Dual Role of Subphthalocyanine Dyes for Optical Imaging and Therapy of Cancer

This is the peer-reviewed version of the following article: van de Winckel, E., Mascaraque, M., Zamarrón, A., Juarranz de la Fuente, Á., Torres, T., & de la Escosura, A. (2018). Dual role of subphthalocyanine dyes for optical imaging and therapy of cancer. Advanced Functional Materials, 28(24), 1705938., which has been published in final form at https://doi.org/10.1002/adfm.201705938. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingThe family of subphthalocyanine (SubPc) macrocycles represents an interesting class of nonplanar aromatic dyes with promising features for energy conversion and optoelectronics. The use of SubPcs in biomedical research is, on the contrary, clearly underexplored, despite their documented high fluorescence and singlet oxygen quantum yields. Herein, for the first time it is shown that the interaction of these chromophores with light can also be useful for theranostic applications, which in the case of SubPcs comprise optical imaging and photodynamic therapy (PDT). In particular, the article evaluates, through a complete in vitro study, the dual-role capacity of a novel series of SubPcs as fluorescent probes and PDT agents, where the macrocycle axial substitution determines their biological activity. The 2D and 3D imaging of various cancer cell lines (i.e., HeLa, SCC-13, and A431) has revealed, for example, different subcellular localization of the studied photosensitizers (PS), depending on the axial substituent they bear. These results also show excellent photocytotoxicities, which are affected by the PS localization. With the best dual-role PS, preliminary in vivo studies have demonstrated their therapeutic potential. Overall, the present paper sets the bases for an unprecedented biomedical use of these well-known optoelectronic materials.E.v.d.W. and M.M. contributed equally to this work. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Program FP7‐PEOPLE‐2012‐ITN under REA grant agreement No. GA 316975. AdlE holds a Ramón y Cajal contract from the Spanish Ministry of Economy (MINECO). This work was supported by EU (CosmoPHOS‐nano, FP7‐NMP‐2012‐6, 310337‐2; GLOBASOL, FP7‐ENERGY‐2012‐J, 309194‐2), the Spanish MINECO (CTQ‐2014‐52869‐P (TT) and CTQ‐2014‐53673‐P (AdlE)), CAM (FOTOCARBON, S2013/MIT‐2841), grants from Instituto de Salud Carlos III, MINECO and Feder Funds (PI15/00974) and by S2010/BMD‐2359 from Comunidad de Madrid

Porphyrinoid biohybrid materials as an emerging toolbox for biomedical light management

The development of photoactive and biocompatible nanomaterials is a current major challenge of materials science and nanotechnology, as they will contribute to promoting current and future biomedical applications. A growing strategy in this direction consists of using biologically inspired hybrid materials to maintain or even enhance the optical properties of chromophores and fluorophores in biological media. Within this area, porphyrinoids constitute the most important family of organic photosensitizers. The following extensive review will cover their incorporation into different kinds of photosensitizing biohybrid materials, as a fundamental research effort toward the management of light for biomedical use, including technologies such as photochemical internalization (PCI), photoimmunotherapy (PIT), and theranostic combinations of fluorescence imaging and photodynamic therapy (PDT) or photodynamic inactivation (PDI) of microorganismsThe work carried out to write this review article has received funding from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program FP7-PEOPLE-2012-ITN under REA grant agreement no. GA 316975. This work was supported by the EU (CosmoPHOS-nano, FP7-NMP-2012-6, 310337-2), Spanish MINECO (CTQ2017-85393-P (TT), CTQ-2014-53673-P and CTQ-2017-89539-P (AdlE), PCIN-2017-042/EuroNanoMed2017-191, TEMPEAT (TT)), and the Comunidad Autonoma de Madrid (FOTOCARBON, S2013/MIT-2841). IMDEA Nanociencia acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686

Una serie anual del comercio exterior español (1821-1913)

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Tuning the nanoaggregates of sialylated biohybrid photosensitizers for intracellular activation of the photodynamic response

In the endeavor of extending the clinical use of photodynamic therapy (PDT) for the treatment of superficial cancers and other neoplastic diseases, deeper knowledge and control of the subcellular processes that determine the response of photosensitizers (PS) are needed. Recent strategies in this direction involve the use of activatable and nanostructured PS. Here, both capacities have been tuned in two dendritic zinc(II) phthalocyanine (ZnPc) derivatives, either asymmetrically or symmetrically substituted with 3 and 12 copies of the carbohydrate sialic acid (SA), respectively. Interestingly, the amphiphilic ZnPc-SA biohybrid (1) self-assembles into well-defined nanoaggregates in aqueous solution, facilitating cellular internalization and transport whereas the PS remains inactive. Within the cells, these nanostructured hybrids localize in the lysosomes, as usually happens for anionic and hydrophilic aggregated PS. Yet, in contrast to most of them (e. g., compound 2), hybrid 1 recovers the capacity for photoinduced ROS generation within the target organelles due to its amphiphilic character; this allows disruption of aggregation when the compound is inserted into the lysosomal membrane, with the concomitant highly efficient PDT responseThis work was supported by EU (CosmoPHOS-nano, EU-FP7- NMP-2012-LARGE-6, 310337), MINECO-Feder funds (CTQ2017- 85393-P (T.T.), CTQ-2014-53673-P and CTQ-2017-89539-P (A.d.l.E.), Instituto de Salud Carlos III; PI18/00708 (A.J.), and PCIN-2017-042/EuroNanoMed2017-191, TEMPEAT (T.T.)), and Comunidad Autonoma de Madrid (FOTOCARBON, S2013/MIT 2841). DLS measurements were carried out by VAM with a Nanotrac Wave analyzer, during an internship in the MESA+ Institute for Nanotechnology of the University of Twente. IMDEA Nanociencia also acknowledges support from the “Severo Ochoa” Programme for Centres of Excellence in R&D (MINECO, grant SEV-2016-0686

Programmed Recognition between Complementary Dinucleolipids To Control the Self-Assembly of Lipidic Amphiphiles

This is the peer reviewed version of the following article: Morales‐Reina, S., Giri, C., Leclercq, M., Vela‐Gallego, S., de la Torre, I., Caston, J. R., ... & de la Escosura, A. (2020). Programmed Recognition between Complementary Dinucleolipids To Control the Self‐Assembly of Lipidic Amphiphiles. Chemistry–A European Journal, 26(5), 1082-1090, which has been published in final form at https://doi.org/10.1002/chem.201904217. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.One of the major goals in systems chemistry is to create molecular assemblies with emergent properties that are characteristic of life. An interesting approach toward this goal is based on merging different biological building blocks into synthetic systems with properties arising from the combination of their molecular components. The covalent linkage of nucleic acids (or their constituents: nucleotides, nucleosides and nucleobases) with lipids in the same hybrid molecule leads, for example, to the so-called nucleolipids. Herein, we describe nucleolipids with a very short sequence of two nucleobases per lipid, which, in combination with hydrophobic effects promoted by the lipophilic chain, allow control of the self-assembly of lipidic amphiphiles to be achieved. The present work describes a spectroscopic and microscopy study of the structural features and dynamic self-assembly of dinucleolipids that contain adenine or thymine moieties, either pure or in mixtures. This approach leads to different self-assembled nanostructures, which include spherical, rectangular and fibrillar assemblies, as a function of the sequence of nucleobases and chiral effects of the nucleolipids involved. We also show evidence that the resulting architectures can encapsulate hydrophobic molecules, revealing their potential as drug delivery vehicles or as compartments to host interesting chemistries in their interior.Research in Madrid received support from the Spanish Ministry of Economy and Competitivity (MINECO: CTQ‐2014‐53673‐P, CTQ‐2017‐89539‐P, and EUIN2017‐87022). This work was also supported in part by grants to JRC from MINECO (BFU2017‐88736‐R), and Comunidad Autónoma de Madrid (P2018/NMT‐4389). A.d.l.E. and M.S. thank the interdisciplinary framework provided by the European COST Action CM1304 (“Emergence and evolution of complex chemical systems”). A.d.l.E. and C.G. acknowledge the “Programme for Post‐Doctoral Talent Attraction to CEI UAM+CSIC—Intertalentum” (GA 713366). Research in Mons was supported by the Wallonia Region and the Fund for Scientific Research (FNRS, Belgium) under the grants MIS No. F.4532.16 (SHERPA) and EOS No. 30650939 (PRECISION). Confocal fluorescence microscopy was performed with the help of Sylvia Gutierrez Erlandsson, from the Advanced Light Microscopy Service of Centro Nacional de Biotecnologia (CNB). The professional editing service NB Revisions was used for technical preparation of the text prior to submission

Una reconstrucción del comercio exterior español, 1914-1935: La rectificación de las estadísticas oficiales

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Modifying the catalytic activity of lipopeptide assemblies with nucleobases

Biohybrid catalysts that operate in aqueous media are intriguing for systems chemistry. In this paper, we investigate whether control over the self-assembly of biohybrid catalysts can tune their properties. As a model, we use the catalytic activity of functional hybrid molecules consisting of a catalytic H-dPro-Pro-Glu tripeptide, derivatized with fatty acid and nucleobase moieties. This combination of simple biological components merged the catalytic properties of the peptide with the self-assembly of the lipid, and the structural ordering of the nucleobases. The biomolecule hybrids self-assemble in aqueous media into fibrillar assemblies and catalyze the reaction between butanal and nitrostyrene. The interactions between the nucleobases enhanced the order of the supramolecular structures and affected their catalytic activity and stereoselectivity. The results point to the significant control and ordering that nucleobases can provide in the self-assembly of biologically inspired supramolecular catalystsPID2020-119306GB-I00, S2018/NMT-4291 TEC2SPACE, CSIC13-4E-179

Programmed Recognition between Complementary Dinucleolipids To Control the SelfAssembly of Lipidic Amphiphiles

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Peripherally crowded cationic phthalocyanines as efficient photosensitizers for photodynamic therapy

Photodynamic therapy is a treatment modality of cancer based on the production of cytotoxic species upon the light activation of photosensitizers. Zinc phthalocyanine photosensitizers bearing four or eight bulky 2,6-di(pyridin-3-yl)phenoxy substituents were synthesized, and pyridyl moieties were methylated. The quaternized derivatives did not aggregate at all in water and retained their good photophysical properties. High photodynamic activity of these phthalocyanines was demonstrated on HeLa, MCF-7, and EA.hy926 cells with a very low EC50 of 50 nM (for the MCF-7 cell line) upon light activation while maintaining low toxicity in the dark (TC50 ≈ 600 μM), giving thus good phototherapeutic indexes (TC50/EC50) above 1400. The compounds localized primarily in the lysosomes, leading to their rupture after light activation. This induced an apoptotic cell death pathway with secondary necrosis because of extensive and swift damage to the cells. This work demonstrates the importance of a bulky and rigid arrangement of peripheral substituents in the development of photosensitizersThe work was supported by the Czech Science Foundation (19-14758Y), Charles University (PRIMUS/20/SCI/013, GAUK 1620219, SVV 260 550), and by the project EFSACDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) cofunded by the ERDF. For affiliations ‡, ∥, and ⊥, the work was supported by MINECO-Feder funds (CTQ2017-85393-P (T.T.), CTQ-2014-53673-P and CTQ-2017-89539-P (A.d.l.E.), PCIN-2017-042/EuroNanoMed2017-191, TEMPEAT (T.T.)). Affiliation ⊥ (IMDEA Nanociencia) also acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV2016-0686

Primitive selection of the fittest emerging through functional synergy in nucleopeptide networks

Many fundamental cellular and viral functions, including replication and translation, involve complex ensembles hosting synergistic activity between nucleic acids and proteins/peptides. There is ample evidence indicating that the chemical precursors of both nucleic acids and peptides could be efficiently formed in the prebiotic environment. Yet, studies on nonenzymatic replication, a central mechanism driving early chemical evolution, have focused largely on the activity of each class of these molecules separately. We show here that short nucleopeptide chimeras can replicate through autocatalytic and cross-catalytic processes, governed syn-ergistically by the hybridization of the nucleobase motifs and the assembly propensity of the peptide segments. Unequal assembly-dependent replication induces clear selectivity toward the formation of a certain species within small networks of complementary nucleopeptides. The selectivity pattern may be influenced and indeed maximized to the point of almost extinction of the weakest replicator when the system is studied far from equilibrium and manipulated through changes in the physical (flow) and chemical (template and inhibition) conditions. We postulate that similar processes may have led to the emergence of the first functional nucleic-acid-peptide assemblies prior to the origin of life. Furthermore, spontaneous formation of related replicating complexes could potentially mark the initiation point for information transfer and rapid progression in complexity within primitive environments, which would have facilitated the development of a variety of functions found in extant biological assembliesThe research was supported by the H2020 FET-Open (A.d.l.E and G.A.; CLASSY project, Grant Agreement Nº 862081), an NSF-BSF grant (GA; BSF-2015671), and the Spanish Ministry of Economy and Competitivity (A.d.l.E; MINECO: CTQ-2014-53673-P, CTQ-2017-89539-P, and EUIN2017-87022). The European COST Action CM1304 funded a Short-Term Scientific Mission of S.M.R. to BGU. A.K.B. received support from the BGU Kreitmann fellowships progra