Publications by authors named "Teresa Sierra"

39 Publications

Fluorescence Liquid Biopsy for Cancer Detection Is Improved by Using Cationic Dendronized Hyperbranched Polymer.

Int J Mol Sci 2021 Jun 17;22(12). Epub 2021 Jun 17.

Joint Units IQFR-CSIC-BIFI and GBsC-CSIC-BIFI, Institute of Biocomputation and Physics of Complex Systems (BIFI), Universidad de Zaragoza, 50018 Zaragoza, Spain.

(1) Background: Biophysical techniques applied to serum samples characterization could promote the development of new diagnostic tools. Fluorescence spectroscopy has been previously applied to biological samples from cancer patients and differences from healthy individuals were observed. Dendronized hyperbranched polymers (DHP) based on bis(hydroxymethyl)propionic acid (bis-MPA) were developed in our group and their potential biomedical applications explored. (2) Methods: A total of 94 serum samples from diagnosed cancer patients and healthy individuals were studied (20 pancreatic ductal adenocarcinoma, 25 blood donor, 24 ovarian cancer, and 25 benign ovarian cyst samples). (3) Results: Fluorescence spectra of serum samples (fluorescence liquid biopsy, FLB) in the presence and the absence of DHP-bMPA were recorded and two parameters from the signal curves obtained. A secondary parameter, the fluorescence spectrum score (FS), was calculated, and the diagnostic model assessed. For pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer, the classification performance was improved when including DHP-bMPA, achieving high values of statistical sensitivity and specificity (over 85% for both pathologies). (4) Conclusions: We have applied FLB as a quick, simple, and minimally invasive promising technique in cancer diagnosis. The classification performance of the diagnostic method was further improved by using DHP-bMPA, which interacted differentially with serum samples from healthy and diseased subjects. These preliminary results set the basis for a larger study and move FLB closer to its clinical application, providing useful information for the oncologist during patient diagnosis.
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http://dx.doi.org/10.3390/ijms22126501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234380PMC
June 2021

Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic-Linear-Dendritic Block Copolymers.

Int J Mol Sci 2021 May 14;22(10). Epub 2021 May 14.

Grupo de Terapia Génica y Celular, Instituto Aragonés de Ciencias de la Salud (IACS/IIS-Aragon), 50009 Zaragoza, Spain.

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic F127 hybrid dendritic-linear-dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2'-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2'-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.
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http://dx.doi.org/10.3390/ijms22105223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156097PMC
May 2021

Janus Dendrimers to Assess the Anti-HCV Activity of Molecules in Cell-Assays.

Pharmaceutics 2020 Nov 7;12(11). Epub 2020 Nov 7.

Instituto de Nanociencia y Materiales de Aragón (INMA), University of Zaragoza-CSIC, Pedro Cerbuna 12, 50009 Zaragoza, Spain.

The use of nanocarriers has been revealed as a valid strategy to facilitate drug bioavailability, and this allows for expanding the drug libraries for the treatment of certain diseases such as viral diseases. In the case of Hepatitis C, the compounds iopanoic acid and 3,3',5-triiodothyroacetic acid (or tiratricol) were identified in a primary screening as bioactive allosteric inhibitors of viral NS3 protease, but they did not exhibit accurate activity inhibiting viral replication in cell-based assays. In this work, dendritic nanocarriers are proposed due to their unique properties as drug delivery systems to rescue the bioactivity of these two drugs. Specifically, four different amphiphilic Janus dendrimers synthesized by combining 2,2'-(hydroxymethyl)propionic acid (-MPA) and 2,2'-(glyciloxy)propionic acid (-GMPA) functionalized with either hydrophilic or lipophilic moieties at their periphery were used to entrap iopanoic acid and tiratricol. Interestingly, differences were found in the loading efficiencies depending on the dendrimer design, which also led to morphological changes of the resulting dendrimer aggregates. The most remarkable results consist of the increased water solubility of the bioactive compounds within the dendrimers and the improved antiviral activity of some of the dendrimer/drug aggregates, considerably improving antiviral activity in comparison to the free drugs. Moreover, imaging studies have been developed in order to elucidate the mechanism of cellular internalization.
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http://dx.doi.org/10.3390/pharmaceutics12111062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695217PMC
November 2020

Promising nanomaterials in the fight against malaria.

J Mater Chem B 2020 10;8(41):9428-9448

Instituto de Nanociencia y Materiales de Aragón (INMA), Dep. Química Orgánica-Facultad de Ciencias, CSIC-Universidad de Zaragoza, 50009 Zaragoza, Spain.

For more than one hundred years, several treatments against malaria have been proposed but they have systematically failed, mainly due to the occurrence of drug resistance in part resulting from the exposure of the parasite to low drug doses. Several factors are behind this problem, including (i) the formidable barrier imposed by the Plasmodium life cycle with intracellular localization of parasites in hepatocytes and red blood cells, (ii) the adverse fluidic conditions encountered in the blood circulation that affect the interaction of molecular components with target cells, and (iii) the unfavorable physicochemical characteristics of most antimalarial drugs, which have an amphiphilic character and can be widely distributed into body tissues after administration and rapidly metabolized in the liver. To surpass these drawbacks, rather than focusing all efforts on discovering new drugs whose efficacy is quickly decreased by the parasite's evolution of resistance, the development of effective drug delivery carriers is a promising strategy. Nanomaterials have been investigated for their capacity to effectively deliver antimalarial drugs at local doses sufficiently high to kill the parasites and avoid drug resistance evolution, while maintaining a low overall dose to prevent undesirable toxic side effects. In recent years, several nanostructured systems such as liposomes, polymeric nanoparticles or dendrimers have been shown to be capable of improving the efficacy of antimalarial therapies. In this respect, nanomaterials are a promising drug delivery vehicle and can be used in therapeutic strategies designed to fight the parasite both in humans and in the mosquito vector of the disease. The chemical analyses of these nanomaterials are essential for the proposal and development of effective anti-malaria therapies. This review is intended to analyze the application of nanomaterials to improve the drug efficacy on different stages of the malaria parasites in both the human and mosquito hosts.
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http://dx.doi.org/10.1039/d0tb01398fDOI Listing
October 2020

Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application.

Pharmaceutics 2020 Aug 29;12(9). Epub 2020 Aug 29.

Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain.

Heparin is a promising antimalarial drug due to its activity in inhibiting invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determined, in in vitro cultures, the antimalarial activity of heparin-derived structures of different origins and sizes, to obtain formulations having a good balance of in vitro safety (neither cytotoxic nor hemolytic), low anticoagulant activity (≤23 IU/mL according to activated partial thromboplastin time assays), and not too low antimalarial activity (IC50 at least around 100 µg/mL). This led to the selection of five chemically modified heparins according to the parameters explored, i.e., chain length, sulfation degree and position, and glycol-split, and whose in vivo toxicity indicated their safety for mice up to an intravenous dose of 320 mg/kg. The in vivo antimalarial activity of the selected formulations was poor as a consequence of their short blood half-life. The covalent crosslinking of heparin onto the surface of polyethylene glycol-containing liposomes did not affect its antimalarial activity in vitro and provided higher initial plasma concentrations, although it did not increase mean circulation time. Finding a suitable nanocarrier to impart long blood residence times to the modified heparins described here will be the next step toward new heparin-based antimalarial strategies.
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http://dx.doi.org/10.3390/pharmaceutics12090825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557421PMC
August 2020

On the Structure and Chiral Aggregation of Liquid Crystalline Star-Shaped Triazines H-Bonded to Benzoic Acids.

Chemistry 2020 Nov 19;26(66):15313-15322. Epub 2020 Oct 19.

Departamento de Química Orgánica, Instituto de Nanociencia y Materiales de Aragón (INMA), Universidad de Zaragoza-CSIC, 50009, Zaragoza, Spain.

The ability of a star-shaped tris(triazolyl)triazine derivative to hierarchically build supramolecular chiral columnar organizations through the formation of H-bonded complexes with benzoic acids was studied from a theoretical and experimental point of view. The combined study has been done at three different levels including the study of the structure of the triazine core, the association with benzoic acids in stoichiometry 1:3, and the assembly of 1:3 complexes in helical aggregates. Although the star-shaped triazine core crystallizes in a non-C conformation, the C -symmetric conformation is theoretically predicted to be more stable and gives rise to a favorable C supramolecular 1:3 complex upon the interaction with three benzoic acids in their voids. In addition, calculations at different levels (DFT, PM7, and MM3) for the 1:3 host-guest complex predict the formation of large stable columnar helical aggregates stabilized by the compact packing of the interstitial acids by π-π and CH⋅⋅⋅π interactions. The acids restrict the movement of the the star-shaped triazine cores along the stacking axis causing a template effect in the self-assembly of the complex. Theoretical predictions correlate with experimental results, since the interaction with achiral or chiral 3,4,5-(4-alkoxybenzyloxy)benzoic acids gives rise to supramolecular complexes that organize in bulk hexagonal columnar mesophases stable at room temperature with intracolumnar order. The existence of supramolecular chirality in the mesophase was determined for complexes formed by acids derived from (S)-2-octanol. Chiral aggregation was also evidenced for complexes formed in dodecane.
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http://dx.doi.org/10.1002/chem.202001271DOI Listing
November 2020

Assessing Toxicokinetic Uncertainty and Variability in Risk Prioritization.

Toxicol Sci 2019 12;172(2):235-251

National Center for Computational Toxicology.

High(er) throughput toxicokinetics (HTTK) encompasses in vitro measures of key determinants of chemical toxicokinetics and reverse dosimetry approaches for in vitro-in vivo extrapolation (IVIVE). With HTTK, the bioactivity identified by any in vitro assay can be converted to human equivalent doses and compared with chemical intake estimates. Biological variability in HTTK has been previously considered, but the relative impact of measurement uncertainty has not. Bayesian methods were developed to provide chemical-specific uncertainty estimates for 2 in vitro toxicokinetic parameters: unbound fraction in plasma (fup) and intrinsic hepatic clearance (Clint). New experimental measurements of fup and Clint are reported for 418 and 467 chemicals, respectively. These data raise the HTTK chemical coverage of the ToxCast Phase I and II libraries to 57%. Although the standard protocol for Clint was followed, a revised protocol for fup measured unbound chemical at 10%, 30%, and 100% of physiologic plasma protein concentrations, allowing estimation of protein binding affinity. This protocol reduced the occurrence of chemicals with fup too low to measure from 44% to 9.1%. Uncertainty in fup was also reduced, with the median coefficient of variation dropping from 0.4 to 0.1. Monte Carlo simulation was used to propagate both measurement uncertainty and biological variability into IVIVE. The uncertainty propagation techniques used here also allow incorporation of other sources of uncertainty such as in silico predictors of HTTK parameters. These methods have the potential to inform risk-based prioritization based on the relationship between in vitro bioactivities and exposures.
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http://dx.doi.org/10.1093/toxsci/kfz205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136471PMC
December 2019

On-Surface Crystallization Behaviors of H-Bond Donor-Acceptor Complexes at Liquid/Solid Interfaces.

Langmuir 2019 Jul 26;35(27):8935-8942. Epub 2019 Jun 26.

Center of Materials Science and Optoelectronics Engineering , University of Chinese Academy of Sciences , Beijing 100049 , P. R. China.

Two-dimensional (2D) crystallization behaviors of A-TPC ( n = 4, 6, 10), T3C, and hydrogen-bonded complexes [email protected] ( n = 4, 6, 10) are investigated by means of scanning tunneling microscope (STM) observations and density functional theory (DFT) calculations. The STM observations reveal that A-TPC, A-TPC, and T3C self-organize into dumbbell-shaped structures, well-ordered bright arrays, and zigzag structures, respectively. Interestingly, [email protected] fails to form the cage-ball structure, whereas [email protected] and [email protected] co-assemble into cage-ball structures with the same lattice parameters. The filling rates of the balls of these two kinds of cage-ball structures depend heavily on the deposition sequence. As a result, the filling rates of the cages in T3C/A-TPC ( n = 4, 6) with deposition of T3C anterior to A-TPC are higher than those in A-TPC /T3C ( n = 4, 6) with the opposite deposition sequence. Furthermore, lattice defects formed by T3C coexist with the cage-ball structures. Moreover, the similar energy per unit area of lattice defects (-0.101 kcal mol Å) and the two cage-ball networks (-0.194 and -0.208 kcal mol Å, respectively), illustrating the similar stabilities of lattice defects and cage-ball networks, demonstrates the rationality of lattice defects. Combining STM investigations and DFT calculations, this work could provide a useful approach to investigate the 2D crystallization mechanisms of supramolecular liquid crystals on surfaces.
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http://dx.doi.org/10.1021/acs.langmuir.9b01350DOI Listing
July 2019

Micelle carriers based on dendritic macromolecules containing bis-MPA and glycine for antimalarial drug delivery.

Biomater Sci 2019 Mar;7(4):1661-1674

Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain.

Biomaterials for antimalarial drug transport still need to be investigated in order to attain nanocarriers that can tackle essential issues related to malaria treatment, e.g. complying with size requirements and targeting specificity for their entry into Plasmodium-infected red blood cells (pRBCs), and limiting premature drug elimination or drug resistance evolution. Two types of dendritic macromolecule that can form vehicles suitable for antimalarial drug transport are herein explored. A new hybrid dendritic-linear-dendritic block copolymer based on Pluronic® F127 and amino terminated 2,2'-bis(glycyloxymethyl)propionic acid dendrons with a poly(ester amide) skeleton (HDLDBC-bGMPA) and an amino terminated dendronized hyperbranched polymer with a polyester skeleton derived from 2,2'-bis(hydroxymethyl)propionic acid (DHP-bMPA) have provided self-assembled and unimolecular micelles. Both types of micelle carrier are biocompatible and exhibit appropriate sizes to enter into pRBCs. Targeting studies have revealed different behaviors for each nanocarrier that may open new perspectives for antimalarial therapeutic approaches. Whereas DHP-bMPA exhibits a clear targeting specificity for pRBCs, HDLDBC-bGMPA is incorporated by all erythrocytes. It has also been observed that DHP-bMPA and HDLDBC-bGMPA incorporate into human umbilical vein endothelial cells with different subcellular localization, i.e. cytosolic and nuclear, respectively. Drug loading capacity and encapsulation efficiencies for the antimalarial compounds chloroquine, primaquine and quinacrine ranging from 30% to 60% have been determined for both carriers. The resulting drug-loaded nanocarriers have been tested for their capacity to inhibit Plasmodium growth in in vitro and in vivo assays.
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http://dx.doi.org/10.1039/c8bm01600cDOI Listing
March 2019

Manipulation of Supramolecular Columnar Structures of H-Bonded Donor-Acceptor Units through Geometrical Nanoconfinement.

Chemphyschem 2019 03 27;20(6):890-897. Epub 2019 Feb 27.

Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.

Ambipolar organic semiconductors are considered promising for organic electronics because of their interesting electric properties. Many hurdles remain yet to be overcome before they can be used for practical applications, especially because their orientation is hard to control. We demonstrate a method to control the orientation of columnar structures based on a hydrogen (H)-bonded donor-acceptor complex between a star-shaped tris(triazolyl)triazine and triphenylene-containing benzoic acid, using physicochemical nanoconfinement. The molecular configuration and supramolecular columnar assemblies in a one-dimensional porous anodic aluminium oxide (AAO) film were dramatically modulated by controlling the pore-size and by chemical modification of the inner surface of the porous AAO film. In situ experiments using grazing-incidence X-ray diffraction (GIXRD) were carried out to investigate the structural evolution produced at the nanometer scale by varying physicochemical conditions. The resulting highly ordered nanostructures may open a new pathway to effectively control the alignment of liquid crystal ambipolar semiconductors.
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http://dx.doi.org/10.1002/cphc.201801042DOI Listing
March 2019

Self-Assembling Hybrid Linear-Dendritic Block Copolymers: The Design of Nano-Carriers for Lipophilic Antitumoral Drugs.

Nanomaterials (Basel) 2019 Jan 29;9(2). Epub 2019 Jan 29.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón (ICMA), Facultad de Ciencias, CSIC, Universidad de Zaragoza, 50009 Zaragoza, Spain.

Two series of amphiphilic block copolymers with a hybrid linear-dendritic structure are presented. The compounds consisted of a hydrophilic poly (ethylene glycol) (PEG) block and a 2,2'-bis(hydroxymethyl)propionic acid (bis-MPA) dendron functionalized with stearic acid chains that impart a hydrophobic nature to the block. Different self-assembled nanostructures with a hydrophobic interior and a hydrophilic external part were obtained depending on the length of the PEG chain ( = 2000 and = 5000) and the generation of the bis-MPA dendron. The materials were characterized by transmission electron microscopy (TEM). The shapes of the aggregates ranged from spherical or cylindrical micelles to flexible bilayers. The hydrophobic core enabled these nanostructures to encapsulate the water-insoluble drug plitidepsin. The efficacy of these new plitidepsin-containing carriers was evaluated in four cancer cell-lines and they showed similar anticancer activity to the current standard drug formulation.
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http://dx.doi.org/10.3390/nano9020161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409548PMC
January 2019

Inspecting the Electronic Architecture and Semiconducting Properties of a Rosette-Like Supramolecular Columnar Liquid Crystal.

Chemistry 2018 Nov 31;24(66):17459-17463. Epub 2018 Oct 31.

Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Ciencia de Materiales de Aragón (ICMA), Universidad de Zaragoza-CSIC., 50009, Zaragoza, Spain.

Computational and experimental studies unravel the structural and electronic properties of a novel supramolecular liquid crystal built through a hierarchical assembly process resulting in an H-bonded melamine rosette decorated with peripheral triphenylenes. The six-fold symmetry of the mesogen facilitates the formation of a highly organized hexagonal columnar mesophase stable at room temperature. X-ray diffraction and electron density maps confirm additional intra- and intercolumn segregation of functional subunits, and this paves the way for 1D charge transport. Indeed, hole mobility has been measured and found to be higher than for related mesogens. DFT calculations of HOMO and LUMO levels and parameters such as reorganization energy and transfer integral of the rosette structure have been achieved, and not only validate the columnar organization but also establish the way it translates into a favorable electronic architecture and molecular orbital interactions to promote charge carrier mobility.
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http://dx.doi.org/10.1002/chem.201804748DOI Listing
November 2018

Cationic poly(ester amide) dendrimers: alluring materials for biomedical applications.

J Mater Chem B 2018 Jun 31;6(23):3956-3968. Epub 2018 May 31.

Instituto de Nanociencia de Aragón (INA), Universidad de Zaragoza, Spain.

Novel cationic poly(ester amide) dendrimers have been synthesized by copper(i) azide-alkyne cycloaddition (CuAAC) of a tripropargylamine core and azide-terminated dendrons, in turn prepared by iterative amide coupling of the new monomer 2,2'-bis(glycyloxymethyl)propionic acid (bis-GMPA). The alternation of ester and amide groups provided a dendritic scaffold that was totally biocompatible and degradable in aqueous media at physiological and acidic pH. The tripodal dendrimers naturally formed rounded aggregates with a drug that exhibited low water solubility, camptothecin, thus improving its cell viability and anti-Hepatitis C virus (anti-HCV) activity. The presence of numerous peripheral cationic groups enabled these dendrimers to form dendriplexes with both pDNA and siRNA and they showed effective in vitro siRNA transfection in tumoral and non-tumoral cell lines.
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http://dx.doi.org/10.1039/c8tb00639cDOI Listing
June 2018

DNA Transfection to Mesenchymal Stem Cells Using a Novel Type of Pseudodendrimer Based on 2,2-Bis(hydroxymethyl)propionic Acid.

Bioconjug Chem 2017 04 13;28(4):1135-1150. Epub 2017 Mar 13.

Departamento de Quı́mica Orgánica, Facultad de Ciencias, Instituto de Nanociencia de Aragón, Universidad de Zaragoza , Zaragoza 50009, Spain.

In the search for effective vehicles to carry genetic material into cells, we present here new pseudodendrimers that consist of a hyperbranched polyester core surrounded by amino-terminated 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) dendrons. The pseudodendrimers are readily synthesized from commercial hyperbranched bis-MPA polyesters of the second, third, and fourth generations and third-generation bis-MPA dendrons, bearing eight peripheral glycine moieties, coupled by the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). This approach provides globular macromolecular structures bearing 128, 256, and 512 terminal amino groups, and these can complex pDNA. The toxicity of the three pseudodendrimers was studied on two cell lines, mesenchymal stem cells, and HeLa, and it was demonstrated that these compounds do not affect negatively cell viability up to 72 h. The complexation with DNA was investigated in terms of N-to-P ratio and dendriplex stability. The three generations were found to promote internalizing of pDNA into mesenchymal stem cells (MSCs), and their transfection capacity was compared with two nonviral commercial transfection agents, Lipofectamine and TransIT-X2. The highest generations were able to transfect these cells at levels comparable to both commercial reagents.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00037DOI Listing
April 2017

H-Bonded Donor-Acceptor Units Segregated in Coaxial Columnar Assemblies: Toward High Mobility Ambipolar Organic Semiconductors.

J Am Chem Soc 2016 09 14;138(38):12511-8. Epub 2016 Sep 14.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón (ICMA), Facultad de Ciencias, Universidad de Zaragoza-CSIC , 50009 Zaragoza, Spain.

A novel approach to ambipolar semiconductors based on hydrogen-bonded complexes between a star-shaped tris(triazolyl)triazine and triphenylene-containing benzoic acids is described. The formation of 1:3 supramolecular complexes was evidenced by different techniques. Mesogenic driving forces played a decisive role in the formation of the hydrogen-bonded complexes in the bulk. All of the complexes formed by nonmesogenic components gave rise to hexagonal columnar (Colh) liquid crystal phases, which are stable at room temperature. In all cases, X-ray diffraction experiments supported by electron density distribution maps confirmed triphenylene/tris(triazolyl)triazine segregation into hexagonal sublattices and lattices, respectively, as well as remarkable intracolumnar order. These highly ordered nanostructures, obtained by the combined supramolecular H-bond/columnar liquid crystal approach, yielded donor/acceptor coaxial organization that is promising for the formation of ambipolar organic semiconductors with high mobilities, as indicated by charge transport measurements.
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http://dx.doi.org/10.1021/jacs.6b06792DOI Listing
September 2016

Polar Switching in a Lyotropic Columnar Nematic Liquid Crystal Made of Bowl-Shaped Molecules.

Adv Mater 2015 Aug 15;27(29):4280-4. Epub 2015 Jun 15.

Departamento de Química Orgánica, Universidad Autónoma de Madrid, 28049, Madrid, Spain.

A polar response in a lyotropic columnar nematic material is reported. The material accommodates bowl-shaped molecules with strong axial dipole moments in column segments without head-to-tail invariance. Optical second-harmonic-generation methods confirm that the nematic columns align unidirectionally under an applied electric field and the material develops remnant macroscopic polarization observable for hours. The switching takes place by a flip of the columns.
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http://dx.doi.org/10.1002/adma.201500238DOI Listing
August 2015

Shell Cross-Linked Polymeric Micelles as Camptothecin Nanocarriers for Anti-HCV Therapy.

Macromol Biosci 2015 Oct 5;15(10):1381-91. Epub 2015 Jun 5.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón (ICMA) - Universidad de Zaragoza-CSIC, 50009, Zaragoza, Spain.

A suitable carrier for camptothecin to act as therapy against the hepatitis C virus is presented. The carrier relies on an amphiphilic hybrid dendritic-linear-dendritic block copolymer, derived from pluronic F127 and bis-MPA dendrons, that forms micelles in aqueous solution. The dendrons admit the incorporation of multiple photoreactive groups that allow the clean and effective preparation of covalently cross-linked polymeric micelles (CLPM), susceptible of loading hydrophilic and lipophilic molecules. Cell-uptake experiments using a newly designed fluorophore, derived from rhodamine B, demonstrate that the carrier favors the accumulation of its cargo within the cell. Furthermore, loaded with camptothecin, it is efficient in fighting against the hepatitis C virus while shows lower cytotoxicity than the free drug.
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http://dx.doi.org/10.1002/mabi.201500094DOI Listing
October 2015

Supramolecular columnar liquid crystals formed by hydrogen bonding between a clicked star-shaped s-triazine and benzoic acids.

Chemistry 2015 Jun 11;21(24):8859-66. Epub 2015 May 11.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza (Spain).

A star-shaped tris(triazolyl)triazine is shown to establish hydrogen-bond interactions with polycatenar benzoic acids. The formation of hydrogen-bonded triazine/acid complexes has been demonstrated both in solution and in bulk by different techniques. The complexes, mainly formed by nonmesogenic components, all show enantiotropic hexagonal columnar mesomorphism, which relies on the formation of hydrogen-bond complexes in a triazine/acid ratio of 1:3. This approach combines the straightforward synthesis of a nonmesomorphic triazine core by click chemistry, and the preparation of a supramolecular complex, providing a much more convenient route than covalent synthesis to modify the periphery of triazine discotics and thus to modulate their functionality.
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http://dx.doi.org/10.1002/chem.201500477DOI Listing
June 2015

New Ionic bis-MPA and PAMAM Dendrimers: A Study of Their Biocompatibility and DNA-Complexation.

Macromol Biosci 2015 May 28;15(5):657-67. Epub 2015 Jan 28.

Departamento de Química Orgánica-Instituto de Nanociencia de Aragón (INA), University of Zaragoza, C/Pedro Cerbuna 12, 50009, Zaragoza, Spain.

Herein, the synthesis of five novel ionic dendrimers and their evaluation as biological carriers is reported. The compounds include an ionic bis-MPA dendrimer and four PAMAM dendrimers of different generations decorated with negatively charged hydrophilic chains of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid as counter ions in order to increase their biocompatibility. The ionic dendrimers derived from bis-MPA have a low cytotoxicity at 0.5 mg · mL(-1) against U251MG and are even less toxic against mesenchymal stem cells; however, the PAMAM derivatives show high cytotoxicity at the same concentration. The five compounds are able to form complexes with plasmid DNA at different N/P ratios. The cytotoxicity and complexation ability of the new dendrimers were also compared with jetPEI, a linear polyethylenimine derivative commercially available as transfection reagent. The results indicate that the cytotoxicity of the ionic PAMAM dendrimers remains as an important drawback, whereas the ionic I-bis-MPA compound exhibits a high ability to complex pDNA and very low toxicity compared with jetPEI.
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http://dx.doi.org/10.1002/mabi.201400422DOI Listing
May 2015

Self-organization of star-shaped columnar liquid crystals with a coaxial nanophase segregation revealed by a combined experimental and simulation approach.

Chem Commun (Camb) 2015 Feb;51(10):1811-4

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón (ICMA) - Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain.

Fully consistent X-ray data and molecular dynamics simulations on new star-shaped liquid crystals yield two nanosegregated architectures with a coaxial stacking of two functional discotic units: tris(triazolyl)triazine and triphenylene. Analysis of lattice order along the principal axes reveals preferential staggered arrangement of the stacked molecules in the columnar assembly.
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http://dx.doi.org/10.1039/c4cc08602cDOI Listing
February 2015

Supermolecular columnar liquid-crystalline phosphorus dendrimers decorated with sulfonamide derivatives.

Chemistry 2014 Dec 21;20(51):17047-58. Epub 2014 Oct 21.

Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola, 08193 Barcelona (Spain).

A series of supermolecular liquid crystals has been synthesized by combining phosphorus dendrimers of the zero, first, and fourth generations with sulfonamide derivatives, thus generating dendromesogens bearing 6, 12, and 96 mesogenic units on their surfaces. The relevant reactions could be monitored by (1) H, (19) F, and (31) P{(1) H} NMR spectroscopies. The thermal and mesomorphic properties of the products have been studied by optical microscopy, differential scanning calorimetry, and X-ray diffraction. All of the new macromolecules prepared in this work have been found to show mesomorphic properties over a wide temperature range; moreover, for all of the compounds, the columnar mesophases observed were maintained or vitrified at room temperature. On increasing the generation of these dendromesogens, mesophases appear at lower temperatures and remain stable over a wider temperature interval. In all cases, on the basis of X-ray analysis, a cylindrical symmetry of the molecules can be proposed to promote the supramolecular columnar arrangement observed in the mesophases. In this type of model, the height of the dendrimer clearly increases with increasing dendrimer generation, whereas its cross- sectional area increases only slightly, probably due to compression of the highly hyperbranched structures as a consequence of their progressive steric constraints. The mesomorphic arrangement is governed by the peripheral sulfonamide units.
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http://dx.doi.org/10.1002/chem.201402539DOI Listing
December 2014

Multifunctional supramolecular dendrimers with an s-triazine ring as the central core: liquid crystalline, fluorescence and photoconductive properties.

Chemistry 2014 Aug 17;20(32):10027-37. Epub 2014 Jun 17.

Departamento de Química Orgánica, Facultad de Ciencias-Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza (Spain).

Novel liquid crystal (LC) dendrimers have been synthesised by hydrogen bonding between an s-triazine as the central core and three peripheral dendrons derived from bis(hydroxymethyl)propionic acid. Symmetric acid dendrons bearing achiral promesogenic units have been synthesised to obtain 3:1 complexes with triazine that exhibit LC properties. Asymmetric dendrons that combine the achiral promesogenic unit and an active moiety derived from coumarin or pyrene structures have been synthesised in order to obtain dendrimers with photophysical and electrochemical properties. The formation of the complexes was confirmed by IR and NMR spectroscopy data. The liquid crystalline properties were investigated by differential scanning calorimetry, polarising optical microscopy and X-ray diffractometry. All complexes displayed mesogenic properties, which were smectic in the case of symmetric dendrons and their complexes and nematic in the case of asymmetric dendrons and their dendrimers. A supramolecular model for the lamellar mesophase, based mainly on X-ray diffraction studies, is proposed. The electrochemical behaviour of dendritic complexes was investigated by cyclic voltammetry. The UV/Vis absorption and emission properties of the compounds and the photoconductive properties of the dendrons and dendrimers were also investigated.
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http://dx.doi.org/10.1002/chem.201402646DOI Listing
August 2014

Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs.

Biomaterials 2014 Sep 13;35(27):7940-50. Epub 2014 Jun 13.

Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain. Electronic address:

It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest. With this objective, dendritic derivatives based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Pluronic(®) polymers have been herein explored. Four different dendritic derivatives have been tested for their capacity to encapsulate the antimalarial drugs chloroquine (CQ) and primaquine (PQ), their specific targeting to Plasmodium-infected red blood cells (pRBCs), and their antimalarial activity in vitro against the human pathogen Plasmodium falciparum and in vivo against the rodent malaria species Plasmodium yoelii. The results obtained have allowed the identification of two dendritic derivatives exhibiting specific targeting to pRBCs vs. non-infected RBCs, which reduce the in vitro IC50 of CQ and PQ by ca. 3- and 4-fold down to 4.0 nm and 1.1 μm, respectively. This work on the application of dendritic derivatives to antimalarial targeted drug delivery opens the way for the use of this new type of chemicals in future malaria eradication programs.
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http://dx.doi.org/10.1016/j.biomaterials.2014.05.061DOI Listing
September 2014

Self-assembly modulation in ionic PAMAM derivatives.

Soft Matter 2014 Jan;10(2):281-9

Departamento de Química Orgánica, Facultad de Ciencias-Instituto de Ciencia de Materiales de Aragón, CSIC, Pedro Cerbuna 12, 50009-Zaragoza, Spain.

The self-assembly behaviour both in the bulk and water of a series of amphiphilic dendrimers constituted by second generation PAMAM ionically functionalized with different amounts of myristic acid is shown here. The number of acids in the dendrimer determines the liquid-crystal properties and the structural parameters of their supramolecular organization. Most of them present mesomorphism, organizing in a smectic A mesophase, with a layer spacing decreasing when increasing the number of acids. All these dendrimers form well-defined nanoobjects in water. Micelles and broken lamellae have been found for compounds with low acid contents. In contrast, dendrimers with higher fatty acid contents self-assemble forming nanospheres with a lamellar nanostructure. All compounds are able to trap the hydrophobic molecule 9,10-diphenylanthracene independent of the acid contents. Interestingly, the trapped hydrophobic molecule dominates the self-assembly trend of the dendrimers with low acid contents and thus different nanoobjects are found after the encapsulation.
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http://dx.doi.org/10.1039/c3sm52393dDOI Listing
January 2014

Nanostructured liquid-crystalline particles for drug delivery.

Expert Opin Drug Deliv 2014 Apr 3;11(4):547-64. Epub 2014 Feb 3.

Universidad de Zaragoza, Instituto de Nanociencia de Aragón , Zaragoza , Spain.

Introduction: Nanostructured lyotropic liquid crystal particles (LLC NPs) have proven to be extremely useful tools for applications in drug delivery. These structured nanoparticles are formed by amphiphilic molecules and contain internal water channels, which are not in contact with external water, and where polar drugs can situate; on the other hand, apolar drugs can be loaded in the lipophilic part of the structure and the amphiphilic drugs can locate at the polar/apolar interfaces.

Areas Covered: A revision of the most relevant results published in the field of LLC NPs has been made. The first section discusses the most common compounds used in these nanoparticles and their preparation and characterization. A summary of recent and relevant results including the composition and type of nanoparticles used, the illness treated, the administration via and some special features in each case have been summarized in a table.

Expert Opinion: LLC NPs are highly versatile drug delivery systems, which can be applied by topical, oral and intravenous treatments. Especially relevant is their use for the release of anticancer drugs, biomolecules and vaccines. Nevertheless a number of critical points need to be solved in order to attain practical applications.
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http://dx.doi.org/10.1517/17425247.2014.884556DOI Listing
April 2014

Liquid crystal organization of self-assembling cyclic peptides.

Chem Commun (Camb) 2014 Jan 27;50(6):688-90. Epub 2013 Nov 27.

Departamento de Química Orgánica, Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela (USC), Campus Vida, 15782, Santiago de Compostela, Spain.

Self-assembling cyclic peptides decorated with mesogens form porous columnar mesophases in which, depending on the number of hydrocarbon chains, double or single channels are formed along each column.
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http://dx.doi.org/10.1039/c3cc47400cDOI Listing
January 2014

NMR spectroscopic study of the self-aggregation of 3-hexen-1,5-diyne derivatives.

Chemistry 2013 Jul 20;19(31):10271-9. Epub 2013 Jun 20.

Instituto de Nanociencia de Aragón, Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.

The self-assembly of polycatenar molecules derived from 1,6-diphenyl-3,4-dipropyl-3-hexen-1,5-diyne has been studied in detail by solution NMR spectroscopy. The analysis of the concentration- and temperature-dependent evolution of the chemical shifts and the diffusion coefficients in [D12]cyclohexane agrees well with an isodesmic model of association in this solvent. The association constants for the stacking and entropy and enthalpy of the process have been obtained. The driving force for the aggregation process is provided by a negative enthalpy (ΔH), which is partially compensated by a negative entropy (ΔS). A structural study of the self-assembly in solution has been carried out with the help of NOESY NMR spectroscopic experiments.
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http://dx.doi.org/10.1002/chem.201204604DOI Listing
July 2013

A facile method to determine the absolute structure of achiral molecules: supramolecular-tilt structures.

Chemistry 2013 May 5;19(19):6044-51. Epub 2013 Mar 5.

Centro Universitario de la Defensa, Academia General Militar, 50090 Zaragoza, Spain.

Achiral compounds 4-methoxy-4-(p-methoxyphenyl)cyclohexanoneethylene ketal (2), 4-hydroxy-4-(p-methoxy phenyl)cyclohexanoneethylene ketal (3), and 3,5-dimethyl-4-nitropyrazole (4) crystallized in chiral structures and the samples showed an enantiomeric excess. We have determined the absolute structures of these compounds by using X-ray diffraction with copper radiation at low temperatures. Moreover, we have also established the prevalent absolute structures in these samples, by comparing their calculated and solid-state vibrational circular dichroism (VCD) spectra. The consistency of this method was confirmed by using (R,R)-2,8-diiodo-4,10-dimethyl-6 H,12H-5,11-methano-dibenzo[b,f][1,5]diazocine, Tröger's base, (R,R)-1, as a chiral compound of known absolute configuration.
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http://dx.doi.org/10.1002/chem.201204197DOI Listing
May 2013

Study of the photoinduced supramolecular chirality in columnar liquid crystals by infrared and VCD spectroscopies.

J Phys Chem B 2012 Apr 18;116(16):5090-6. Epub 2012 Apr 18.

Department of Physical and Analytical Chemistry, Experimental Sciences Faculty, University of Jaén , Campus Las Lagunillas, E-23071 Jaén, Spain.

IR and VCD spectroscopies are employed to clarify the molecular origins of supramolecular chirality in azobenzene-containing columnar liquid crystals. The different columnar mesomorphic assemblies, Colr and Colh, of an achiral and a chiral propeller-like hydrogen-bonded complex, respectively, are used for this study. The mesomorphic behavior of the achiral complex is studied here for the first time, and the structural parameters of its Colr mesophase are determined by X-ray diffraction. Both complexes bear azobenzene units and this makes it possible to implement photoresponsive columnar architectures, the chirality of which can be induced and modulated by irradiation with 488 nm circularly polarized light (CPL). Thin films of the respective rectangular and hexagonal columnar phases of these complexes have been processed in order to study the IR absorption spectra and the vibrational circular dichroism responses upon irradiation with CPL. These studies allow confirming that the outer part of the columns, consisting on azobenzene groups, is mainly involved in the photoinduced supramolecular chirality, rather than the inner part of the columns where a melamine core is located. This supports a structural model based on the helical disposition of the azobenzene groups along the stacked propeller-like complexes.
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http://dx.doi.org/10.1021/jp3017453DOI Listing
April 2012

Control of self-assembly of a 3-hexen-1,5-diyne derivative: toward soft materials with an aggregation-induced enhancement in emission.

J Am Chem Soc 2011 Jun 6;133(21):8110-3. Epub 2011 May 6.

Instituto de Nanociencia de Aragón (INA), Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.

The supramolecular architectures of a fluorophore are controlled through the design of a conjugated polycatenar molecule, the self-assembly of which can be addressed toward a columnar liquid-crystalline phase and organogels. Thus, depending on the environmental conditions for self-assembly, compound CA9 organizes into an unprecedented hexagonal columnar mesophase in the condensed state, in which half a molecule constitutes the slice of the column, or into a rectangular mesomorphic-like organization in the presence of apolar solvents such as cyclohexane and dodecane, at a concentration in which fibers form and gelling conditions are fulfilled. In this Col(r)-type arrangement, the organization within the columns depends on the solvent. All of the materials prepared show luminescence, and moreover, a remarkable 3-fold increase in fluorescence intensity was observed in going from the solution to the gel state.
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http://dx.doi.org/10.1021/ja2018898DOI Listing
June 2011
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