- Prof. Ramon ERITJA obtained his Ph.D. degree in 1983 at University of Barcelona supervised by Prof. Giralt in peptide... moreProf. Ramon ERITJA obtained his Ph.D. degree in 1983 at University of Barcelona supervised by Prof. Giralt in peptide synthesis. Postdoctoral training in oligonucleotide synthesis at the Beckman Research Institute of City of Hope (Dr. B. Kaplan and K. Itakura) from 1984-1987 and at University of Colorado at Boulder (Dr. M. H. Caruthers) 1987-1988. He returned to University of Barcelona in 1988. He was group leader at CSIC, Barcelona 1990-1994. He was group leader and director of DNA synthesis core facility at European Molecular Biology Laboratory (EMBL), Heidelberg (Germany) 1994-1999. He is research professor at CSIC, Barcelona from 2000 until now. He was the Director of the Institute for Advanced Chemistry of Catalonia (IQAC) from 2012 to 2017. His group is a member of the CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine. He is coauthor of more than 350 publications and several patents on the synthesis and properties of nucleic acids derivatives. Research efforts have been concentrated in the following areas: 1) Development of novel RNA derivatives to enhance specific gene silencing properties of siRNA by RNA interference, including nuclease resistant siRNAs, lipid-RNA and development of lipid formulation for siRNA transfection. 2) Conformational analysis of biologically relevant non-canonical DNA structures such as G-quadruplex, and i-motif. 3) Development of biosensors using clamp oligonucleotides for enhanced binding by triple helix formation. 4) Functionalization of DNA origami to enhance biomedical properties. 5) Synthesis and properties of oligonucleotides carrying non-natural nucleobases for the study of mutagenesis, DNA repair, and DNA methylase inhibition. 6) Synthesis of oligonucleotide-peptide and protein conjugates(Prof. Ramon ERITJA obtained his Ph.D. degree in 1983 at University of Barcelona supervised by Prof. Giralt in peptide synthesis. Postdoctoral training in oligonucleotide synthesis at the Beckman Research Institute of City of Hope (Dr. B. Kaplan and K. Itakura) from 1984-1987 and at University of Colorado at Boulder (Dr. M. H. Caruthers) 1987-1988. He returned to University of Barcelona in 1988. He was group leader at CSIC, Barcelona 1990-1994. He was group leader and director of DNA synthesis core facility at European Molecular Biology Laboratory (EMBL), Heidelberg (Germany) 1994-1999. He is research professor at CSIC, Barcelona from 2000 until now. He was the Director of the Institute for Advanced Chemistry of Catalonia (IQAC) from 2012 to 2017. His group is a member of the CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine. He is coauthor of more than 350 publications and several patents on the synthesis and properties of nucleic acids derivatives. Research efforts have been concentrated in the following areas: 1) Development of novel RNA derivatives to enhance specific gene silencing properties of siRNA by RNA interference, including nuclease resistant siRNAs, lipid-RNA and development of lipid formulation for siRNA transfection. 2) Conformational analysis of biologically relevant non-canonical DNA structures such as G-quadruplex, and i-motif. 3) Development of biosensors using clamp oligonucleotides for enhanced binding by triple helix formation. 4) Functionalization of DNA origami to enhance biomedical properties. 5) Synthesis and properties of oligonucleotides carrying non-natural nucleobases for the study of mutagenesis, DNA repair, and DNA methylase inhibition. 6) Synthesis of oligonucleotide-peptide and protein conjugates)edit
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Instituto de Carboquimica, CSIC. Miguel Luesma,4 Zaragoza, Spain b Electrical Engineering and Computer Science Department. Cory Hall, Berkeley CA 94720-1770 UC, California. c CIDETEC Po Miramon, 196 Parque Tecn. Miramon.,20009 San... more
Instituto de Carboquimica, CSIC. Miguel Luesma,4 Zaragoza, Spain b Electrical Engineering and Computer Science Department. Cory Hall, Berkeley CA 94720-1770 UC, California. c CIDETEC Po Miramon, 196 Parque Tecn. Miramon.,20009 San Sebastian, Spain d Instituto de Investigaciones Quimicas y Ambientales CSIC. IIQAB-CSIC Jordi Girona, 18-26 , 08034-Barcelona, Spain Molecular Foundry, LBNL, One Cyclotron road, MS 67R3208-22 Berkeley, California, 94720, USA mtmatinez@icb.csic.es
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Lipid nanocarriers, such as niosomes, are considered attractive candidates for non-viral gene delivery due to their suitable biocompatibility and high versatility. In this work, we studied the influence of incorporating chloroquine in... more
Lipid nanocarriers, such as niosomes, are considered attractive candidates for non-viral gene delivery due to their suitable biocompatibility and high versatility. In this work, we studied the influence of incorporating chloroquine in niosomes biophysical performance, as well as the effect of non-ionic surfactant composition and protocol of incorporation in their biophysical performance. An exhaustive comparative evaluation of three niosome formulations differing in these parameters was performed, which included the analysis of their thermal stability, rheological behavior, mean particle size, dispersity, zeta potential, morphology, membrane packing capacity, affinity to bind DNA, ability to release and protect the genetic material, buffering capacity and ability to escape from artificially synthesized lysosomes. Finally, in vitro biological studies were, also, performed in order to determine the compatibility of the formulations with biological systems, their transfection efficienc...
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Alginate (ALG) is a lineal hydrophilic polysaccharide present in brown algae cell walls, which turns into a gel state when hydrated. Gelation readily produces a series of three dimensional (3D) architectures like fibers, capillaries, and... more
Alginate (ALG) is a lineal hydrophilic polysaccharide present in brown algae cell walls, which turns into a gel state when hydrated. Gelation readily produces a series of three dimensional (3D) architectures like fibers, capillaries, and microspheres, used as biosensors and bio‐actuators in a plethora of biomedical applications like drug delivery and wound healing. Hydrogels have made a great impact on regenerative medicine and tissue engineering because they are able to mimic the mechanical properties of natural tissues due to their high water content. Recent advances in neurosciences have led to promising strategies for repairing and/or regenerating the damaged nervous system. Spinal cord injury (SCI) is particularly challenging, owing to its devastating medical, human, and social consequences. Although effective therapies to repair the damaged spinal cord (SC) are still lacking, multiple pharmacological, genetic, and cell‐based therapies are currently under study. In this framewo...
Research Interests: Chemistry, Tissue Engineering, Biotechnology, Drug delivery, Industrial Biotechnology, and 12 moreRegeneration (Biology), Spinal Cord Injury, Regenerative Medicine, Medicine, Environmental Biotechnology, Alginate, Medical Biotechnology, Spinal Cord, Central Nervous System, Biomaterial, Neural Tissue Engineering, and Bioprinting
Hydrogels are tridimensional networks that are able to retain important amounts of water. These soft materials can be obtained through self-assembling processes involving either hydrophilic molecules or polymers, allowing the formation of... more
Hydrogels are tridimensional networks that are able to retain important amounts of water. These soft materials can be obtained through self-assembling processes involving either hydrophilic molecules or polymers, allowing the formation of the corresponding covalently and physically cross-linked networks. Although the applicability of hydrogels in biomedicine has been exponentially growing due to their biocompatibility and different responses to stimuli, these materials have exhibited the particular feature of poor mechanical strength, and consequently, are brittle materials with low deformation. Due to this reason, a race has started to obtain more stretchable and tough hydrogels through different approaches. Within this context, this review article describes the most representative strategies and examples involving synthetic polymers with potential for biomedical applications.
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Cationic niosomes have become important non-viral vehicles for transporting a good number of small drug molecules and macromolecules. Growing interest shown by these colloidal nanoparticles in therapy is determined by their structural... more
Cationic niosomes have become important non-viral vehicles for transporting a good number of small drug molecules and macromolecules. Growing interest shown by these colloidal nanoparticles in therapy is determined by their structural similarities to liposomes. Cationic niosomes are usually obtained from the self-assembly of non-ionic surfactant molecules. This process can be governed not only by the nature of such surfactants but also by others factors like the presence of additives, formulation preparation and properties of the encapsulated hydrophobic or hydrophilic molecules. This review is aimed at providing recent information for using cationic niosomes for gene delivery purposes with particular emphasis on improving the transportation of antisense oligonucleotides (ASOs), small interference RNAs (siRNAs), aptamers and plasmids (pDNA).
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Molecular self-assembling is ubiquitous in nature providing structural and functional machinery for the cells. In recent decades, material science has been inspired by the nature’s assembly principles to create artificially higher-order... more
Molecular self-assembling is ubiquitous in nature providing structural and functional machinery for the cells. In recent decades, material science has been inspired by the nature’s assembly principles to create artificially higher-order structures customized with therapeutic and targeting molecules, organic and inorganic fluorescent probes that have opened new perspectives for biomedical applications. Among these novel man-made materials, DNA nanostructures hold great promise for the modular assembly of biocompatible molecules at the nanoscale of multiple shapes and sizes, designed via molecular programming languages. Herein, we summarize the recent advances made in the designing of DNA nanostructures with special emphasis on their application in biomedical research as imaging and diagnostic platforms, drug, gene, and protein vehicles, as well as theranostic agents that are meant to operate in-cell and in-vivo.
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Boronic acid-modified alginate allows the direct formation of biocompatible hydrogels under basic conditions with remarkable injectable, self-healing and multistimuli-responsive properties.
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Supramolecular hydrogels based on N-protected phenylalanine (Fmoc–Phe–OH) were used to encapsulate non-ionic surfactant vesicles (niosomes).
Research Interests: Chemistry, Supramolecular Chemistry, Nanotechnology, Chemie, RSC, and 2 moreDDC and Nucleic Acid(DDC and Nucleic Acid)
(DDC and Nucleic Acid)
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Liposome-encapsulated hydrogels have emerged as an attractive strategy for medical and pharmaceutical applications.
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We designed niosomes based on three lipids that differed only in the polar-head group to analyze their influence on the transfection efficiency.
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ABSTRACT
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Deoxyribonucleotide insertion efficiencies were measured opposite site-directed abasic template lesions using human immunodeficiency virus 1 reverse transcriptase (HIV-1RT), and the efficiencies to continue primer synthesis beyond the... more
Deoxyribonucleotide insertion efficiencies were measured opposite site-directed abasic template lesions using human immunodeficiency virus 1 reverse transcriptase (HIV-1RT), and the efficiencies to continue primer synthesis beyond the lesion, by addition of the "next correct" deoxynucleotide, were measured as a function of sequence context. Insertion of purines was favored over pyrimidines, A > G > T approximately C. Primer extension past the lesion occurred by two distinct mechanisms, either by direct or by misalignment extension. An "A-rule" appeared to hold for the case of direct extension, where the abasic template moiety is intrahelical, aligned opposite the primer 3'-terminus. In misalignment extension, the primer terminus is realigned from a site directly opposite the lesion to a new position opposite a neighboring template base 5' to the lesion. Direct extension efficiencies were measured in 16 different configurations, by varying 4 bases at the primer 3'-termini and 4 at the 5'-side (downstream) of the lesion. The predominant order of direct extension was A > G > T approximately C, similar to that observed for insertion. Reduced primer extension rates were not caused by a reduction in HIV-1 RT-DNA binding. Primers terminating in C showed inefficient direct extension, but were readily extended via misaligned configurations. The ratios of direct-to-misalignment extension efficiencies were 27:1, 2.5:1, and 1:25 for A, G, and C opposite the lesion, respectively. For the case of primers terminating in T, misalignment extension was not observed. A striking result was that while primers were extended past an abasic lesion by HIV-1 RT in both direct and misalignment modes, avian myeloblastosis virus RT failed to catalyze significant extension by either mode.
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... Ramon ERI'rJA*l, )ordi ROBLF52, Dolor, FERNANDEZFORNER2, Fernando ALBERICI(72 Ernest GIRAla'2 and Enrique PEDROSO2. IDepartocnt of Molecular Genetics. CIDCSIC. ... b) deBear, J,S.; Hayes, JA; Koleck, MP;... more
... Ramon ERI'rJA*l, )ordi ROBLF52, Dolor, FERNANDEZFORNER2, Fernando ALBERICI(72 Ernest GIRAla'2 and Enrique PEDROSO2. IDepartocnt of Molecular Genetics. CIDCSIC. ... b) deBear, J,S.; Hayes, JA; Koleck, MP; Cough, GR; Nucleosides and Nucleotides (1987), 6, 821. ...
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full... more
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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... SYNTHESIS OF PROTECTED PEPTIDESlz Fe mando Albericioa,;, Ernest Giraltaand Ramon Rritjab" aDepartment of Organic Chemistry, University of Barcelona, E08028 Barcelona, Spain. ... 1284; b) G. Barany, N. KneibCordonier, and DG... more
... SYNTHESIS OF PROTECTED PEPTIDESlz Fe mando Albericioa,;, Ernest Giraltaand Ramon Rritjab" aDepartment of Organic Chemistry, University of Barcelona, E08028 Barcelona, Spain. ... 1284; b) G. Barany, N. KneibCordonier, and DG Mullen, Int. ...
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full... more
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select... more
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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The preparation of synthetic oligodeoxynucleotides containing O4-benzylthymidine (Tbn) is described. The use of standard and t-butylphenoxyacetyl amino protecting groups is compared. The thermal stabilities of duplexes containing Tbn... more
The preparation of synthetic oligodeoxynucleotides containing O4-benzylthymidine (Tbn) is described. The use of standard and t-butylphenoxyacetyl amino protecting groups is compared. The thermal stabilities of duplexes containing Tbn paired with adenine and guanine have been measured.
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Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel... more
Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4+ AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4+ AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4+ leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients.
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The last decade has witnessed the blooming of nucleic acids for therapeutic and diagnostic applications. In the present article, we describe the most important results from our group in this area covering the international context that... more
The last decade has witnessed the blooming of nucleic acids for therapeutic and diagnostic applications. In the present article, we describe the most important results from our group in this area covering the international context that surrounded this research. These include the study of modifications at the terminal and internal positions of siRNA duplexes to enhance nuclease resistance, increase loading of the antisense strand to RISC and avoid side effects such as activation of immune response and sense strand misloading. Then, we describe the design of novel lipid, carbohydrate and peptide conjugates to enhance cellular uptake. Finally, we describe the use of nanostructures for drug delivery and for the controlled deposition of matter on surfaces. We invite the readers to submerge into a highly interdisciplinary discipline that combines organic chemistry, biochemical assays, pharmacology issues as well as materials chemistry and structural studies in order to increase the applications of nucleic acids.
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Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a... more
Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates ...
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Green fluorescent protein (GFP) is a widely used scaffold for protein-based targeted nanomedicines because of its high biocompatibility, biological neutrality and outstanding structural stability. However, being immunogenicity a major... more
Green fluorescent protein (GFP) is a widely used scaffold for protein-based targeted nanomedicines because of its high biocompatibility, biological neutrality and outstanding structural stability. However, being immunogenicity a major concern in the development of drug carriers, the use of exogenous proteins such as GFP in clinics might be inadequate. Here we report a human nidogen-derived protein (HSNBT), rationally designed to mimic the structural and functional properties of GFP as a scaffold for nanomedicine. For that, a GFP-like β-barrel, containing the G2 domain of the human nidogen, has been rationally engineered to obtain a biologically neutral protein that self-assembles as 10nm-nanoparticles. This scaffold is the basis of a humanized nanoconjugate, where GFP, from the well-characterized protein T22-GFP-H6, has been substituted by the nidogen-derived GFP-like HSNBT protein. The resulting construct T22-HSNBT-H6, is a humanized CXCR4-targeted nanoparticle that selectively delivers conjugated genotoxic Floxuridine into cancer CXCR4+ cells. Indeed, the administration of T22-HSNBT-H6-FdU in a CXCR4-overexpressing colorectal cancer mouse model results in an even more efficient selective antitumoral effect than that shown by its GFP-counterpart, in absence of systemic toxicity. Therefore, the newly developed GFP-like protein scaffold appears as an ideal candidate for the development of humanized protein nanomaterials and successfully supports the tumor-targeted nanoscale drug T22-HSNBT-H6-FdU.
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Pneumocystis pneumonia (PcP) is a disease produced by the opportunistic infection of the fungus Pneumocystis jirovecii. As delayed or unsuitable treatments increase the risk of mortality, the development of rapid and accurate diagnostic... more
Pneumocystis pneumonia (PcP) is a disease produced by the opportunistic infection of the fungus Pneumocystis jirovecii. As delayed or unsuitable treatments increase the risk of mortality, the development of rapid and accurate diagnostic tools for PcP are of great importance. Unfortunately, current standard methods present severe limitations and are far from adequate. In this work, a time-competitive, sensitive and selective biosensor based on DNA-gated nanomaterials for the identification of P. jirovecii is presented. The biosensor consists of a nanoporous anodic alumina (NAA) scaffold which pores are filled with a dye reporter and capped with specific DNA oligonucleotides. In the presence of P. jirovecii genomic DNA, the gated biosensor is open, and the cargo is delivered to the solution where it is monitored through fluorescence spectroscopy. The use of capping oligonucleotides able to form duplex or triplex with P. jirovecii DNA is studied. The final diagnostic tool shows a limit...