Manuel Pernia Leal
@universidad de sevilla
RESEARCH, TEACHING, or OTHER INTERESTS
Chemistry, Organic Chemistry
Scopus Publications
Scopus Publications
Victoria Valdivia, Rocío Recio, Patricia Lerena, Esther Pozo, Rosario Serrano, Raúl Calero, Cristina Pintado, Manuel Pernia Leal, Nazaret Moreno-Rodríguez, Juan Ángel Organero,et al.
Elsevier BV
José María Paez-Muñoz, Francisco Gámez, Yilian Fernández-Afonso, Roberto Gallardo, Manuel Pernia Leal, Lucía Gutiérrez, Jesús M. de la Fuente, Carlos Caro, and María Luisa García-Martín
Royal Society of Chemistry (RSC)
Deciphering the most suitable shape to improve the magnetocaloric effect of superparamagnetic iron oxide nanoparticles (SPIONs) for in vivo magnetic hyperthermia therapy (MHT) of high-grade gliomas.
Ashish Avasthi, Carlos Caro, María Luisa Garcia-Martin, and Manuel Pernia Leal
Royal Society of Chemistry (RSC)
This article introduces a modified method to yield small IONPs (∼4 nm) with high reproducibility and scalability after revisiting established synthesis methods and investigating the effect of variations in several parameters involved in these methods.
Nadja C. Bigall, Marina Rodio, Sahitya Avugadda, Manuel Pernia Leal, Riccardo Di Corato, John S. Conteh, Romuald Intartaglia, and Teresa Pellegrino
American Chemical Society (ACS)
The growing interest in multifunctional nano-objects based on polymers and magnetic nanoparticles for biomedical applications motivated us to develop a scale-up protocol to increase the yield of polymeric magnetic nanobeads while aiming at keeping the structural features at optimal conditions. The protocol was applied to two different types of magnetic ferrite nanoparticles: the Mn-ferrite selected for their properties as contrast agents in magnetic resonance imaging and iron oxide nanostar shaped nanoparticles chosen for their heat performance in magnetic hyperthermia. At the same time, some experiments on surface functionalization of nanobeads with amino modified polyethyelene glycol (PEG) molecules have provided further insight into the formation mechanism of magnetic nanobeads and the need to cross-link the polymer shell to improve the stability of the beads, making them more suitable for further manipulation and use. The present work summarizes the most important parameters required to be controlled for the upscaling of nanobead synthesis in a bench protocol and proposes an alternative cross-linking strategy based on prefunctionalization of the polymer prior to the nanobead formation as a key parameter to improve the nanobead structural stability in solutions at different pHs and during surface functionalization.
Victoria Valdivia, Raúl Gimeno-Ferrero, Manuel Pernia Leal, Chiara Paggiaro, Ana María Fernández-Romero, María Luisa González-Rodríguez, and Inmaculada Fernández
MDPI AG
The preparation of new and functional nanostructures has received more attention in the scientific community in the past decade due to their wide application versatility. Among these nanostructures, micelles appear to be one of the most interesting supramolecular organizations for biomedical applications because of their ease of synthesis and reproducibility and their biocompatibility since they present an organization similar to the cell membrane. In this work, we developed micellar nanocarrier systems from surfactant molecules derived from oleic acid and tetraethylene glycol that were able to encapsulate and in vitro release the drug dexamethasone. In addition, the designed micelle precursors were able to functionalize metallic NPs, such as gold NPs and iron oxide NPs, resulting in monodispersed hybrid nanomaterials with high stability in aqueous media. Therefore, a new triazole-derived micelle precursor was developed as a versatile encapsulation system, opening the way for the preparation of new micellar nanocarrier platforms for drug delivery, magnetic resonance imaging, or computed tomography contrast agents for therapeutic and diagnostic applications.
Esther Pozo-Torres, Carlos Caro, Ashish Avasthi, Jose María Páez-Muñoz, María Luisa García-Martín, Inmaculada Fernández, and Manuel Pernia Leal
Royal Society of Chemistry (RSC)
Correction for ‘Clickable iron oxide NPs based on catechol derived ligands: synthesis and characterization’ by Esther Pozo-Torres et al., Soft Matter, 2020, 16, 3257–3266, DOI: 10.1039/C9SM02512J.
Carlos Caro, Ashish Avasthi, Jose M. Paez-Muñoz, Manuel Pernia Leal, and María L. García-Martín
Royal Society of Chemistry (RSC)
Passive targeting by the EPR effect of long-circulating metallic NPs to GBMs is highly inefficient and limited to sizes ≤50 nm. This is mainly attributable to the restraints imposed by the BBTB, yet other factors are likely involved, such as NP stiffness.
Ashish Avasthi, Carlos Caro, Esther Pozo-Torres, Manuel Pernia Leal, and María Luisa García-Martín
Springer Science and Business Media LLC
A correction to this paper has been published: https://doi.org/10.1007/s41061-021-00340-y
Rocío Recio, Patricia Lerena, Esther Pozo, José Manuel Calderón-Montaño, Estefanía Burgos-Morón, Miguel López-Lázaro, Victoria Valdivia, Manuel Pernia Leal, Bernard Mouillac, Juan Ángel Organero,et al.
American Chemical Society (ACS)
NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α, as an interesting hit exhibiting significant NK1R antagonist effect (kinact 0.209 ± 0.103 μM) and high binding affinity for NK1R (IC50 = 50.4 nM, Ki = 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.
Carlos Caro, Jose M. Paez-Muñoz, Ana M. Beltrán, Manuel Pernia Leal, and María Luisa García-Martín
American Chemical Society (ACS)
Diagnostic imaging strongly relies on the use of contrast agents (CAs). In general terms, current CAs present undesirable side effects that encourage researchers and pharmaceutical companies to con...
Carlos Caro, Francisco Gámez, Pedro Quaresma, Jose María Páez-Muñoz, Alejandro Domínguez, John R. Pearson, Manuel Pernía Leal, Ana M. Beltrán, Yilian Fernandez-Afonso, Jesús M. De la Fuente,et al.
MDPI AG
In this study, we report the synthesis of gold-coated iron oxide nanoparticles capped with polyvinylpyrrolidone (Fe@Au NPs). The as-synthesized nanoparticles (NPs) exhibited good stability in aqueous media and excellent features as contrast agents (CA) for both magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Additionally, due to the presence of the local surface plasmon resonances of gold, the NPs showed exploitable “light-to-heat” conversion ability in the near-infrared (NIR) region, a key attribute for effective photothermal therapies (PTT). In vitro experiments revealed biocompatibility as well as excellent efficiency in killing glioblastoma cells via PTT. The in vivo nontoxicity of the NPs was demonstrated using zebrafish embryos as an intermediate step between cells and rodent models. To warrant that an effective therapeutic dose was achieved inside the tumor, both intratumoral and intravenous routes were screened in rodent models by MRI and CT. The pharmacokinetics and biodistribution confirmed the multimodal imaging CA capabilities of the Fe@AuNPs and revealed constraints of the intravenous route for tumor targeting, dictating intratumoral administration for therapeutic applications. Finally, Fe@Au NPs were successfully used for an in vivo proof of concept of imaging-guided focused PTT against glioblastoma multiforme in a mouse model.
Ashish Avasthi, Carlos Caro, Esther Pozo-Torres, Manuel Pernia Leal, and María Luisa García-Martín
Springer Science and Business Media LLC
AbstractIron oxide nanoparticles (IONPs) have emerged as a promising alternative to conventional contrast agents (CAs) for magnetic resonance imaging (MRI). They have been extensively investigated as CAs due to their high biocompatibility and excellent magnetic properties. Furthermore, the ease of functionalization of their surfaces with different types of ligands (antibodies, peptides, sugars, etc.) opens up the possibility of carrying out molecular MRI. Thus, IONPs functionalized with epithelial growth factor receptor antibodies, short peptides, like RGD, or aptamers, among others, have been proposed for the diagnosis of various types of cancer, including breast, stomach, colon, kidney, liver or brain cancer. In addition to cancer diagnosis, different types of IONPs have been developed for other applications, such as the detection of brain inflammation or the early diagnosis of thrombosis. This review addresses key aspects in the development of IONPs for MRI applications, namely, synthesis of the inorganic core, functionalization processes to make IONPs biocompatible and also to target them to specific tissues or cells, and finally in vivo studies in animal models, with special emphasis on tumor models.
Valentin Nica, Carlos Caro, Jose Maria Páez-Muñoz, Manuel Pernia Leal, and Maria Luisa Garcia-Martin
MDPI AG
In this work, we report the synthesis and characterization of three magnetic nanosystems, CoFe2O4, CoFe2O4@ZnFe2O4, and CoFe2O4@MnFe2O4, which were developed as potential theranostic agents for magnetic hyperthermia and magnetic resonance imaging (MRI). These nanosystems have been thoroughly characterized by X-ray Diffraction (XRD), Transmission Electron Miscroscopy (TEM), Dark Field-TEM (DF-TEM), Vibrating Sample Magnetometry (VSM), and inductive heating, in order to elucidate their structure, morphology, and magnetic properties. The bi-magnetic CoFe2O4@ZnFe2O4 and CoFe2O4@MnFe2O4 nanoparticles (NPs) exhibited a core-shell structure with a mean average particle size of 11.2 ± 1.4 nm and 14.4 ± 2.4 nm, respectively. The CoFe2O4@MnFe2O4 NPs showed the highest specific absorption rate (SAR) values (210–320 W/g) upon exposure to an external magnetic field, along with the highest saturation magnetization (Ms). Therefore, they were selected for functionalization with the PEGylated ligand to make them stable in aqueous media. After the functionalization process, the NPs showed high magnetic relaxivity values and very low cytotoxicity, demonstrating that CoFe2O4@MnFe2O4 is a good candidate for in vivo applications. Finally, in vivo MRI experiments showed that PEGylated CoFe2O4@MnFe2O4 NPs produce high T2 contrast and exhibit very good stealth properties, leading to the efficient evasion of the mononuclear phagocyte system. Thus, these bi-magnetic core-shell NPs show great potential as theranostic agents for in vivo applications, combining magnetic hyperthermia capabilities with high MRI contrast.
Esther Pozo-Torres, Carlos Caro, Ashish Avasthi, Jose María Páez-Muñoz, María Luisa García-Martín, Inmaculada Fernández, and Manuel Pernia Leal
Royal Society of Chemistry (RSC)
Clickable magnetic NPs for nanomedical applications were prepared using a high-yield synthetic route based on a modular hetero bi-functional PEG spacer with an azide group and catechol anchor moieties with different stereo-electronic features.
Carlos Caro, David Egea-Benavente, Rocio Polvillo, Jose Luis Royo, Manuel Pernia Leal, and María Luisa García-Martín
Elsevier BV
Carlos Caro, Pedro Quaresma, Eulália Pereira, Jaime Franco, Manuel Pernia Leal, Maria García-Martín, Jose Royo, Jose Oliva-Montero, Patrick Merkling, Ana Zaderenko,et al.
MDPI AG
Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 107) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.
Carlos Caro, M. Carmen Muñoz-Hernández, Manuel Pernia Leal, and María Luisa García-Martín
Springer New York
Maria Elena Materia, Manuel Pernia Leal, Marco Scotto, Preethi Bala Balakrishnan, Sahitya Kumar Avugadda, María L. García-Martín, Bruce E. Cohen, Emory M. Chan, and Teresa Pellegrino
American Chemical Society (ACS)
We report the fabrication of aqueous multimodal imaging nanocomposites based on superparamagnetic nanoparticles (MNPs) and two different sizes of photoluminescent upconverting nanoparticles (UCNPs). The controlled and simultaneous incorporation of both types of nanoparticles (NPs) was obtained by controlling the solvent composition and the addition rate of the destabilizing solvent. The magnetic properties of the MNPs remained unaltered after their encapsulation into the polymeric beads as shown by the T2 relaxivity measurements. The UCNPs maintain photoluminescent properties even when embedded with the MNPs into the polymer bead. Moreover, the light emitted by the magnetic and upconverting nanobeads (MUCNBs) under NIR excitation (λexc = 980 nm) was clearly observed through different thicknesses of agarose gel or through a mouse skin layer. The comparison with magnetic and luminescent nanobeads based on red-emitting quantum dots (QDs) demonstrated that while the QD-based beads show significant autofluorescence background from the skin, the signal obtained by the MUCNBs allows a decrease in this background. In summary, these results indicate that MUCNBs are good magnetic and optical probes for in vivo multimodal imaging sensors.
Manuel Pernia Leal, Carlos Caro, and María Luisa García-Martín
Royal Society of Chemistry (RSC)
Over the last few years several studies have dealt with the importance of the surface charge of nanoparticles in prolonging their blood circulation and minimizing their interaction with plasma proteins. These investigations claimed that zwitterionic nanoparticles exhibited a minimal macrophage response and long blood circulation times compared to nanoparticles with other surface charges. These differences in their in vivo behavior are mainly attributed to the interaction of nanoparticles with plasma proteins. Interestingly, most of these studies considered the total surface charge, instead of the outermost layer of the nanomaterial, as being mainly responsible for these undesirable interactions. However, the first contact with plasma proteins is most likely due to the outermost layer on the nanomaterials. Therefore, here we report a detailed study on the effect of the outermost surface charge of magnetic nanoparticles with regard to biodistribution, pharmacokinetics and bioavailability. Magnetic nanoparticles, coated with PEG chains functionalized with neutral, positive or zwitterionic groups, were intravenously injected into mice, followed in vivo by MRI and then quantified by ICP-MS in blood and the main organs. We found that neutral nanoparticles exhibited long blood circulation times, very good stealth properties and the highest bioavailability, whereas zwitterionic nanoparticles were readily recognized by the mononuclear phagocyte system and avidly taken up by the liver. Also, zwitterionic nanoparticles showed high non-specific cell internalization, whereas neutral nanoparticles showed the lowest cellular uptake, indicating that they require active transport to cross the plasma membrane, which is the desirable situation for therapeutic vehicles with low side effects. Thus, neutral nanoparticles exhibit very favorable characteristics for in vivo applications, whereas zwitterionic nanoparticles show important limitations.
Carlos Caro, Mariona Dalmases, Albert Figuerola, María Luisa García-Martín, and Manuel Pernia Leal
Royal Society of Chemistry (RSC)
X-ray computed tomography (CT) is a powerful and widely used medical non-invasive technique that often requires intravenous administration of contrast agents (CAs) to better visualize soft tissues. In this work, we have developed a novel CT contrast agent based on ternary Ag-Au-Se chalcogenide nanoparticles (NP). A facile ligand exchange by using a 3 kDa PEGylated ligand with a dithiol dihydrolipoic acid as an anchor group resulted in highly water-soluble and monodisperse nanoparticles. These PEGylated ternary NPs were tested in vivo in mice, showing slow uptake by the mononuclear phagocyte system, long blood circulation times, low toxicity, and very good X-ray contrast, thus being promising candidates as CT contrast agents for clinical applications.
Carlos Caro, María Luisa García-Martín, and Manuel Pernia Leal
American Chemical Society (ACS)
pH-responsive nanogels (NGs) were used to prepare high-efficiency magnetic resonance imaging dual T1/T2 contrast agents for pH imaging. The polymeric NG matrix acts as a strong polydentate ligand that chelates the Mn cations in its inner cavity generating a hybrid NG structure. The Mn chelate NG is sensitive to pH changes, such that protonation induces a change of the polymer hydration state and consequent swelling. The swollen nanogel allows water molecules to enter and interact with the Mn chelate, shortening the relaxation time (switch ON) and giving rise to positive or negative contrast on T1- or T2-weighted magnetic resonance images.
M. Pernía Leal, M. Assali, J. J. Cid, V. Valdivia, J. M. Franco, I. Fernández, D. Pozo, and N. Khiar
Royal Society of Chemistry (RSC)
A shotgun-like approach allowing the synthesis of functional, biocompatible glyconanoring-coated single wall carbon nanotubes with a shish-kebab topology and lectin specificity is reported.
Yang Han, Piotr Nowak, Mathieu Colomb-Delsuc, Manuel Pernia Leal, and Sijbren Otto
American Chemical Society (ACS)
The application of nanoparticles to the multivalent recognition of biomacromolecules or programmed self-assembly requires control over the relative placement of chemical groups on their surface. We have developed a method to direct the functionalization of surfaces of aldehyde-equipped gold nanoparticles using a DNA template. An error-correction mechanism is built into the functionalization process thanks to the thermodynamic control enabled by the hydrazone exchange reaction. This reversible reaction can be conveniently switched off by removing the catalyst, preserving the functionalization.
Manuel Pernia Leal, Carmen Muñoz-Hernández, Catherine C. Berry, and María Luisa García-Martín
Royal Society of Chemistry (RSC)
PEGylated SPIONs using PEG MWs from 1500 to 8000 were intravenously injected in mice. Parametric MRI allowed us to track the pharmacokinetics and determine the effect of MW on the biodistribution and circulation times of PEG-SPIONs (HD < 50 nm).
Hamilton Kakwere, Manuel Pernia Leal, Maria Elena Materia, Alberto Curcio, Pablo Guardia, Dina Niculaes, Roberto Marotta, Andrea Falqui, and Teresa Pellegrino
American Chemical Society (ACS)
Herein, we prepare nanohybrids by incorporating iron oxide nanocubes (cubic-IONPs) within a thermoresponsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR), but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermoresponsive shell is composed of poly(N-isopropylacrylamide-co-polyethylene glycolmethyl ether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 °C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 °C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes.