Publications
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Antitumour activity of coordination polymer nanoparticles
Suárez-García S., Solórzano R., Alibés R., Busqué F., Novio F., Ruiz-Molina D. Coordination Chemistry Reviews; 441 (213977) 2021. 10.1016/j.ccr.2021.213977. IF: 22.315
Nanoscale coordination polymers (NCPs) have fascinated researchers over the last years. Their intrinsic theranostic properties of metal ions and organic ligands, the encapsulation of several drugs/biomolecules with excellent yields and the surface functionalisation, enhancing their biocompatibility and targeting, have remarkably impacted in prospective drug delivery alternatives in medicine. Moreover, the properties and characteristics of these nanoparticles (NPs) can be fine-tuned thanks to the synthetic flexibility of coordination chemistry. For all these reasons, the number of examples published has grown exponentially over the last years, embracing different disciplines such as molecular electronics, sensors or nanomedicine, among others. Specifically, significant advances in antitumoural applications are reported, one of the areas where this novel family of NPs has experienced a considerable advance. NCPs have accomplished a high sophistication degree and efficiency as theranostic nanoplatforms (i.e., drug delivery carriers and bioimaging probes) with long residence time in the bloodstream, targeting capacities and remarkable cellular internalisation. In this review, an introduction emphasizing the advantages of NPs for cancer treatment is included. Later on, the most representative examples of NCPs for antitumoural applications are described grouped into six mean representative areas: i) encapsulation approaches, ii) stimuli-responsive NCPs, iii) metal chemotherapy, iv) photodynamic therapy (PDT), v) unconventional therapeutic approaches and vi) theranostics. Particular emphasis is given to understand the encapsulation/release properties of these particles at the nanoscale and their interaction with biological environments, highlighting any limitation and challenges that these systems are facing from a clinical translation perspective and envisioning possible future trends and areas that will deserve further attention for the following years. © 2021 The Authors
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Bioinspired theranostic coordination polymer nanoparticles for intranasal dopamine replacement in parkinson's disease
García-Pardo J., Novio F., Nador F., Cavaliere I., Suárez-García S., Lope-Piedrafita S., Candiota A.P., Romero-Gimenez J., Rodríguez-Galván B., Bové J., Vila M., Lorenzo J., Ruiz-Molina D. ACS Nano; 15 (5): 8592 - 8609. 2021. 10.1021/acsnano.1c00453. IF: 15.881
Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson's disease (PD). Symptomatic therapy for PD has been centered in the precursor l-DOPA administration, an amino acid precursor of DA that crosses the blood-brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. Our methodology, in addition to being simple and inexpensive, results in DA loading efficiencies of up to 60%. In vitro, DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats in vivo showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administrations with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy. © 2021 American Chemical Society.
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Coordination polymers nanoparticles for bioimaging
Suárez-García S., Solórzano R., Novio F., Alibés R., Busqué F., Ruiz-Molina D. Coordination Chemistry Reviews; 432 (213716) 2021. 10.1016/j.ccr.2020.213716. IF: 22.315
Early diagnosis of patient diseases is subjected to the appropriate use of bioimaging techniques. For this reason, the development of contrast agents that improve and enhance the response of current clinical imaging practices is a pressing concern. Non-invasive bioimaging techniques most often need specific probes to follow and measure biological routes in living systems. These molecular imaging agents must exhibit: I) a remarkable contrast effect, i.e. a high signal-to-noise ratio under real physiological conditions, II) pronounced in vivo stability under the effect of numerous enzymes or proteases present in serum or targeted tissue equilibrated with a fast clearance from healthy organs and III) low cost and eco-friendly production. To overcome current drawbacks that hindrance the full development of the different bioimaging techniques, several groups are exploring nanoparticles as contrast agents. In this scenario, coordination polymer nanoparticles have emerged as a handy platform offering predesigned unique advantages thanks to their chemical flexibility, structural diversity and tailoring skills. Indeed, these systems reveal high metal cargos, low toxicity and multifunctional character by adequately selecting the combination of metal ions and ligands. Moreover, in a reminiscent way of organic polymeric nanoparticles, coordination polymer nanoparticles have also demonstrated its ability to encapsulate therapeutic-active molecules, thus combining diagnostic and therapeutic functionalities, the so-called Theranostic nanomedicine. For all these reasons, the use of this family of nanoparticles as imaging contrast agents has attracted broad interest over the last years with numerous examples being reported. Herein, we review main accomplishments in the area grouped according to the used technology, including magnetic resonance imaging, computed tomography, optical imaging, radioimaging or photoacoustic imaging. © 2020 Elsevier B.V.
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Encapsulation and sedimentation of nanomaterials through complex coacervation
González-Monje P., Ayala García A., Ruiz-Molina D., Roscini C. Journal of Colloid and Interface Science; 589: 500 - 510. 2021. 10.1016/j.jcis.2020.12.067. IF: 8.128
Hypothesis: Nanoparticles removal from seawage water is a health and environmental challenge, due to the increasing use of these materials of excellent colloidal stability. Herein we hypothesize to reach this objective through complex coacervation, a straightforward, low-cost process, normally accomplished with non-toxic and biodegradable macromolecules. Highly dense polymer-rich colloidal droplets (the coacervates) obtained from a reversible charge-driven phase separation, entrap suspended nanomaterials, allowing their settling and potential recovery. Experiments: In this work we apply this process to highly stable aqueous colloidal dispersions of different surface charge, size, type and state (solid or liquid). We systematically investigate the effects of the biopolymers excess and the nanomaterials concentration and charge on the encapsulation and sedimentation efficiency and rate. This strategy is also applied to real laboratory water-based wastes. Findings: Long-lasting colloidal suspensions are succesfully destabilized through coacervate formation, which ensures high nanomaterials encapsulation efficiencies (~85%), payloads and highly tranparent supernatants (%T ~90%), within two hours. Lower polymer excess induces faster clearance and less sediments, while preserving effective nanomaterials removal. Preliminary experiments also validate the method for the clearance of real water residuals, making complex coacervation a promising scalable, low-cost and ecofriendly alternative to concentrate, separate or recover suspended micro/nanomaterials from aqueous sludges. © 2020 Elsevier Inc.
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Gossypol treatment restores insufficient apoptotic function of dff40/cad in human glioblastoma cells
Martínez-Escardó L., Alemany M., Sánchez-Osuna M., Sánchez-Chardi A., Roig-Martínez M., Suárez-García S., Ruiz-Molina D., Vidal N., Plans G., Majós C., Ribas J., Baltrons M.A., Bayascas J.R., Barcia C., Bruna J., Yuste V.J. Cancers; 13 (21, 5579) 2021. 10.3390/cancers13215579. IF: 6.639
Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DFF40/CAD is the main endonuclease implicated in apoptotic nuclear disassembly. To be properly activated, DFF40/CAD should reside in the cytosol. However, the endonuclease is poorly expressed in the cytosol and remains cumulated in the nucleus of GBM cells. Here, by employing commercial and non-commercial patient-derived GBM cells, we demonstrate that the natural terpenoid aldehyde gossypol prompts DFF40/CAD-dependent nuclear fragmentation. A comparative analysis between gossypol-and staurosporine-treated cells evidenced that levels of neither caspase activation nor DNA damage were correlated with the ability of each compound to induce nuclear fragmentation. Deconvoluted confocal images revealed that DFF40/CAD was almost completely excluded from the nucleus early after the staurosporine challenge. However, gossypol-treated cells maintained DFF40/CAD in the nucleus for longer times, shaping a ribbon-like structure piercing the nuclear fragments and building a network of bridged masses of compacted chromatin. Therefore, GBM cells can fragment their nuclei if treated with the adequate insult, making the cell death process irreversible. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Hybrid Metal-Phenol Nanoparticles with Polydopamine-like Coating for PET/SPECT/CT Imaging
SuÃirez-GarcÃ-A S., Esposito T.V.F., Neufeld-Peters J., Bergamo M., Yang H., Saatchi K., Schaffer P., HÃfeli U.O., Ruiz-Molina D., RodrÃ-Guez-RodrÃ-Guez C., Novio F. ACS Applied Materials and Interfaces; 13 (9): 10705 - 10718. 2021. 10.1021/acsami.0c20612. IF: 9.229
The validation of metal-phenolic nanoparticles (MPNs) in preclinical imaging studies represents a growing field of interest due to their versatility in forming predesigned structures with unique properties. Before MPNs can be used in medicine, their pharmacokinetics must be optimized so that accumulation in nontargeted organs is prevented and toxicity is minimized. Here, we report the fabrication of MPNs made of a coordination polymer core that combines In(III), Cu(II), and a mixture of the imidazole 1,4-bis(imidazole-1-ylmethyl)-benzene and the catechol 3,4-dihydroxycinnamic acid ligands. Furthermore, a phenolic-based coating was used as an anchoring platform to attach poly(ethylene glycol) (PEG). The resulting MPNs, with effective hydrodynamic diameters of around 120 nm, could be further derivatized with surface-embedded molecules, such as folic acid, to facilitate in vivo targeting and multifunctionality. The prepared MPNs were evaluated for in vitro plasma stability, cytotoxicity, and cell internalization and found to be biocompatible under physiological conditions. First, biomedical evaluations were then performed by intrinsically incorporating trace amounts of the radioactive metals 111In or 64Cu during the MPN synthesis directly into their polymeric matrix. The resulting particles, which had identical physicochemical properties to their nonradioactive counterparts, were used to perform in vivo single-photon emission computed tomography (SPECT) and positron emission tomography (PET) in tumor-bearing mice. The ability to incorporate multiple metals and radiometals into MPNs illustrates the diverse range of functional nanoparticles that can be prepared with this approach and broadens the scope of these nanoconstructs as multimodal preclinical imaging agents. ©
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Photoactivable ruthenium-based coordination polymer nanoparticles for light-induced chemotherapy
Zhang J., Ramu V., Zhou X.-Q., Frias C., Ruiz-Molina D., Bonnet S., Roscini C., Novio F. Nanomaterials; 11 (11, 3089) 2021. 10.3390/nano11113089. IF: 5.076
Green light photoactive Ru-based coordination polymer nanoparticles (CPNs), with chemical formula [[Ru(biqbpy)]1.5 (bis)](PF6)3 (biqbpy = 6,6′-bis[N-(isoquinolyl)-1-amino]-2,2′-bipyridine; bis = bis(imidazol-1-yl)-hexane), were obtained through polymerization of the trans-[Ru(biqbpy) (dmso)Cl]Cl complex (Complex 1) and bis bridging ligands. The as-synthesized CPNs (50 ± 12 nm di-ameter) showed high colloidal and chemical stability in physiological solutions. The axial bis(imidazole) ligands coordinated to the ruthenium center were photosubstituted by water upon light irradiation in aqueous medium to generate the aqueous substituted and active ruthenium complexes. The UV-Vis spectral variations observed for the suspension upon irradiation corroborated the photoactivation of the CPNs, while High Performance Liquid Chromatography (HPLC) of irradiated particles in physiological media allowed for the first time precisely quantifying the amount of photoreleased complex from the polymeric material. In vitro studies with A431 and A549 cancer cell lines revealed an 11-fold increased uptake for the nanoparticles compared to the monomeric complex [Ru(biqbpy)(N-methylimidazole)2 ](PF6)2 (Complex 2). After irradiation (520 nm, 39.3 J/cm2), the CPNs yielded up to a two-fold increase in cytotoxicity compared to the same CPNs kept in the dark, indicating a selective effect by light irradiation. Meanwhile, the absence of1 O2 production from both nanostructured and monomeric prodrugs concluded that light-induced cell death is not caused by a photodynamic effect but rather by photoactivated chemotherapy. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Solvent-tuned ultrasonic synthesis of 2D coordination polymer nanostructures and flakes
Pepió B., Contreras-Pereda N., Suárez-García S., Hayati P., Benmansour S., Retailleau P., Morsali A., Ruiz-Molina D. Ultrasonics Sonochemistry; 72 (105425) 2021. 10.1016/j.ultsonch.2020.105425. IF: 7.491
Herein, a new 2-dimensional coordination polymer based on copper (II), {Cu2(L)(DMF)2}n, where L stands for 1,2,4,5-benzenetetracarboxylate (complex 1) is synthesized. Interestingly, we demonstrate that both solvent and sonication are relevant in the top-down fabrication of nanostructures. Water molecules are intercalated in suspended crystals of complex 1 modifying not only the coordination sphere of Cu(II) ions but also the final chemical formula and crystalline structure obtaining {[Cu(L)(H2O)3]·H2O}n (complex 2). On the other hand, ultrasound is required to induce the nanostructuration. Remarkably, different morphologies are obtained using different solvents and interconversion from one morphology to another seems to occur upon solvent exchange. Both complexes 1 and 2, as well as the corresponding nanostructures, have been fully characterized by different means such as infrared spectroscopy, x-ray diffraction and microscopy. © 2020 The Authors
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Synthesis of 2D Porous Crystalline Materials in Simulated Microgravity
Contreras-Pereda N., Rodríguez-San-Miguel D., Franco C., Sevim S., Vale J.P., Solano E., Fong W.-K., Del Giudice A., Galantini L., Pfattner R., Pané S., Mayor T.S., Ruiz-Molina D., Puigmartí-Luis J. Advanced Materials; 33 (30, 2101777) 2021. 10.1002/adma.202101777. IF: 30.849
To date, crystallization studies conducted in space laboratories, which are prohibitively costly and unsuitable to most research laboratories, have shown the valuable effects of microgravity during crystal growth and morphogenesis. Herein, an easy and highly efficient method is shown to achieve space-like experimentation conditions on Earth employing custom-made microfluidic devices to fabricate 2D porous crystalline molecular frameworks. It is confirmed that experimentation under these simulated microgravity conditions has unprecedented effects on the orientation, compactness and crack-free generation of 2D porous crystalline molecular frameworks as well as in their integration and crystal morphogenesis. It is believed that this work will provide a new “playground” to chemists, physicists, and materials scientists that desire to process unprecedented 2D functional materials and devices. © 2021 The Authors. Advanced Materials published by Wiley-VCH GmbH
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Thermoresponsive multicolor-emissive materials based on solid lipid nanoparticles
Otaegui J.R., Ruiz-Molina D., Latterini L., Hernando J., Roscini C. Materials Horizons; 8 (11): 3043 - 3054. 2021. 10.1039/d1mh01050f. IF: 13.266
Despite the recent advances in the field of thermofluorochromism, the fabrication of thermoresponsive multicolor-emissive materials in a simple, low-cost and versatile manner still remains a challenge. Herein we accomplish this goal by expanding the concept of matrix-induced thermofluorochromism, where a sudden two-state variation of dyes' emission is promoted by the solid-liquid transition of a surrounding phase change material (e.g., paraffins). We demonstrate that this behavior can be transferred to the nanoscale by the synthesis of dye-loaded solid lipid nanoparticles, different types of which can then be combined into a single platform to obtain multicolor thermofluorochromism using a single type of emitter. Because of the reduced dimensions of these particles, they can be utilized to prepare transparent nanocomposites and inkjet-printed patterns showing complex thermoresponsive luminescence signals and applications ranging from smart displays to thermal sensing and high-security anti-counterfeiting. © 2021 The Royal Society of Chemistry.
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Thiol-yne click reaction: an interesting way to derive thiol-provided catechols
Nador F., Mancebo-Aracil J., Zanotto D., Ruiz-Molina D., Radivoy G. RSC Advances; 11 (4): 2074 - 2082. 2021. 10.1039/d0ra09687c. IF: 3.361
The hydrothiolation of activated alkynes is presented as an attractive and powerful way to functionalize thiols bearing catechols. The reaction was promoted by a heterogeneous catalyst composed of copper nanoparticles supported on TiO2 (CuNPs/TiO2) in 1,2-dichloroethane (1,2-DCE) under heating at 80 °C. The catalyst could be recovered and reused in three consecutive cycles, showing a slight decrease in its catalytic activity. Thiol derivatives bearing catechol moieties, obtained through a versatile Michael addition, were reacted with different activated alkynes, such as methyl propiolate, propiolic acid, propiolamide or 2-ethynylpyridine. The reaction was shown to be regio- and stereoselective towards anti-Markovnikov Z-vinyl sulfide in most cases studied. Finally, some catechol derivatives obtained were tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the advantage of their different coordination sites with metals such as iron and cobalt. © 2021 The Royal Society of Chemistry.
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Ultrasound-assisted exfoliation of a layered 2D coordination polymer with HER electrocatalytic activity
Contreras-Pereda N., Moghzi F., Baselga J., Zhong H., Janczak J., Soleimannejad J., Dong R., Ruiz-Molina D. Ultrasonics Sonochemistry; 70 (105292) 2021. 10.1016/j.ultsonch.2020.105292. IF: 7.491
Large blue rectangular crystals of the 2D layered coordination polymer 1 have been obtained. The interest for this complex is two-fold. First, complex 1 is made of 2D layers packing along the (0–11) direction favored by the presence of lattice and coordinated water molecules. And second, nanostructures that could be derived by delamination are potentially suitable for catalytic purposes. Therefore it represents an excellent example to study the role of interlayer solvent molecules on the ultrasound-assisted delamination of functionally-active 2D metal-organic frameworks in water, a field of growing interest. With this aim, ultrasound-assisted delamination of the crystals was optimized with time, leading to stable nanosheet colloidal water suspensions with very homogeneous dimensions. Alternative bottom-up synthesis of related nanocrystals under ultrasound sonication yielded similar shaped crystals with much higher size dispersions. Finally, experimental results evidence that the nanostructures have higher catalytic activities in comparison to their bulk counterparts, due to larger metallic center exposition. These outcomes confirm that the combination of liquid phase exfoliation and a suitable synthetic design of 2D coordination polymers represents a very fruitful approach for the synthesis of functional nanosheets with an enhancement of catalytic active sites, and in general, with boosted functional properties. © 2020 Elsevier B.V.
