preserve the viability of cultured cells. Our results demonstrate that this approach can be applied to the design of extracellular matrix (ECM) substitutes for future regenerative therapies.
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- 2018
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12. Glycosaminoglycans from marine sources as therapeutic agents.
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Valcarcel J, Novoa-Carballal R, Pérez-Martín RI, Reis RL, and Vázquez JA
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- Animals, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents therapeutic use, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Antiviral Agents chemistry, Antiviral Agents therapeutic use, Glycosaminoglycans chemistry, Humans, Aquatic Organisms chemistry, Chondroitin Sulfates therapeutic use, Glycosaminoglycans therapeutic use
- Abstract
Glycosaminoglycans (GAGs) in marine animals are different to those of terrestrial organisms, mainly in terms of molecular weight and sulfation. The therapeutic properties of GAGs are related to their ability to interact with proteins, which is very much influenced by sulfation position and patterns. Since currently GAGs cannot be chemically synthesized, they are sourced from natural products, with high intra- but also inter-species variability, in terms of chain length, disaccharide composition and sulfation pattern. Consequently, sulfated GAGs are the most interesting molecules in the marine environment and constitute the focus of the present review. In particular, chondroitin sulfate (CS) appears as the most promising compound. CS-E chains [GlcA-GalNAc(4S,6S)] extracted from squid possess antiviral and anti-metastatic activities and seem to impart signalling properties and improve the mechanical performance of cartilage engineering constructs; Squid CS-E and octopus CS-K [GlcA(3S)-GalNAc(4S)], dermatan sulfate (DS) from sea squirts [-iK units, IdoA(3S)-GalNAc(4S)] and sea urchins [-iE units, IdoA-GalNAc(4S,6S)] and hybrids CS/DS from sharks (-B/iB [GlcA/IdoA(2S)-GalNAc(4S)], -D/iD [GlcA/IdoA(2S)-GalNAc(6S)] and -E/iE units [GlcA/IdoA-GalNAc(4S,6S)]) promote neurite outgrowth and could be valuable materials for nerve regeneration. Also displaying antiviral and anti-metastatic properties, a rare CS with fucosylated branches isolated from sea cucumbers is an anticoagulant and anti-inflammatory agent. In this same line, marine heparin extracted from shrimp and sea squirt has proven anti-inflammatory properties, with the added advantage of decreased risk of bleeding because of its low anticoagulant activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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13. Design of protein delivery systems by mimicking extracellular mechanisms for protection of growth factors.
- Author
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Silva C, Carretero A, Soares da Costa D, Reis RL, Novoa-Carballal R, and Pashkuleva I
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- Animals, Cell Line, Click Chemistry, Drug Liberation, Dynamic Light Scattering, Heparin analogs & derivatives, Heparin chemical synthesis, Heparin chemistry, Humans, Mice, Osmolar Concentration, Particle Size, Polyelectrolytes chemistry, Polyethylene Glycols chemical synthesis, Polyethylene Glycols chemistry, Proteoglycans chemical synthesis, Proteoglycans chemistry, Drug Delivery Systems, Extracellular Space chemistry, Fibroblast Growth Factor 2 pharmacology
- Abstract
Heparin sulfate proteoglycans (HSPGs) are responsible for the storage and stabilization of numerous growth factors in the extracellular matrix. In this complex native environment, the efficient binding of the growth factors is determined by multivalent, specific and reversible electrostatic interactions between the sulfate groups of HSPGs and the positively charged amino acids of the growth factor. Inspired by this naturally occurring stabilization process, we propose the use of diblock copolymers of heparin and polyethylene glycol (Hep-b-PEG) for protection and delivery of FGF-2. We describe the encapsulation of FGF-2 into spontaneously assembling polyelectrolyte complexes (PECs) with Hep-b-PEG in which the Hep block ensures the formation of the PECs, while the PEG moiety confers stability of the generated complex by a stealth corona. Our results demonstrate that by this method we can generate homogeneous complexes (ca. 400nm diameter, PDI 0.29±0.07) with a very high encapsulation efficiency (about 99% encapsulated FGF-2). The release of the growth factor in response to different stimuli such as pH, ionic strength or presence of heparinase was also studied. We report a sustained release of up to 80% during 28days which is not influenced by the presence of heparinase - a result that clearly demonstrates the protective effect of the stealth corona. We also show that FGF-2 remains bioactive as it influences the morphology of bone marrow mesenchymal stem cells., Statement of Significance: We describe a biopolymer that uses the way the cells shield a type of proteins (growth factors) to simultaneously assemble, slowly deliver and shield the protein in a "nanocarrier". Growth factors are essential for the regeneration of cartilage, bones by stem cell therapies but have a short life time as when added directly to tissues. Our design makes use of the heparin bioactivity towards such proteins in combination with a polyethylene glycol moiety (PEG) that makes a protecting shell. PEG, is biocompatible and used in approved medicines and countless cosmetic products. The highest novelty is the reaction (oxime click) used to bound these molecules that does not require modification of heparin and allows preservation of its bioactivity., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2017
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14. Systemically administered brain-targeted nanoparticles transport peptides across the blood-brain barrier and provide neuroprotection.
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Yemisci M, Caban S, Gursoy-Ozdemir Y, Lule S, Novoa-Carballal R, Riguera R, Fernandez-Megia E, Andrieux K, Couvreur P, Capan Y, and Dalkara T
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- Animals, Blood-Brain Barrier, Male, Mice, Fibroblast Growth Factor 2 administration & dosage, Nanoconjugates administration & dosage, Neuroprotective Agents administration & dosage, Oligopeptides administration & dosage, Stroke pathology
- Abstract
Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood-brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.
- Published
- 2015
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15. GATG dendrimers and PEGylated block copolymers: from synthesis to bioapplications.
- Author
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Sousa-Herves A, Novoa-Carballal R, Riguera R, and Fernandez-Megia E
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- Active Transport, Cell Nucleus, Animals, Chemistry, Pharmaceutical, Dendrimers metabolism, Gallic Acid analogs & derivatives, Gallic Acid metabolism, Humans, Ligands, Models, Molecular, Molecular Structure, Nanoparticles, Nanotechnology, Polyethylene Glycols metabolism, Structure-Activity Relationship, Contrast Media chemistry, Dendrimers chemistry, Drug Carriers, Gallic Acid chemistry, Gene Transfer Techniques, Magnetic Resonance Imaging methods, Polyethylene Glycols chemistry, Technology, Pharmaceutical methods
- Abstract
Dendrimers are synthetic macromolecules composed of repetitive layers of branching units that emerge from a central core. They are characterized by a tunable size and precise number of peripheral groups which determine their physicochemical properties and function. Their high multivalency, functional surface, and globular architecture with diameters in the nanometer scale makes them ideal candidates for a wide range of applications. Gallic acid-triethylene glycol (GATG) dendrimers have attracted our attention as a promising platform in the biomedical field because of their high tunability and versatility. The presence of terminal azides in GATG dendrimers and poly(ethylene glycol) (PEG)-dendritic block copolymers allows their efficient functionalization with a variety of ligands of biomedical relevance including anionic and cationic groups, carbohydrates, peptides, or imaging agents. The resulting functionalized dendrimers have found application in drug and gene delivery, as antiviral agents and for the treatment of neurodegenerative diseases, in diagnosis and as tools to study multivalent carbohydrate recognition and dendrimer dynamics. Herein, we present an account on the preparation and recent applications of GATG dendrimers in these fields.
- Published
- 2014
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16. A nanomedicine transports a peptide caspase-3 inhibitor across the blood-brain barrier and provides neuroprotection.
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Karatas H, Aktas Y, Gursoy-Ozdemir Y, Bodur E, Yemisci M, Caban S, Vural A, Pinarbasli O, Capan Y, Fernandez-Megia E, Novoa-Carballal R, Riguera R, Andrieux K, Couvreur P, and Dalkara T
- Subjects
- Animals, Blood-Brain Barrier drug effects, Brain Ischemia pathology, Brain Ischemia prevention & control, Caspase 3 metabolism, Cysteine Proteinase Inhibitors pharmacology, Cysteine Proteinase Inhibitors therapeutic use, Mice, Nanospheres, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Oligopeptides metabolism, Oligopeptides pharmacology, Oligopeptides therapeutic use, Peptides pharmacology, Peptides therapeutic use, Protein Transport physiology, Rats, Blood-Brain Barrier metabolism, Caspase Inhibitors, Cysteine Proteinase Inhibitors metabolism, Nanomedicine methods, Neuroprotective Agents metabolism, Peptides metabolism
- Abstract
Caspases play an important role as mediators of cell death in acute and chronic neurological disorders. Although peptide inhibitors of caspases provide neuroprotection, they have to be administered intracerebroventricularly because they cannot cross the blood-brain barrier (BBB). Herein, we present a nanocarrier system that can transfer chitosan nanospheres loaded with N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a relatively specific caspase-3 inhibitor, across BBB. Caspase-3 was chosen as a pharmacological target because of its central role in cell death. Polyethylene glycol-coated nanospheres were conjugated to an anti-mouse transferrin receptor monoclonal antibody (TfRMAb) that selectively recognizes the TfR type 1 on the cerebral vasculature. We demonstrate with intravital microscopy that this nanomedicine is rapidly transported across the BBB without being measurably taken up by liver and spleen. Pre- or post-treatment (2 h) with intravenously injected Z-DEVD-FMK-loaded nanospheres dose dependently decreased the infarct volume, neurological deficit, and ischemia-induced caspase-3 activity in mice subjected to 2 h of MCA occlusion and 24 h of reperfusion, suggesting that they released an amount of peptide sufficient to inhibit caspase activity. Similarly, nanospheres inhibited physiological caspase-3 activity during development in the neonatal mouse cerebellum on postnatal day 17 after closure of the BBB. Neither nanospheres functionalized with TfRMAb but not loaded with Z-DEVD-FMK nor nanospheres lacking TfRMAb but loaded with Z-DEVD-FMK had any effect on either paradigm, suggesting that inhibition of caspase activity and subsequent neuroprotection were due to efficient penetration of the peptide into brain. Thus, chitosan nanospheres open new and exciting opportunities for brain delivery of biologically active peptides that are useful for the treatment of CNS disorders.
- Published
- 2009
- Full Text
- View/download PDF
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