This is a colloquial story of my research interests and my research journey

My research is based on the interrelation between material´s synthesis, properties and function, including applications such as catalysis, drug delivery, and gas separation. My main motivation is to understand the self-assembly process of MOFs to control their properties, and consequently, their performance towards different applications. To be honest, what I enjoy the most is data analysis. Research is a puzzle, and I love solving it. Thus, even my applied research has a big part of fundamental research within it. I always try to understand why things work (or not).

Below, you can find a summary of my research journey since my PhD. But it starts before that. During my undergraduate degree, I was curious about the merging of Inorganic, Organic and Medicinal Chemistry. Thus, I did several placements that provided me with a solid background in Analytical Chemistry (in my opinion needed for any discipline), Inorganic and Organic Chemistry and Molecular Biology techniques. This allowed me to start a PhD that combined all of this techniques after I finished my BsC degree.

PhD (2014-2018)- The effect of surface functionalisation of zirconium MOFs in drug delivery.

During my PhD at the University of Glasgow (under the supervision of Prof. Ross Forgan) I engineered the surface of MOFs for their enhanced anticancer drug delivery applications and studied the interplay between surface chemistry and therapeutic activity. I worked on the innovative application of the coordination modulation protocols to surface-functionalize MOFs, and I expanded these synthetic protocols to synthesize drug-containing surface-functionalised nanoMOFs by one-pot synthesis.

But first things first…

What are MOFs?

Metal-Organic Frameworks (MOFs) are a generation of hybrid one-, two- or three-dimensional structures composed of metal ions or clusters coordinated by multidentate organic ligands. Owing to MOFs’ attractive properties, such as high porosity and unlimited chemical and structural diversity for a rich landscape of functions, these porous solids have aroused tremendous interest within the scientific community during the last 15 years, as the applications derived from combining organic ligands with metals in an ordered manner, resulting in porous versatile structures, are nearly infinite (i.e. selective gas capture or storage, catalysis, water treatment, sensing and drug delivery among others).

And what is coordination modulation?

Coordination modulation is, in my opinion, the synthetic key of solvothermal MOFs synthesis. It is based on the introduction of organic ligands with less coordination sites than the linker (typically monotopic) that compete for the metal coordination sites during MOFs´ synthesis. Thus, coordination modulation has been widely applied to fine-tune MOF properties such as crystallinity, particle size, defectivity, dispersity, porosity, chemical reactivity and stability, among others. Under certain conditions, modulators can be attached to the metal clusters generating defects (this really captivated my interest). During coordination modulation, both the pH of the reaction mixture and the acidity of the modulators/organic linkers are competing variables. Acid solutions lead to a lower fraction of deprotonated species and subsequent slower nucleation and crystallization. At the same time, the use of highly acidic modulators will yield a higher fraction of deprotonated modulators with stronger competition for metal complexation, also through inhibition of the linker deprotonation. Hence, the acidity of single modulators has been considered a key parameter for the control of MOFs particle size and defects.

I developed the click modulation protocol to introduce surface functionality through coordination modulation and use it as a platform for further postsynthethic functionalisation (Chem 2017), resulting in pH-stimuli responsive drug release. I studied the concept of defect-loading of drugs, using a pyruvate kinase inhibitor (dichloroacetate, DCA) as a modulator of UiO-MOFs, synthesizing defected structures in which DCA is attached to Zr6 clusters as a defect compensation ligand (2 ACS Appl. Mater. Interfaces 2018). The defect-drug loading protocols resulted in highly porous materials, thus enabling the storage of a second drug in their pore space (Chem. Comm. 2018).

By making use of the versatile coordination modulation of MOFs, I could also synthesise drug-containing surface functionalised samples with a variety of units (i.e. PEG, alkanes, heparin, biotin, folic acid, polyacrylamide, polylactide etc) . I studied the effect of surface functionality on drug release kinetics, cell internalization pathways (collaboration with Prof. D. Fairen, University of Cambridge), and selective anticancer therapeutic activity, providing rationalization of the interrelation between synthesis, properties, and function (2 ACS Appl. Mater. Interfaces 2018). Moreover, I also studied the biocompatibility and the immune response towards my materials in collaboration with Prof. V. del Pozo (Fundacion Jimenez Diaz).

These protocols resulted in valuable information to understand the effect of surface functionality on MOFs therapeutic activity (for example cell internalisation pathways could be tuned from clathrin to caveolae upon PEG and folic acid functionalisation, being the second able to escape lysosomes and thus resulting in drastic enhancements in anticancer activity). For example, Folic acid/coated samples were 300 times more cytotoxic towards cancer cells than the naked drug, while not altering the cell viability of non-cancerous cells.

After having performed this research, the potential of the coordination modulation protocols to introduce multiple functionalities as defect-compensating ligands captivated me. Thus, as postodoctoral researcher, I expanded these protocols to the introduction of up to 4 simultaneous anticancer drugs as defect-compensating ligands into a single MOF phase, terming the concept Modulation. This resulted in highly porous materials that could store a fourth drug, and that had an outstanding anticancer selectivity (Angew. Chem. Int. Ed. 2020).

During my time at the Forgan group, I also collaborated in a number of projects involving enhancing drug delivery through MOFs’ amorphisation (J. Mat. Chem. B 2016), tuning endocytosis pathways through linker functionalization (ACS Appl. Mater. Interfaces 2017) and targeting the mitochondria through surface functionalisation (JACS 2020).

If you are corious about my PhD thesis, please follow the link.

Nevertheless, being a drug delivery of materials chemist at that time, using defect engineering of MOFs to tune their physical and chemical properties was stealing my sleep. As Prof. Ada Yonah told us during lunch at the 71st Nobel Laureate Lindau Meeting, Curiosity is the driving force. Thus, I applied for an MSCA Individual Fellowship to study the defect engineering of Titanium MOFs, which was elusive at the time, working towards their catalytic applications.

MSCA Fellowship (2019-2021) – Defect engineering of Titanium MOFs

Despite crystal defects can be classified as structural imperfections, structural disorder is a fascinating area in crystal chemistry and materials science, as defects can strongly affect the physical and chemical properties of the material. Defects have implications in mechanical and thermal stability, photostimulation, transport and storage performance, chemical reactivity and porosity, and thus are strongly related with the material function. Thus, as I always say, It is our “imperfections” what make us special. And MOFs imperfections were something that I needed to understand.

During my MSCA Fellowship at the Funimat research group (ICMol) I unravelled the defect chemistry of Ti-MOFs, which remained underexplored to date, and their multivariate modulation, enhancing their catalytic applications.

After researching different Titanium MOFs (with some great unpublished work that some day might see the light), I found a Titanium heterometallic MOF – MUV-10- that can stand a high amount of defects in its structure while maintaining its crystallinity. I studied the effect of the modulator topicity on the introduction of defects (Chem. Sci. 2021), as well as the effect of tuning the linker-to-metal ratio in the formation of defects, finding that this promoted missing cluster defects within the structure that have an important impact on its pore size distribution (Chem. Sci. 2021).

By tuning the modulator functionality and concentration, I applied this defect-functionalized Ti-MOFs to water splitting. In collaboration with Prof. H. Garcia and Dr. J. Albero, I performed a comprehensive study on the defect engineering of the titanium heterometallic MOF MUV-10 by fluoro- and hydroxy-isophthalic acid (Iso) modulators, rationalizing the effect of the materials’ properties on their photocatalytic activity for hydrogen production. The Iso-OH modified MOFs present a volcano-type profile with a 2.3-fold increase in comparison to the pristine materials, whereas the Iso-F modified samples have a gradual increase with up to a 4.2-fold enhancement. We found that the higher photocatalytic activity in Iso-F modulated MOF was due to the effect of the divergent defect-compensation modes on the materials’ photostability and to the increase in the external surface area upon introduction of Iso-F modulator. Our results highlighted the complexity of the coordination modulation protocol. Changing only a functional group in the modulator results in different defect compensation modes that have a drastic effect on the materials’ properties. The Iso-F modulator is more efficient than the Iso-OH modulator in compensating the induced defectivity of the samples upon benzene tricarboxylate (linker) displacement, with ca. 1 modulator per missing linker defect, while the Iso-OH modulator induces a higher number of defects that are only in part compensated by Iso-OH modulator, leading to metal clusters that are coordinated in majority by OH/H₂O pair as defect-compensating ligands. These differences in defect-compensation have a direct impact in the material´s thermal and chemical stabilities and in their porosity among other properties: While Iso-OH has a higher surface area and pore volume, Iso-F is more stable. (ACS Appl. Mater 2022)

In collaboration with Dr F. Cirujano, I studied other defected Zr MOFs as catalyst (Dalton Trans. 2021 and 2022).

However, those were not the first publication of my MSCA project. An important but unexpected result of my MSCA fellowship came during the COVID-19 quarantine. Having had trouble determining the composition of my defective MOFs by combining TGA and 1HNMR (among other techniques), I realized that the reported methodology (that for so long I was happily using) gave error in the determinations because we were not considering that a part of the oxygen needed to form the metal-oxide residues during the thermal decomposition of MOFs was coming from the linkers (EurJIC 2020). Again, curiosity was the driving force and I developed mathematical equations – combining TGA with other techniques – to obtain the exact composition of virtually any MOF material and composite.This paper is a comprehensive guide to help any researcher to obtain their MOFs´ composition. I did this because I did not want any person to have such a hard time as I did trying to figure the composition of my MOFs out and because I want the fastest advancement of science. I hope it will help. Knowledge is power, and we should always share it.

The multivariate modulation of MOFs that I first designed to introduce multiple anticancer drugs to one material was a key aspect of my MSCA proposal. I aimed to develop this protocol for the multi-functionalisation of defective Titanium MOFs.

I further developed the multivariate modulation of MOFs to simultaneously introduce 5 different functionalized modulators as defect-compensating ligands in a Titanium MOF in significant quantities (ca. 30 mol%). In contrast to the common approach of multivariate MOFs – introducing functionality through ligands – the multivariate modulation protocol results in an increase in the materials’ porosity (up to a 1.6-fold increase) and reactivity (J. Mat. Chem. A 2022). I rationalized the co-incorporation degree of multiple functionalized modulators based on the modulators’ acidity and repulsion/attraction interaction between them, something that was elusive in the literature. As a result of introducing an array of defect-compensating functionalities at MOFs’ pores, a 1.8-fold increase in the catalytic activity of the MOFs was found. This enhancement was not related to the defectivity of the materials, nor their porosity or particle size, but to the functionalities introduced. Thus, the most hydrophobic materials had the highest performance because of the enhancement of the hydrophobic reactants’ diffusion through the pore. Combining hydrophobic units with functionalities able to activate the reagents, had also a drastic increase in their catalytic activity.

And as drug delivery is a part of my life and I belive that in order to be applicable, materials should be biocompatible, I studied the biocompatibiity of some of my materials (J. Mat. Chem. B 2021) in collaboration with Prof. V. del Pozo (Fundacion Jimenez Diaz), finding outstanding results.

If you want to know more about the project DefTiMOFs, please visit www.deftimofs.es

Juan de la Cierva Incorporacion Fellowship (2022-June 2023)

As JdCI Fellow working within the Crystal Engineering Lab of the ICMol, I have the gained knowledge to engineer new materials, tuning the pore size and the nature and concentration of open metal sites for their gas separation, magnetic and catalytic applications. For example, we have published the design of ultramicroporous MOFs for selective gas separation (J. Mat. Chem. A. 2023) . Their reduced pore space (<4Å) decorated with pendant pyridines from tangling isonicotinic ligands enables the combination of size-exclusion kinetic gas separation (their small pores allow the adsorption of CO₂ molecules and forbids N₂) with thermodynamics (due to the interaction of the linker with CO₂ molecules). This results in efficient materials for dynamic breakthrough gas separation with infinite CO₂/N₂ selectivity in a wide operando range and with complete renewability at room temperature and ambient pressure. This positions these materials as some of the best candidates for CO₂/N₂ separation, with complete selectivity, and energy-free complete renewability. I have also participated in the synthesis of robust Metal-Organic Polyhedra, the 0-dimension molecular analagues of MOFs (Dalton Trans, 2023).

I have also applied my drug delivery and molecular biology knowledge to study the drug delivery applications of a very promising material (including degradation, drug release kinetics, targeting functionalisation, cell internalisation, biocompatibility and therapeutic activity). The application of MOFs for the delivery of specific large biomolecules is limited by their pore size and window opening and the ease of in situ formation. In this regard, we present the synthesis of nanostructured MUV-2 (MUV stands for Materials of University of Valencia), a hierarchical mesoporous iron-based MOF that can store high payloads of the macromolecular drug paclitaxel (ca. 23% w/w), increasing its selectivity towards HeLa cancer cells over HEK non-cancerous cells. Moreover, NanoMUV-2 permits full degradation under simulated physiological conditions while maintaining biocompatibility, and is amenable to specific surface modifications that increase its cell permeation, efficient cytosol delivery and cancer-targeting effect, further intensifying the cancer selectivity of paclitaxel (J. Mat. Chem. B, 2023).

The publication of this research is currently under preparation, and I will update the information once the related publications are in repositories.

Junior Leader la Caixa Retaining Fellowship- (June 2023-Currently)

Inspired by the multivariate modulation of MOFs , my Junior Leader la Caixa Fellowship, entitled »Coding Multivariate Modulated MOFs’ composition, structure and adaptability for enhanced applications» is focused on the most fundamental understanding of the MTVM approach to control heterogeneity, structural arrangement and adaptative response of MOFs through defect engineering.

This project has just started, stay tuned!!