Ricardo Riguera

University of Santiago de Compostela, Santiago, Galicia, Spain

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Publications (225)743.46 Total impact

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    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.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.220.
    12/2014;
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    ABSTRACT: The paramagnetic spin relaxation (PSR) filter allows the suppression of the NMR resonances of individual components in mixtures according to their Gd3+ complexing ability. The difficulty in predicting this property hampers, however, the widespread application of this filter. Herein we describe that the PSR filter is dominated by the transverse relaxation enhancement (R2p) experienced by nuclei in the presence of Gd3+ and so, that R2p represents a reliable predictive tool of suppression in the 1D and 2D PSR filter of complex mixtures. The robustness of R2p as a predictive tool in PSR filters has been demonstrated at different magnetic fields and for the 1H, 13C, COSY and HMQC filtering of commercial multicomponent compositions, including beverages and drugs.
    Analytical chemistry. 12/2014;
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    ABSTRACT: The interaction of a highly dynamic poly(aryl acetylene) (poly-1) with Li+, Na+, and Ag+ leads to macroscopically chiral supramolecular nanospheres, nanotubes, toroids, and gels. With Ag+, nanospheres with M helicity and tunable sizes are generated, which complement those obtained from the same polymer with divalent cations. With Li+ or Na+, poly-1 yields chiral nanotubes, gels, or toroids with encapsulating properties and M helicity. Right-handed supramolecular structures can be obtained by using the enantiomeric polymer. The interaction of poly-1 with Na+ produces nanostructures whose helicity is highly dependent on the solvation state of the cation. Therefore, structures with either of the two helicities can be prepared from the same polymer by manipulation of the cosolvent. Such chiral nanotubes, toroids, and gels have previously not been obtained from helical polymer–metal complexes. Chiral nanospheres made of poly(aryl acetylene) that were previously assembled with metal(II) species can now be obtained with metal(I) species.
    Angewandte Chemie 09/2014;
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    ABSTRACT: The interaction of a highly dynamic poly(aryl acetylene) (poly-1) with Li+, Na+, and Ag+ leads to macroscopically chiral supramolecular nanospheres, nanotubes, toroids, and gels. With Ag+, nanospheres with M helicity and tunable sizes are generated, which complement those obtained from the same polymer with divalent cations. With Li+ or Na+, poly-1 yields chiral nanotubes, gels, or toroids with encapsulating properties and M helicity. Right-handed supramolecular structures can be obtained by using the enantiomeric polymer. The interaction of poly-1 with Na+ produces nanostructures whose helicity is highly dependent on the solvation state of the cation. Therefore, structures with either of the two helicities can be prepared from the same polymer by manipulation of the cosolvent. Such chiral nanotubes, toroids, and gels have previously not been obtained from helical polymer–metal complexes. Chiral nanospheres made of poly(aryl acetylene) that were previously assembled with metal(II) species can now be obtained with metal(I) species.
    Angewandte Chemie International Edition 09/2014; · 11.34 Impact Factor
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    ABSTRACT: A novel class of stereocomplex is described by interaction of helically complementary poly(phenylacetylene)s (PPAs) carrying a α-methoxy-α-trifluoromethylphenylacetamide group as pendant. The stereocomplex formation requires the presence of exposed cis amide bonds on the polymer helical threads to provide efficient cooperative supramolecular hydrogen bonding between matching enantiomeric helical structures. Interlocking of the chains gives rise to supramolecular fiber-like aggregates that at higher concentrations results in gels. Modification of the cis-trans amide conformation at the pendants allows the controlled formation and cleavage of the stereocomplex due to a dramatic change between intermolecular and intramolecular hydrogen bond interactions.
    Chemical Science 09/2014; · 8.31 Impact Factor
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    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.
    The AAPS Journal 07/2014; · 4.39 Impact Factor
  • Silvia Porto, Emilio Quiñoá, Ricardo Riguera
    Tetrahedron 05/2014; 70(20):3276–3283. · 2.80 Impact Factor
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    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.
    Die Pharmazie. 05/2014; 69(5):340-5.
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    ABSTRACT: EDGE ARTICLE Félix Freire, Ricardo Riguera et al. The ON/OFF switching by metal ions of the "Sergeants and Soldiers" chiral amplifi cation eff ect on helical poly(phenylacetylene)s Volume 5 Number 6 June 2014 Pages 2103–2590 The ON/OFF switching by metal ions of the "Sergeants and Soldiers" chiral amplification effect on helical poly(phenylacetylene)s Here we report copolymers where the "Sergeants and Soldiers effect" can be switched ON and OFF by the presence of a metal ion. These copolymers have been prepared by a combination of achiral and chiral monomer units, where the chiral ones are unable to drive the chiral amplification unless a small amount of mono-or divalent metal ions is added. In this way, the ions act as promoters upgrading some of the chiral pendants, initially unable to induce a preferential helical sense, to a higher rank forcing the arrangement of the rest of the chain in a specific helical sense. In these copolymers, the classical "Sergeant" and "Soldier" roles are modified in such a way that the chiral units become "Sergeants" only by the effect of an achiral external stimulus, namely the metal ion. The structure of the metal complex determines its interaction in the helix with the surrounding chiral and achiral "Soldiers" and therefore also determines both the intensity of the amplification and the response of a copolymer to a certain metal. For instance, poly(1 r -co-7 (1Àr)) shows chiral amplification ("Sergeants and Soldiers effect") towards the right-handed helix only with divalent ions, while poly(1 r -co-8 (1Àr)) amplifies the helix to the left-handed sense with mono-and to the right-handed sense with divalent ions. This behaviour allows, using a single copolymer, to selectively induce any of the two helical senses. The aggregation and encapsulation properties of these copolymers are also described.
    Chemical Science 01/2014; 5:2170. · 8.31 Impact Factor
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    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.
    Pharmazie 01/2014; 69(5). · 0.96 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: Here we report copolymers where the “Sergeants and Soldiers effect” can be switched ON and OFF by the presence of a metal ion. These copolymers have been prepared by a combination of achiral and chiral monomer units, where the chiral ones are unable to drive the chiral amplification unless a small amount of mono- or divalent metal ions is added. In this way, the ions act as promoters upgrading some of the chiral pendants, initially unable to induce a preferential helical sense, to a higher rank forcing the arrangement of the rest of the chain in a specific helical sense. In these copolymers, the classical “Sergeant” and “Soldier” roles are modified in such a way that the chiral units become “Sergeants” only by the effect of an achiral external stimulus, namely the metal ion. The structure of the metal complex determines its interaction in the helix with the surrounding chiral and achiral “Soldiers” and therefore also determines both the intensity of the amplification and the response of a copolymer to a certain metal. For instance, poly(1r-co-7(1−r)) shows chiral amplification (“Sergeants and Soldiers effect”) towards the right-handed helix only with divalent ions, while poly(1r-co-8(1−r)) amplifies the helix to the left-handed sense with mono- and to the right-handed sense with divalent ions. This behaviour allows, using a single copolymer, to selectively induce any of the two helical senses. The aggregation and encapsulation properties of these copolymers are also described.
    Chemical Science 01/2014; 5(6):2170-2176. · 8.31 Impact Factor
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    ABSTRACT: The characteristic distribution of transverse relaxation times (T2) within dendrimers (lower values at the core than the periphery) can be exploited in T2-edited 1D and 2D NMR experiments for the stepwise filtering of internal nuclei according to their topology within the dendritic structure. The resulting filtered spectra, which can be conceived as corresponding to virtual hollow dendrimers, benefit from reduced signal overlapping and so facilitate signal assignment and characterization. The generality of the method as a powerful tool in structural and end-group analysis has been confirmed with various dendritic families and nuclei ((1)H, (13)C, (31)P).
    Journal of the American Chemical Society 07/2013; · 10.68 Impact Factor
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    ABSTRACT: An unexpected 1H NMR invisible fraction (IF) for chitosan (CS) and CS-g-PEG is reported. The presence of this IF is remarkable considering that solution NMR is recognized as the method of choice for studying structural modifications in CS, including the degrees of acetylation (DA) and substitution (DS). In spite of IF figures as high as 50%, this IF does not interfere in the correct determination of the DA by 1H NMR, pointing to a homogeneous distribution of acetyl groups along the visible and invisible fractions. Quite in contrast, the IF negatively biases the determination of the DS in CS-g-PEG, with relative errors as high as 150% in a broad range of temperatures, pH values, and concentrations. This fact raises concerns about the accuracy of previously reported DS data for CS-g-PEG and many other CS copolymers. Efficient user-friendly conditions have been developed for the correct determination of the DS of CS-g-PEG by depolymerization by nitrous acid.
    Molecular Pharmaceutics 07/2013; · 4.57 Impact Factor
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    ABSTRACT: The elasticity (stretched/compressed) and helical sense (clockwise/anticlockwise) of a dynamic helical poly(phenylacetylene) (PPA), bearing (R)-a-methoxytrifluorophenyl acetic acid (MTPA) pendants [poly- (R)-1], can be selectively controlled by the donor and the polar character of the solvent. The basis for this effect lies on the presence in the pendants of two independently tuneable bonds: (O])C–C(–O) and (H–)N–C(]O). An increase in polarity shifts the conformational equilibrium of the (O])C–C(–O) bond in favour of the most polar synperiplanar (sp) conformer, that is more sterically demanding, thus forcing the polymer to invert its helix. A donor solvent associates with the (H–)N–C(]O) bond favouring the shift to the cis form of the amide and inducing both the elongation of the polymer chain and the inversion of the helical sense (visualized as UV-Vis bathochromic shift and CD inversion respectively). This ability of poly-(R)-1 to respond to donor/polar properties occurs in solution as well as in film state. Poly- (R)-1 presents in CHCl3 identical helical sense for both the internal (polyene backbone) and for the external (described by the pendants) helices (3/1 clockwise), while in THF their senses are opposite (internal anticlockwise; external 2/1 clockwise), as proven by DSC.
    Chemical Science 05/2013; 4:2735. · 8.31 Impact Factor
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    ABSTRACT: Multivalency is a key, ubiquitous phenomenon in nature characterized by a complex combination of binding mechanisms, with special rele-vance in carbohydrate-lectin recognition. Herein we introduce an original surface plasmon resonance (SPR) kinetic approach to analyze multivalent interactions that has been validated with dendrimers as monodisperse multivalent analytes binding to lectin clusters. The method, based on the analysis of early association and late dissociation phases of the sensorgrams provides robust information of the gly-coconjugate binding efficiency and real-time structural data of the binding events under the complex scenario of the glycocluster effect. Notably, it reveals the dynamical nature of the interaction and offers experimental evidence on the contribution of binding mechanisms.
    Journal of the American Chemical Society 04/2013; 135(16):5966-5969. · 10.68 Impact Factor
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    ABSTRACT: NMR is a powerful tool to study the dynamics of dendrimers. By analogy to linear polymers, shorter T1 relaxation times have been traditionally associated to less mobile nuclei and hence, dendrimers described with reduced local motions either at the core or the periphery. Herein we report a NMR relaxation study [1H and 13C T1, T2; 13C{1H}NOE; various fields and temperatures] which reveals profound differences between the relaxation behavior of dendrimers and linear polymers. Dendrimers show slower dynamics at internal layers and on increasing generation, and may display internal nuclei in the slow motional regime with larger T1 values than the periphery. In contrast to the relaxation properties of linear polymers, these T1 increments should not be interpreted as resulting from faster dynamics. Only the recording of T1 data at various temperatures (alternatively, T2 or NOE at one temperature) ensures the correct interpretation of dendrimer dynamics.
    Journal of the American Chemical Society 01/2013; 135(5):1972-1977. · 10.68 Impact Factor
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    ABSTRACT: The aggregation of chitosan (CS) has been studied as a function of concentration, degree of acetylation (DA), and degree of polymerization (DP) by means of pyrene fluorescence and rheology. Fluorescence experiments show that aggregation of CS involves hydrophobic domains (HD) which are more favoured as lower the DA and DP. Consistent with these results, the viscosity of CS solutions decreases continuously on increasing DA, in the whole range of DP. These results, which rule out the participation of the acetyl groups in the HD, have been interpreted by the theory of hydrophobic polyelectrolytes in terms of the electrostatic energy of the aggregates.
    Polymer 01/2013; 54(8):2081-2087. · 3.77 Impact Factor
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    ABSTRACT: A critical objective in cancer therapy is to reduce the systemic toxicity through the modification of the biodistribution of anticancer drugs. Herein, we disclose a new biodegradable nanocarrier, polyglutamic acid (PGA) nanocapsules, and present the in vivo pharmacokinetics/toxicity proof-of-concept for the anticancer drug plitidepsin. These novel nanocapsules were prepared using a modified solvent displacement technique where the polyamino acid was electrostatically deposited onto the lipid core. The nanocapsules exhibited an average size of 200 nm, a negative zeta potential and a great capacity for the encapsulation of plitidepsin (encapsulation efficiency above 90%). In addition, the nanocapsules could be freeze-dried and showed an adequate stability profile upon storage. Finally, the in vivo proof-of-concept studies performed in mice indicated that the encapsulation provided the drug with a prolonged blood circulation and a significantly reduced toxicity. In fact, the maximum tolerated dose of the nanoencapsulated drug was more than 3 times that of the reference formulation (Cremophor® EL plitidepsin solution). Overall, beyond the value of this specific formulation, the work reported here represents the evidence of the potential of polyamino acid nanocapsules in nano-oncological therapy.
    Journal of Controlled Release 01/2013; 169(1–2):10-16. · 7.63 Impact Factor
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    ABSTRACT: New helical poly(phenylacetylene)s have been successfully designed and synthesised and their properties checked. The new polymers behave as sensors of metal cation valences and/or the polar and donor character of solvents. In the presence of metal salts, poly(phenylacetylene)s form helical polymer–metal complexes (HPMCs) that, in the case of α-methoxyphenylacetic acid (MPA)-containing poly(phenylacetylene), has led to a new family of nanospheres made by complexation between the polymer and divalent metal ions. These HPMC nanostructures present properties such as: (1) their diameter can be tuned to different sizes, (2) the helicity of the polymeric material can be tuned to either of the two helical senses, and (3) they can encapsulate a number of inorganic and organic substances. These polymers also display phenomena such as helical inversion, chiral amplification and axial chirality selection, making them versatile materials.
    Advances in Polymer Science 01/2013; 262:123-140. · 3.67 Impact Factor

Publication Stats

1k Citations
743.46 Total Impact Points

Institutions

  • 1989–2014
    • University of Santiago de Compostela
      • • Department of Organic Chemistry
      • • Facultad de Química
      Santiago, Galicia, Spain
  • 2012
    • University of Lodz
      • Department of General Biophysics
      Łódź, Łódź Voivodeship, Poland
    • Scuola Normale Superiore di Pisa
      Pisa, Tuscany, Italy
    • University of Chichester
      Chichester, England, United Kingdom
  • 2001–2010
    • University of Vigo
      • Department of Organic Chemistry
      Vigo, Galicia, Spain
  • 2009
    • Hacettepe University
      • Department of Pharmaceutical Technology
      Ankara, Ankara, Turkey
  • 2003
    • Pacific Institute of Bioorganic Chemistry
      Wladiwostok, Primorskiy, Russia
  • 1997–2003
    • Russian Academy of Sciences
      • G.B. Elyakov Pacific Institute of Bioorganic Chemistry
      Moskva, Moscow, Russia
  • 1995–2003
    • University of A Coruña
      • • Faculty of Science
      • • Department of Fundamental Chemistry
      A Coruña, Galicia, Spain
  • 1994–2003
    • University of Santiago, Chile
      CiudadSantiago, Santiago, Chile
  • 2002
    • University of New Caledonia
      Port de France, Province Sud, New Caledonia
  • 2000
    • Santiago University of Technology
      Santiago, Santiago, Dominican Republic
    • University of Valencia
      • Departamento de Farmacología
      Valencia, Valencia, Spain
  • 1990
    • Colorado State University
      • Chemistry
      Fort Collins, CO, United States