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We report herein a very efficient synthesis strategy for the construction of artificial transient-binding protein-mimic nano-objects. Michael addition-mediated multidirectional self-assembly of individual polymeric chains at r.t. leads to >Michael> nanocarriers that in solution resemble disordered multidomain proteins, as revealed by a combination of small angle neutron scattering measurements and coarse-grained molecular dynamics simulation results, whereas in the dry state adopt a collapsed, globular morphology, as observed by transmission electron microscopy. This extended-to-compact morphology transition taking place upon solvent removal is of paramount importance, among other applications, for the construction of efficient biosensors based on immobilized protein-mimic nano-objects and for the development of transient vitamin-binding systems. As a proof of concept, we show the controlled delivery of vitamin B9 from these novel transient-binding nanocarriers. © 2013 American Chemical Society. ; Financial support from the projects MAT2012-31088 (MINECO) and IT-654-13 (GV) is acknowledged. A. S.-S. thanks the PhD grant support of Basque Government. Has been supported by the European Commission under the 7th Framework Programme through the 'Research Infrastructures' action of the 'Capacities' Programme, NMI3-II Grant number 283883. ; Peer Reviewed

This is the accepted manuscript of the following article: Saraiva, S., Castro-López, V., Pañeda, C., & Alonso, M. (2017). Synthetic nanocarriers for the delivery of polynucleotides to the eye. European Journal Of Pharmaceutical Sciences, 103, 5-18. doi:10.1016/j.ejps.2017.03.001 ; This review is a comprehensive analysis of the progress made so far on the delivery of polynucleotide-based therapeutics to the eye, using synthetic nanocarriers. Attention has been addressed to the capacity of different nanocarriers for the specific delivery of polynucleotides to both, the anterior and posterior segments of the eye, with emphasis on their ability to (i) improve the transport of polynucleotides across the different eye barriers; (ii) promote their intracellular penetration into the target cells; (iii) protect them against degradation and, (iv) deliver them in a long-term fashion way. Overall, the conclusion is that despite the advantages that nanotechnology may offer to the area of ocular polynucleotide-based therapies (especially AS-ODN and siRNA delivery), the knowledge disclosed so far is still limited. This fact underlines the necessity of more fundamental and product-oriented research for making the way of the said nanotherapies towards clinical translation ; This work was supported by the European Union's Horizon 2020 - Research and Innovation Framework Programme under the Marie Sklodowska-Curie Grant agreement No. 642028 (NABBA) and by the Spanish Ministry of Economy and Competitiveness (MINECO) under Grant agreement No. RTC-2014-2375-1 (SURFeye) ; SI

Targeted nanomaterials for cancer theranostics have been the subject of an expanding volume of research studies in recent years. Mesoporous silica nanoparticles (MSNs) are particularly attractive for such applications due to possibilities to synthesize nanoparticles (NPs) of different morphologies, pore diameters and pore arrangements, large surface areas and various options for surface functionalization. Functionalization of MSNs with different organic and inorganic molecules, polymers, surface-attachment of other NPs, loading and entrapping cargo molecules with on-desire release capabilities, lead to seemingly endless prospects for designing advanced nanoconstructs exerting multiple functions, such as simultaneous cancer-targeting, imaging and therapy. Describing composition and multifunctional capabilities of these advanced nanoassemblies for targeted therapy (passive, ligand-functionalized MSNs, stimuli-responsive therapy), including one or more modalities for imaging of tumors, is the subject of this review article, along with an overview of developments within a novel and attractive research trend, comprising the use of MSNs for CRISPR/Cas9 systems delivery and gene editing in cancer. Such advanced nanconstructs exhibit high potential for applications in image-guided therapies and the development of personalized cancer treatment. ; The authors would like to thank the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No: 451-03-9/2021-14/200358), the Science Fund of the Republic of Serbia, PROMIS (PRECAST Grant No: 6060755) and European Union's Horizon 2020 research and innovation programme under grant agreement No. 952259 (NANOFACTS) and grant agreement No. 758887 (REACT) for financial support.

Publisher's version (útgefin grein) ; Nowadays, advancements in the oncology sector regarding diagnosis methods allow us to specifically detect an increased number of cancer patients, some of them in incipient stages. However, one of the main issues consists of the invasive character of most of the diagnosis protocols or complex medical procedures associated with it, that impedes part of the patients to undergo routine checkups. Therefore, in order to increase the number of cancer cases diagnosed in incipient stages, other minimally invasive alternatives must be considered. The current review paper presents the value of rare RNA species isolated from circulatory exosomes as biomarkers of diagnosis, prognosis or even therapeutic intervention. Rare RNAs are most of the time overlooked in current research in favor of the more abundant RNA species like microRNAs. However, their high degree of stability, low variability and, for most of them, conservation across species could shift the interest toward these types of RNAs. Moreover, due to their low abundance, the variation interval in terms of the number of sequences with differential expression between samples from healthy individuals and cancer patients is significantly diminished and probably easier to interpret in a clinical context. ; This research was funded by three national research grants from the Romanian Government: the first one awarded for Frontiers Research Projects 2018-2022 (grant number PN-III-P4-ID-PCCF-2016-112) to Babes Bolyai University, Cluj-Napoca, in collaboration with the Ion Chiricuta Oncology Institute, Cluj-Napoca; the second one awarded for Young Research Teams 2020-2022 (grant number PN-III-P1-1.1-TE2019-0271) to Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, and the third one awarded for Postdoctoral Research Projects 2020-2022 (grant number PN-III-P1-1.1-PD-2019-0805) to Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca. The APC was funded by an international collaborative grant from the European Economic Space between Romania and Iceland 2020-2022 (grant number 19-COP-0031). ; "Peer Reviewed"

To access publisher's full text version of this article click on the hyperlink below ; Nowadays, advancements in the oncology sector regarding diagnosis methods allow us to specifically detect an increased number of cancer patients, some of them in incipient stages. However, one of the main issues consists of the invasive character of most of the diagnosis protocols or complex medical procedures associated with it, that impedes part of the patients to undergo routine checkups. Therefore, in order to increase the number of cancer cases diagnosed in incipient stages, other minimally invasive alternatives must be considered. The current review paper presents the value of rare RNA species isolated from circulatory exosomes as biomarkers of diagnosis, prognosis or even therapeutic intervention. Rare RNAs are most of the time overlooked in current research in favor of the more abundant RNA species like microRNAs. However, their high degree of stability, low variability and, for most of them, conservation across species could shift the interest toward these types of RNAs. Moreover, due to their low abundance, the variation interval in terms of the number of sequences with differential expression between samples from healthy individuals and cancer patients is significantly diminished and probably easier to interpret in a clinical context. ; Romanian Government Ion Chiricuta Oncology Institute, Cluj-Napoca European Economic Space between Romania and Iceland 2020-2022

[EN] One appealing concept in the field of hybrid materials is related to the design of gated materials. These materials are prepared in such a way that the release of chemical or biochemical species from voids of porous supports to a solution is triggered upon the application of external stimuli. Such gated materials are mainly composed of two subunits: i) a porous inorganic scaffold in which a cargo is stored, and ii) certain molecular or supramolecular entities, grafted onto the external surface, that can control mass transport from the interior of the pores. On the basis of this concept, a large number of examples are developed in the past ten years. A comprehensive overview of gated materials used in drug delivery applications in in vivo models from 2016 to date is thus given here. ; The authors thank Spanish Government (Project No. RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE)) and Generalitat Valenciana (PROMETEO2018/024) for their support. ; García-Fernández, A.; Aznar, E.; Martínez-Máñez, R.; Sancenón Galarza, F. (2020). New Advances in In Vivo Applications of Gated Mesoporous Silica as Drug Delivery Nanocarriers. Small. 16(3):1-62. https://doi.org/10.1002/smll.201902242 ; S ; 1 ; 62 ; 16 ; 3 ; Tang, Q., Yu, B., Gao, L., Cong, H., Song, N., & Lu, C. (2018). Stimuli Responsive Nanoparticles for Controlled Anti-cancer Drug Release. Current Medicinal Chemistry, 25(16), 1837-1866. doi:10.2174/0929867325666180111095913 ; Aftab, S., Shah, A., Nadhman, A., Kurbanoglu, S., Aysıl Ozkan, S., Dionysiou, D. D., … Aminabhavi, T. M. (2018). Nanomedicine: An effective tool in cancer therapy. International Journal of Pharmaceutics, 540(1-2), 132-149. doi:10.1016/j.ijpharm.2018.02.007 ; Kozlovskaya, V., Xue, B., & Kharlampieva, E. (2016). Shape-Adaptable Polymeric Particles for Controlled Delivery. Macromolecules, 49(22), 8373-8386. doi:10.1021/acs.macromol.6b01740 ; Mishra, D. K., Shandilya, R., & Mishra, P. K. (2018). Lipid based nanocarriers: a translational perspective. Nanomedicine: Nanotechnology, Biology ...

Current chemotherapy for colorectal cancer (CRC) includes the use of oxaliplatin (Oxa), a first-line cytotoxic drug which, in combination with irinotecan/5-fluorouracil or biologic agents, increases the survival rate of patients. However, the administration of this drug induces side effects that limit its application in patients, making it necessary to develop new tools for targeted chemotherapy. MamC-mediated biomimetic magnetic nanoparticles coupled with Oxa (Oxa-BMNPs) have been previously demonstrated to efficiently reduce the IC50 compared to that of soluble Oxa. However, their strong interaction with the macrophages revealed toxicity and possibility of aggregation. In this scenario, a further improvement of this nanoassembly was necessary. In the present study, Oxa-BMNPs nanoassemblies were enveloped in phosphatidylcholine unilamellar liposomes (both pegylated and non-pegylated). Our results demonstrate that the addition of both a lipid cover and further pegylation improves the biocompatibility and cellular uptake of the Oxa-BMNPs nanoassemblies without significantly reducing their cytotoxic activity in colon cancer cells. In particular, with the pegylated magnetoliposome nanoformulation (a) hemolysis was reduced from 5% to 2%, being now hematocompatibles, (b) red blood cell agglutination was reduced, (c) toxicity in white blood cells was eliminated. This study represents a truly stepforward in this area as describes the production of one of the very few existing nanoformulations that could be used for a local chemotherapy to treat CRC. ; Ministerio de Economia y Competitividad from Spain CGL2016-76723 ; European Union (EU) CGL2016-76723 ; Junta de Andalucia A-BIO-376-UGR18 ; Unidad Cientifica de Excelencia of the University of Granada UCE-PP2016-05 ; Junta de Andalucia PI-0102-2017 ; Instituto de Salud Carlos III European Union (EU) PI19/01478 ; Andalusian Government CTS-107 ; Ministerio de Educacion, Ciencia y Deporte y Competitividad (Spain) FPU16_04580 FPU16_01716

The synthesis of nanosized metal–organic frameworks (NMOFs) is requisite for their application as injectable drug delivery systems (DDSs) and other biorelevant purposes. Herein, we have critically examined the role of different synthetic parameters leading to the production of UiO-66 crystals smaller than 100 nm. Of note, we demonstrate the co-modulator role conferred by halide ions, not only to produce NMOFs with precise morphology and size, but also to significantly improve the reaction yield. The resulting NMOFs are highly crystalline and exhibit sustained colloidal stability in different biologically relevant media. As a proof of concept, these NMOFs were loaded with Rhodamine 6G (R6G), which remained trapped in most common biologically relevant media. When incubated with living mammalian cells, the R6G-loaded NMOFs were efficiently internalized and did not impair cell viability even at relatively high doses. ; The authors acknowledge the financial support of the MCIN/AEI (PID2019-108624RB-I00, RYC-2017-23457, RYC-2019-028238-I), the Xunta de Galicia (ED431F 2017/02, ED431F 2020/11, 2021-CP090, Centro Singular de Investigación de Galicia Accreditation 2019–2022, ED431G 2019/03), the European Union (European RegionalDevelopment Fund – ERDF; H2020-MSCA-ITN grant agreement no. 860942; H2020-FET-Open grant agreement no. 899612; H2020-ICT grant agreement no. 10101694 and INTERREG V-A Spain–Portugal, project 0624_2IQBIONEURO_6_E), and the European Research Council (starting grant no. 950421). M.C.-M. thanks the AEI (FPU19/03155). The authors are grateful for the use of RIAIDT-USC analytical facilities. ; SI

Over the past ten years, the global biopharmaceutical market has remarkably grown, with ten over the top twenty worldwide high performance medical treatment sales being biologics. Thus, biotech R&D (research and development) sector is becoming a key leading branch, with expanding revenues. Biotechnology offers considerable advantages compared to traditional therapeutic approaches, such as reducing side effects, specific treatments, higher patient compliance and therefore more effective treatments leading to lower healthcare costs. Within this sector, smart nanotechnology and colloidal self-assembling systems represent pivotal tools able to modulate the delivery of therapeutics. A comprehensive understanding of the processes involved in the self assembly of the colloidal structures discussed therein is essential for the development of relevant biomedical applications. In this review we report the most promising and best performing platforms for specific classes of bioactive molecules and related target, spanning from siRNAs, gene/plasmids, proteins/growth factors, small synthetic therapeutics and bioimaging probes. ; Istituto Italiano di Tecnologia (IIT) ; COST Action [CA 15107] ; People Program (Marie Curie Actions) of the European Union's Seventh Framework Program under REA [606713 BIBAFOODS] ; Portuguese Foundation for Science and Technology (FCT) [PTDC/AGR-TEC/4814/2014, IF/01005/2014] ; Fundacao para a Ciencia e Tecnologia [SFRH/BPD/99982/2014] ; Danish National Research Foundation [DNRF 122] ; Villum Foundation [9301] ; Italian Ministry of Instruction, University and Research (MIUR), PRIN [20109PLMH2] ; "Fondazione Beneficentia Stiftung" Vaduz ; Fondo di Ateneo FRA ; FRA ; info:eu-repo/semantics/publishedVersion

Gonzalez-Alvarez, M.; Coll Merino, MC.; Gonzalez-Alvarez, I.; Giménez Morales, C.; Aznar, E.; Martínez-Bisbal, M.; Lozoya Agulló, I. (2017). Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue. Molecular Pharmaceutics. 14(12):4442-4453. https://doi.org/10.1021/acs.molpharmaceut.7b00565 ; 4442 4453 14 12 ; S ; [EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat ...

[EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects. ; The authors acknowledge the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, SAF2016-78756 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project GVA/2014/13). ; Gonzalez-Alvarez, M.; Coll Merino, MC.; Gonzalez-Alvarez, I.; Giménez Morales, C.; Aznar, ...

Simple Summary: The application of simultaneous and di erent strategies to treat cancer appears a promising therapeutic approach. Herein we proposed the application of chemotherapy combined with a magnetic nanocarrier delivery system to an in vitro and an in vivo experimental mammary carcinoma model. Drug-loaded biomimetic magnetic nanoparticle can be directed and concentrated on the tumor cells or site by the apposition of a magnet. Moreover, these nanoparticles can respond to an alternating magnetic field by developing hyperthermia around 43 C, a temperature at which tumor cells, but not healthy cells, are particularly sensitive and thus induced to death. Indeed, when this nanoformulation is injected in vivo in the tumor site, and hyperthermia is generated, the combined chemo-thermal therapy mediated by these drug-loaded magnetic nanoparticles have a stronger therapeutic benefit compared to that carried out by the chemotherapeutic alone. These nanoformulation and strategy are thus promising tools for translational applications in cancer therapy. Abstract: Biomimetic magnetic nanoparticles mediated by magnetosome proteins (BMNPs) are potential innovative tools for cancer therapy since, besides being multifunctional platforms, they can be manipulated by an external gradient magnetic field (GMF) and/or an alternating magnetic field (AMF), mediating targeting and hyperthermia, respectively. We evaluated the cytocompatibility/cytotoxicity of BMNPs and Doxorubicin (DOXO)-BMNPs in the presence/absence of GMF in 4T1 and MCF-7 cells as well as their cellular uptake. We analyzed the biocompatibility and in vivo distribution of BMNPs as well as the e ect of DOXO-BMNPs in BALB/c mice bearing 4T1 induced mammary carcinomas after applying GMF and AMF. Results: GMF enhanced the cell uptake of both BMNPs and DOXO-BMNPs and the cytotoxicity of DOXO-BMNPs. BMNPs were biocompatible when injected intravenously in BALB/c mice. The application of GMF on 4T1 tumors after each of the repeated (6 ) iv administrations of DOXO-BMNPs enhanced tumor growth inhibition when compared to any other treatment, including that with soluble DOXO. Moreover, injection of DOXO-BMNPs in the tumor combined with application of an AMF resulted in a significant tumor weight reduction. These promising results show the suitability of BMNPs as magnetic nanocarriers for local targeted chemotherapy and as local agents for hyperthermia. ; Spanish Government RYC-2014-16901 ; Junta de Andalucía, Programa Operativo FEDER 2014-2020 A1-FQM-341-UGR18 C-FQM-497-UGR18 ; Progetto di Ricerca Fondi di Ateneo per la Ricerca-FAR 2017 "Development of innovative biological materials for the functional regeneration of cardiac tissue models" ; Ministerio de Economia y Competitividad from Spain CGL2016-76723 ; European Union (EU) ; Junta de Andalucía A-BIO-376-UGR18 ; Unidad Científica de Excelencia of the University of Granada UCE-PP2016-05 ; Ministry of Economy and Competitiveness, Spain EST2019-013134-I EEBB-I-17-12558 58