Idoia Castellanos-Rubio

A modular microfabrication strategy is presented for developing multifunctional magnetic microdiscs (MDs) with structural control and tunable composition. Combining photolithography with layer‐by‐layer assembly, this approach enables the fabrication of perfectly flat microdiscs with nanometric thickness. By selecting distinct lithographic methods, the disc diameter is tailored to modulate cellular interaction: large discs (≈18 µm) remain at the cell surface, while smaller ones (≈1.5 µm) are readily internalized. This dimensional tunability defines whether the platform operates extracellularly or intracellularly. Both microdisc types show excellent biocompatibility (at 4 MD‐18/cell and 3000 MD‐1.5/cell) and deliver spatially confined, non‐cytotoxic heating (AFM = 677 kHz, 25 mT, 1 h). These features support their use not for thermal ablation but for magnetothermal stimulation or enhanced molecular delivery. The fabrication method allows independent control of the inorganic thin film, polymeric layers, magnetic nanoparticle (MNP) content, and biomolecular payloads. Integrating Fe ₃ O ₄ MNPs of optimized size and shape maximizes magnetic responsiveness. Additionally, BSA‐loaded microdiscs are fabricated to illustrate the system's potential for programmable biomolecule delivery using the HCT116 cell line. Time‐lapse assays reveal efficient uptake dynamics, with protein loading influencing internalization. These hybrid MDs combine adjustable design and predictable uptake, offering strong potential for next‐generation magnetically actuated biomedical strategies.

Neurodegenerative diseases (NDDs) are a major global health concern, exacerbated by the blood–brain barrier (BBB), which limits effective drug delivery to the brain. Designing nanoparticles (NPs) to cross the BBB and deliver drugs could greatly improve the treatment of NDDs; however, current approaches to designing materials for drug delivery are generally slow. This study introduces an approach integrating information fusion, Python encoding, perturbation theory, and machine learning to predict the behaviour of NPs as drug delivery systems. Using an extensive pharmacokinetic database, random forest, extreme gradient boosting, and decision tree algorithms are trained and optimised. The random forest model achieves accuracies of 95.1% and 89.7% on training and testing data, respectively. As a proof of concept for the model’s utility, four novel Fe₃O₄ NP systems are synthesised via thermal decomposition and functionalised for water solubility. Structural, morphological, and magnetic characterisations are performed. The ML model is then applied to these synthesised NPs, with predictions identifying PMAO-coated NPs as promising candidates for BBB and neuronal cell lines. This design framework offers significant advancements in the efficient identification of promising potential NP candidates for NDDs drug delivery, enabling predictions of desirable bioactivity profiles.

The present work represents a significant advancement in the design of magnetic nanoparticles for biomedical applications. Herein, an improved chemical approach is presented, involving the thermal decomposition of various Fe-M bimetallic oleates (where M = Mn, Co, and Zn). Through this method a series of nanoparticles (NPs) with moderate doping levels have been successfully synthesized, categorized into monodoped (M_xFe_3-xO₄) or multidoped (M_AxM_ByFe_3-x-yO₄). This advanced synthesis technique has yielded six highly monodisperse samples composed of single nanocrystals with an octahedral-like shape and with high saturation magnetization. The uniform composition of the samples has been verified using DC magnetometry, and the dopants' lattice occupation has been analyzed via ⁵⁷Fe-Mössbauer spectroscopy. By modeling the AC/DC hysteresis loops, the magnetic anisotropy constants at low and room temperatures have been determined. Furthermore, the biomedical potential of the PEGylated NPs has been investigated by evaluating their magnetothermal performance, magnetic targeting capability, cytotoxicity, and antitumoral therapeutic capacity in a colon cancer-derived cell line. These findings highlight the tunable nature of the synthesized nanoplatforms, enabling precise optimization of their magnetic properties for diverse nanomedicine applications. Notably, Mn-doped nanoparticles have shown efficient heating power at 15 mT, while Mn-Co-doped counterparts have achieved exceptionally high heating at 45 mT. Additionally, the Mn-Zn nanosystem has demonstrated strong potential for both magnetic targeting and magnetic hyperthermia, further underscoring the versatility of these engineered nanomaterials.

Magnetic nanoparticles (NPs) are gaining significant interest in the field of biomedical functional nanomaterials because of their distinctive chemical and physical characteristics, particularly in drug delivery and magnetic hyperthermia applications. In this paper, we experimentally synthesized and characterized new Fe₃O₄-based NPs, functionalizing its surface with a 5-TAMRA cadaverine modified copolymer consisting of PMAO and PEG. Despite these advancements, many combinations of NP cores and coatings remain unexplored. To address this, we created a new data set of NP systems from public sources. Herein, 11 different AI/ML algorithms were used to develop the predictive AI/ML models. The linear discriminant analysis (LDA) and random forest (RF) models showed high values of sensitivity and specificity (>0.9) in training/validation series and 3-fold cross validation, respectively. The AI/ML models are able to predict 14 output properties (CC₅₀ (μM), EC₅₀ (μM), inhibition (%), etc.) for all combinations of 54 different NP cores classes vs. 25 different coats and vs. 41 different cell lines, allowing the short listing of the best results for experimental assays. The results of this work may help to reduce the cost of traditional trial and error procedures.

Neurodegenerative diseases involve progressive neuronal death. Traditional treatments often struggle due to solubility, bioavailability, and crossing the Blood-Brain Barrier (BBB). Nanoparticles (NPs) in biomedical field are garnering growing attention as neurodegenerative disease drugs (NDDs) carrier to the central nervous system. Here, we introduced computational and experimental analysis. In the computational study, a specific IFPTML technique was used, which combined Information Fusion (IF) + Perturbation Theory (PT) + Machine Learning (ML) to select the most promising Nanoparticle Neuronal Disease Drug Delivery (N2D3) systems. For the application of IFPTML model in the nanoscience, NANO.PTML is used. IF-process was carried out between 4403 NDDs assays and 260 cytotoxicity NP assays conducting a dataset of 500,000 cases. The optimal IFPTML was the Decision Tree (DT) algorithm which shown satisfactory performance with specificity values of 96.4% and 96.2%, and sensitivity values of 79.3% and 75.7% in the training (375k/75%) and validation (125k/25%) set. Moreover, the DT model obtained Area Under Receiver Operating Characteristic (AUROC) scores of 0.97 and 0.96 in the training and validation series, highlighting its effectiveness in classification tasks. In the experimental part, two samples of NPs (Fe₃O₄_A and Fe₃O₄_B) were synthesized by thermal decomposition of an iron(III) oleate (FeOl) precursor and structurally characterized by different methods. Additionally, in order to make the as-synthesized hydrophobic NPs (Fe₃O₄_A and Fe₃O₄_B) soluble in water the amphiphilic CTAB (Cetyl Trimethyl Ammonium Bromide) molecule was employed. Therefore, to conduct a study with a wider range of NP system variants, an experimental illustrative simulation experiment was performed using the IFPTML-DT model. For this, a set of 500,000 prediction dataset was created. The outcome of this experiment highlighted certain NANO.PTML systems as promising candidates for further investigation. The NANO.PTML approach holds potential to accelerate experimental investigations and offer initial insights into various NP and NDDs compounds, serving as an efficient alternative to time-consuming trial-and-error procedures.

Nanosystems that simultaneously contain fluorescent and magnetic modules can offer decisive advantages in the development of new biomedical approaches. A biomaterial that enables multimodal imaging and contains highly efficient nanoheaters together with an intrinsic temperature sensor would become an archetypical theranostic agent. In this work, we have designed a magneto-luminescent system based on Fe₃O₄ NPs with large heating power and thermosensitive rhodamine (Rh) fluorophores that exhibits the ability to self-monitor the hyperthermia degree. Three samples composed of highly homogeneous Fe₃O₄ NPs of ∼25 nm and different morphologies (cuboctahedrons, octahedrons, and irregular truncated-octahedrons) have been finely synthesized. These NPs have been thoroughly studied in order to choose the most efficient inorganic core for magnetic hyperthermia under clinically safe radiofrequency. Surface functionalization of selected Fe₃O₄ NPs has been carried out using fluorescent copolymers composed of PMAO, PEG and Rh. Copolymers with distinct PEG tail lengths (5-20 kDa) and different Rh percentages (5, 10, and 25%) have been synthesized, finding out that the copolymer with 20 kDa PEG and 10% Rh provides the best coating for an efficient fluorescence with minimal aggregation effects. The optimized Fe₃O₄@Rh system offers very suitable fluorescence thermosensitivity in the therapeutic hyperthermia range. Additionally, this sample presents good biocompatibility and displays an excellent heating capacity within the clinical safety limits of the AC field (≈ 1000 W/g at 142 kHz and 44 mT), which has been confirmed by both calorimetry and AC magnetometry. Thus, the current work opens up promising avenues toward next-generation medical technologies.

Local heat generation from magnetic nanoparticles (MNPs) exposed to alternating magnetic fields can revolutionize cancer treatment. However, the application of MNPs as anticancer therapy is limited by serious drawbacks. Foremost among these are the fast uptake and biodegradation of NPs by cancer cells and the unpredictable magnetic behavior of NPs when they accumulate within cells or tissues. In fact, several studies have reported that the heating power of MNPs is severely reduced in the cellular environment, probably due to a combination of increased viscosity and strong NP agglomeration. Herein, we present an optimized protocol to coat magnetite (Fe3O4) NPs larger than 20 nm with high molecular weight PEG molecules that avoid collective coatings, prevent the formation of large clusters of NPs and keep constant their high heating performance in environments with very different ionic strengths and viscosities (distilled water, physiological solutions, agar and cell culture media). The great reproducibility and reliability of the heating capacity of this [email protected] system in such different environments has been confirmed by AC magnetometry and by more conventional calorimetric measurements. The explanation of this behavior has been shown to lie in preserving as much as possible the magnetic single domain-type behavior of nearly isolated NPs. In-vitro endocytosis experiments in colon cancer derived cell line indicate that [email protected] formulations with PEGs of higher molecular weight (20 kDa) are more resistant to endocytosis than formulations with smaller PEGs (5 kDa), showing quite large uptake mean-life ( > 5 h) in comparison with other NP systems. The in-vitro magnetic hyperthermia was performed at 21 mT and 650 kHz during one hour in a pre-endocytosis stage and complete cell death was achieved 48 h post-hyperthermia. These optimal [email protected] formulations with high resistance to endocytosis and predictable magnetic response will aid the progress and the reliability of the emerging era of theranostics.

Background and importance ABP 215 (MVASI) is the first approved biosimilar to Avastin (bevacizumab reference product, RP). ABP 215 presents an alternative and effective treatment option. ABP 215 is administered intravenously after dilution in an infusion bag and confers its action by binding vascular endothelial growth factor (VEGF)-A and preventing its interaction with VEGF receptors on endothelial cells, resulting in angiogenesis inhibition. Extended physicochemical stability under in use conditions is valuable to enable administration flexibility by ensuring efficacy during handling conditions not covered by standard stability studies. Aim and objectives The aim of the study was to evaluate the physicochemical stability of ABP 215 after dilution, storage and infusion during potentially worst case handling conditions. Material and methods Low and high dose ABP 215 solutions were prepared in polyvinyl chloride and polyolefin intravenous (IV) bags. Prepared bags were stored at 2–8°C for 35 days and then stored at 30°C for 2 days, followed by IV infusion simulation. Stability indicating assays were selected to assess product quality on initial dilution into the IV bags, at prespecified time points during the 2–8°C refrigerated storage, 30°C storage, and prior and following the infusion. Stability indicating assays were selected to assess drug product quality. Size variants were assessed via size exclusion chromatography. Fragmentation was assessed via reduced capillary electrophoresis. Charge heterogeneity was assessed via cation exchange chromatography. Subvisible particle formation trends were assessed via subvisible particle testing and potential visible proteinaceous particle formation trends were assessed via visual inspection. Protein concentration was monitored for changes. Product quality consistency was evaluated via potency measurements. Results After dilution, storage and infusion, ABP 215 solutions showed no changes outside of product acceptance criteria in molecular size or charge variants, fragmentation, particulate formation, protein concentration or potency. Conclusion and relevance Across the evaluated worst case handling conditions, a robust set of stability indicating assays showed that ABP 215 product quality and activity remained within the product acceptance ranges over the examined extended storage. Conflict of interest Corporate sponsored research or other substantive relationships: All authors are employees and stockholders of Amgen Inc.