Judith Guasch

Bistability in Fc-PTM crystals: the role of intermolecular electrostatic interactions.

Fc-PTM is a valence tautomeric radical, where the ferrocene (Fc) group, a good electron donor, is linked by an ethylenic spacer to a perchlorotriphenylmethyl radical (PTM(*)), a good electron acceptor. In solution this compound exists mainly in the neutral Fc-PTM(*) form which can be photoexcited through an intramolecular electron transfer to the zwitterionic Fc(+*)-PTM(-) form. By contrast, in crystals of Fc-PTM at room temperature both the neutral and the zwitterionic forms coexist, pointing to a true bistability phenomenon. We rationalize these findings accounting for the role of intermolecular electrostatic interactions in Fc-PTM crystals. In fact the energy of the zwitterionic Fc(+*)-PTM(-) form is lowered in the crystal by attractive electrostatic intermolecular interactions and the cooperative nature of these interactions explains the observed coexistence of neutral Fc-PTM(*) and zwitterionic Fc(+*)-PTM(-) species. The temperature evolution of Mossbauer spectra of Fc-PTM is quantitatively reproduced adopting a bottom-up modeling strategy that combines a molecular model, derived from optical spectra of Fc-PTM in solution, with a model for intermolecular electrostatic interactions, supported by quantum-chemical calculations. Fc-PTM then offers the first experimental demonstration of bistability induced by electrostatic interactions in crystals of valence tautomeric donor-acceptor molecules.

Intra- and Intermolecular Charge Transfer in Aggregates of Tetrathiafulvalene-Triphenylmethyl Radical Derivatives in Solution

An extensive investigation of aggregation phenomena occurring in solution for a family of electron donor-acceptor derivatives, based on polychlorotriphenylmethyl radicals (PTM) linked via a vinylene-bridge to tetrathiafulvalene (TTF) units, is presented. A large set of temperature and/or concentration dependent optical absorption and electron spin resonance (ESR) spectra in a solution of dyads bearing different number of electrons and/or with a hydrogenated PTM residue offer reliable information on the formation of homo dimers and mixed valence dimers. The results shed light on the reciprocal influence of intramolecular electron transfer (IET) within a dyad and the intermolecular charge transfer (CT) occurring in a dimer between the TTF residues and are rationalized based on a theoretical model that describes both interactions.

Essential State Models for Solvatochromism in Donor-Acceptor Molecules : The Role of the Bridge

Essential state models are presented to discuss absorption spectra of two related donor-acceptor (DA) chromophores that show two solvatochromic bands in the near-infrared spectral region. The two-state model only accounts for the lowest energy band and results in a very small value of mu(0), the dipole moment associated with the D(+)A(-) state. The model is then extended to account for the active role of the bridge: the resulting three-state model satisfactorily reproduces the double solvatochromism, leading at the same time to a roughly doubled estimate of mu(0). This result, supported by a detailed analysis of an N-state model that explicitly accounts for bridge states, rationalizes the well-known discrepancy between the geometrical DA distance and the dipole length extracted from the analysis of optical spectra of DA chromophores as reflecting the active role of bridge states, not explicitly accounted for in essential state models.

A Molecular Toolkit for the Functionalization of Titanium‐Based Biomaterials That Selectively Control Integrin‐Mediated Cell Adhesion

We present a click chemistry-based molecular toolkit for the biofunctionalization of materials to selectively control integrin-mediated cell adhesion. To this end, α5β1-selective RGD peptidomimetics were covalently immobilized on Ti-based materials, and the capacity to promote the selective binding of α5β1 was evaluated using a solid-phase integrin binding assay. This functionalization strategy yielded surfaces with a nine-fold increased affinity for α5β1, in comparison to control samples, and total selectivity against the binding of the closely related integrin αvβ3. Moreover, our methodology allowed the screening of several phosphonic acid containing anchoring units to find the best spacer-anchor moiety required for establishing an efficient binding to titanium and to promote selective integrin binding. The integrin subtype specificity of these biofunctionalized surfaces was further examined in vitro by inducing selective adhesion of genetically modified fibroblasts, which express exclusively the α5β1 integrin. The versatility of our molecular toolkit was proven by shifting the cellular specificity of the materials from α5β1- to αvβ3-expressing fibroblasts by using an αvβ3-selective peptidomimetic as coating molecule. The results shown here represent the first functionalization of Ti-based materials with α5β1- or αvβ3-selective peptidomimetics that allow an unprecedented control to discriminate between α5β1- and αvβ3-mediated adhesions. The role of these two integrins in different biological events is still a matter of debate and is frequently discussed in literature. Thus, such bioactive titanium surfaces will be of great relevance for the study of integrin-mediated cell adhesion and the development of new biomaterials targeting specific cell types.

Electronic and Cytotoxic Properties of 2-Amino-naphtho[2,3-b]furan-4,9-diones

The electronic properties of a new set of cytotoxic 2-amino-naphtho[2,3-b]furan-4,9-dione derivatives (1-8) are evaluated. The electron delocalization of these compounds is described by means of their redox potentials and solvatochromic properties. The large solvatochromism of their intramolecular electron transfer band is analyzed using the linear solvation energy relationship method. In addition, this method determined the importance of the molecular environment, quantifying the interactions that compounds (1-8) establish with their surrounding media, with the capacity of acting as hydrogen-bond acceptors (HBA) and hydrogen-bond donors (HBD) and the dipolarity/polarizability being the most significant ones. As a result, a relationship between the electronic and the cytotoxic properties of these compounds is proposed.

Cooperativity from electrostatic interactions: understanding bistability in molecular crystals

A general model for explaining bistability in crystals of donor–acceptor (DA) molecules, associated with an intramolecular charge-transfer process, is thoroughly discussed. Specifically, an extension from the two- to the three-essential states model for D-bridge-A molecular units taking into account the active role of the bridge states in the charge-transfer process is proposed. We demonstrate that the phenomenon of bistability is so robust that it survives when such an extended model is adopted. Finally, we discuss the molecular and supramolecular requirements for the observation of bistability phenomena in molecular crystals.

The perchlorotriphenylmethyl (PTM) radical.

In spite of the considerable understanding and development of perchlorotriphenylmethyl (PTM) radical derivatives, the preparation of crystals of the pure unsubstituted PTM radical, C19Cl15, suitable for single-crystal X-ray diffraction has remained a challenge since its discovery, and only two studies dealing with the crystal structure of the unsubstituted PTM radical have been published. In one study, the radical forms clathrates with aromatic solvents [Veciana, Carilla, Miravitlles & Molins (1987). J. Chem. Soc. Chem. Commun. pp. 812-814], and in the other the structure was determined ab initio from powder X-ray diffraction data [Rius, Miravitlles, Molins, Crespo & Veciana (1990). Mol. Cryst. Liq. Cryst. 187, 155-163]. We report here the preparation of PTM crystals for single-crystal X-ray diffraction and their resolution. The structure, which shows monoclinic symmetry (C2/c), revealed a nonsymmetric molecular propeller conformation (D3 symmetry) caused by the steric strain between the ortho-Cl atoms, which protect the central C atom (sp(2)-hybridization and major spin density) and give high chemical and thermal persistence to the PTM. The supramolecular structure of PTM shows short Cl...Cl intermolecular interactions and can be described in terms of layers formed by rows of molecules positioned in a head-to-tail manner along the c axis.

Integrin-Assisted T-Cell Activation on Nanostructured Hydrogels

Adoptive cell therapy (ACT) has shown very promising results as treatment for cancer in a few clinical trials, such as the complete remissions of otherwise terminal leukemia patients. Nevertheless, the introduction of ACT into clinics requires overcoming not only medical but also technical challenges, such as the ex vivo expansion of large amounts of specific T-cells. Nanostructured surfaces represent a novel T-cell stimulation technique that enables us to fine-tune the density and orientation of activating molecules presented to the cells. In this work, we studied the influence of integrin-mediated cell-adhesion on T-cell activation, proliferation, and differentiation using nanostructured surfaces, which provide a well-defined system at the nanoscale compared with standard cultures. Specifically, we synthesized a polymeric polyethylene glycol (PEG) hydrogel cross-linked with two fibronectin-derived peptides, cyclic Arg-Gly-Asp (cRGD) and cyclic Leu-Asp-Val (cLDV), that are known to activate different integrins. Moreover, the hydrogels were decorated with a quasi-hexagonal array of gold nanoparticles (AuNPs) functionalized with the activating antibody CD3 to initiate T-cell activation. Both cLDV and cRGD hydrogels showed higher T-cell activation (CD69 expression and IL-2 secretion) than nonfunctionalized PEG hydrogels. However, only the cRGD hydrogels clearly supported proliferation giving a higher proportion of cells with memory (CD4+CD45RO+) than naı̈ve (CD4+CD45RA+) phenotypes when interparticle distances smaller than 150 nm were used. Thus, T-cell proliferation can be enhanced by the activation of integrins through the RGD sequence.

Combining adhesive nanostructured surfaces and costimulatory signals to increase T cell activation

Adoptive cell therapies are showing very promising results in the fight against cancer. However, these therapies are expensive and technically challenging in part due to the need of a large number of specific T cells, which must be activated and expanded in vitro. Here we describe a method to activate primary human T cells using a combination of nanostructured surfaces functionalized with the stimulating anti-CD3 antibody and the peptidic sequence arginine-glycine-aspartic acid, as well as costimulatory agents (anti-CD28 antibody and a cocktail of phorbol 12-myristate 13-acetate, ionomycin, and protein transport inhibitors). Thus, we propose a method that combines nanotechnology with cell biology procedures to efficiently produce T cells in the laboratory, challenging the current state-of-the-art expansion methodologies.

Stimuli-Responsive Functionalization Strategies to Spatially and Temporally Control Surface Properties: Michael vs Diels–Alder Type Additions

Stimuli-responsive self-assembled monolayers (SAMs) are used to confer switchable physical, chemical, or biological properties to surfaces through the application of external stimuli. To obtain spatially and temporally tunable surfaces, we present microcontact printed SAMs of a hydroquinone molecule that are used as a dynamic interface to immobilize different functional molecules either via Diels-Alder or Michael thiol addition reactions upon the application of a low potential. In spite of the use of such reactions and the potential applicability of the resulting surfaces in different fields ranging from sensing to biomedicine through data storage or cleanup, a direct comparison of the two functionalization strategies on a surface has not yet been performed. Although the Michael thiol addition requires molecules that are commercial or easy to synthesize in comparison with the cyclopentadiene derivatives needed for the Diels-Alder reaction, the latter reaction produces more homogeneous coverages under similar experimental conditions.