Periodic Reporting for period 1 - NeuroMOF (Self-propelled Metal-Organic Framework nanocarriers as promising brain delivery platform)
Período documentado: 2021-07-01 hasta 2023-06-30
This MSCA-IF project has addressed a challenging objective: the presence of the blood-brain barrier (BBB) has limited the treatments of neurological diseases since it constrains the drug delivery to the brain. Although novel nanomedicines have emerged as promising alternatives to overcome the BBB, their clinical application is still limited by their lack of in vivo efficacy. In this context, NeuroMOF has proposed the design of a biosafe and efficient tailored drug delivery system based on nanoscaled porous Metal Organic Frameworks (nanoMOFs) for brain delivery. To achieve this goal, two original targeting strategies by a suitable macromolecule immobilization: 1) MOF targeting (external functionalization with BBB-specific ligands) & 2) MOF motion (self-propelled nanomotors using enzymes, MOFtor). Apart from a complete characterization, we have been able to evaluate their BBB crossing in a 3D in vitro model along with their preliminary in vivo performance. This achieved progress has been related mainly with several of the tasked aims: 1) Preparation & characterization of engineered surface MOFs, monitoring their efficacy under working conditions; 2) in terms of the in vitro assays, a representative prototype of each conceived immobilized MOFs were tested, assessing both their biocompatibility & permeability in presence of specific endothelial cells; and finally, 3), their biosafety and biodistribution was also investigated at in vivo level by using female rats. Every engineered MOF prototype was carefully selected based on the proven biodistribution, biocompatibility and bioactivity assays. To achieve the challenging approach, a collaboration has been implemented between the IMDEA research group of Advanced Porous Materials Unit (APMU), led by P. Horcajada and recognized as expert in the nanoMOF synthesis, characterization & bioaplication together with the Molecular Bionics Labs, led by G. Battaglia (IBEC-Spain) in which specialists worked on the design & evaluation of chemotactic delivery systems to cross the CNS barriers by using adapted in vitro & in vivo BBB models. In this case, Dr. Hidalgo, as main beneficiary of this prestigious MSCA fellow, was in charge for overall scientific (material performance, in vitro & in vivo assays) & managerial aspects. These accomplished outcomes will serve as great proof of concept, providing new insights for effective targeted therapies based on nanoMOFs, not only at the neurological level but also for other unexplored scenarios such as pulmonary, vaginal or nasal pathways.
NeuroMOF has successfully designed a biosafe and efficient tailored drug delivery system (DDS) based on nanoscaled porous Metal-Organic Frameworks (nanoMOFs) for brain delivery, by using two targeting strategies: external functionalization with BBB-specific ligands (MOF targeting) & enzyme immobilization (MOF motion, self-propelled nanomotors). From the selective composition, 12-engineered MOF composites were synthesized and fully characterized grafting on the external surface 2- diverse macromolecules: the transferring ligand-Tf for neuronal receptors and the active motion enzyme, glucose oxidase-Gox. A successful immobilization (53% and 14% of Gox & Tf coating efficacy) was obtained, showing an adequate nanometric particle size over the time in diverse biorelevant media as well the maintenance of their crystalline structure and lower degradation profiles. In addition, the safety and effective internalization of these engineered MOFs were regularly addressed on a simple neuronal cell type, evaluating their potential toxicological impact (both cellular & immunological). A final selection of the 4-best engineered MOF prototypes was putting in contact with a more complex neuronal BBB model, demonstrating an adequate biocompatibility and permeability profile (100% of viability by MTT and no detectable TEER changes) after 24h. And finally, a preclinical in vivo evaluation (biodistribution, toxicity, histology) of the best 3 engineered MOF candidates were carried out, observing a preliminary absence of toxicity (no weight loss, spontaneous deaths or stained brains) after their intravenous administration in rats. However, further quantification analysis need to be completed. Therefore, NeuroMOF project has served as starting point for shedding light on potential triggered mobility mechanisms for more targeted & effective MOF therapies.
NeuroMOF aims has favoured the opening of a new challenging research line that Dr. Hidalgo is trying to pursue for the next years: new generation of smart nano/micro materials combining MOF features with self-locomotion devices, resulting in attractive penetrating-nanomedicine machines for targeted therapies. Despite other research areas have been benefited with the performance of diverse Janus materials (eg. decontamination, batteries, sensing), the presence of self-propelled MOFs (called as MOFtors) in drug delivery is still at its infancy (<50 articles since 2012, pointing out <10 publications in biomedicine in 2022-23). Thus, there is still room for the investigations of MOF self-locomotion and their potential biopermeability. Taking in account the increasing MOF trend in academic and industrial domains together with the potential of these micro/nanomotor technology, the prestigious support received by the MSCA Individual Fellow, it has encouraged and enhanced the candidate expertise providing an excellent research & valuable finding on this hot topic such as the nanoMOF neuronal delivery trough the BBB crossing. Considering the scientific background of Dr. Hidalgo (MOF platforms, drug delivery, biology or immunology) and her contribution during the last years in the MOF biological field, it´s important to highlight that further progress in this challenging topic will boost her profile to young leader research positions, not only at the junior level but also to more independent senior status. In addition, the raised trans-disciplinary MOFtor approach will significantly contribute to develop breakthrough enabling-technologies (mainly at biomedical science & chemical engineering fields) since, the wealth of fundamental knowledge potentially generated here (eg. MOFtor stability, muco-diffusion, cellular or immune-repercussion, etc.) will be highly valuable for other socioeconomic relevant fields such as challenging illnesses (eg. infectious, neurological, cardiovascular), environment, catalysis or sensing, among others. In fact, this hot topic is highly accordance with the 5 missions marked by the EU in Horizon2020 (eg. design of advanced materials to meet specific applications needs such as cancer, climate-change adaptation, oceans restoration, etc.), thus, if this MOFtor technology investigation continue in a fruitful and result-oriented manner, not only the patient ‘quality-life would be significantly transformed, but also will potentially reduce the current healthcare costs (€380bn for EU countries). Therefore, NeuroMOF project has served as starting point for shedding light on potential triggered mobility mechanisms for a safe tissue penetration and more targeted & effective MOF therapies, which could impact on the EU healthcare system in a medium-long term.