Magnetic colloidal nanoformulations to remotely trigger mechanotransduction for osteogenic differentiation.

Nowadays, diseases associated with an ageing population, such as osteoporosis, require the development of new biomedical approaches to bone regeneration. In this regard, mechanotransduction has emerged as a discipline within the field of bone tissue engineering. Herein, we have tested the efficacy of superparamagnetic iron oxide nanoparticles (SPIONs), obtained by the thermal decomposition method, with an average size of 13 nm, when exposed to the application of an external magnetic field for mechanotransduction in human bone marrow-derived mesenchymal stem cells (hBM-MSCs). The SPIONs were functionalized with an Arg-Gly-Asp (RGD) peptide as ligand to target integrin receptors on cell membrane and used in colloidal state. Then, a comprehensive and comparative bioanalytical characterization of non-targeted versus targeted SPIONs was performed in terms of biocompatibility, cell uptake pathways and mechanotransduction effect, demonstrating the osteogenic differentiation of hBM-MSCs. A key conclusion derived from this research is that when the magnetic stimulus is applied in the first 30 min of the in vitro assay, i.e., when the nanoparticles come into contact with the cell membrane surface to initiate endocytic pathways, a successful mechanotransduction effect is observed. Thus, under the application of a magnetic field, there was a significant increase in runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) gene expression as well as ALP activity, when cells were exposed to RGD-functionalized SPIONs, demonstrating osteogenic differentiation. These findings open new expectations for the use of remotely activated mechanotransduction using targeted magnetic colloidal nanoformulations for osteogenic differentiation by drug-free cell therapy using minimally invasive techniques in cases of bone loss.

Large-scale production of superparamagnetic iron oxide nanoparticles by flame spray pyrolysis: In vitro biological evaluation for biomedical applications.

Despite the large number of synthesis methodologies described for superparamagnetic iron oxide nanoparticles (SPIONs), the search for their large-scale production for their widespread use in biomedical applications remains a mayor challenge. Flame Spray Pyrolysis (FSP) could be the solution to solve this limitation, since it allows the fabrication of metal oxide nanoparticles with high production yield and low manufacture costs. However, to our knowledge, to date such fabrication method has not been upgraded for biomedical purposes. Herein, SPIONs have been fabricated by FSP and their surface has been treated to be subsequently coated with dimercaptosuccinic acid (DMSA) to enhance their colloidal stability in aqueous media. The final material presents high quality in terms of nanoparticle size, homogeneous size distribution, long-term colloidal stability and magnetic properties. A thorough in vitro validation has been performed with peripheral blood cells and mesenchymal stem cells (hBM-MSCs). Specifically, hemocompatibility studies show that these functionalized FSP-SPIONs-DMSA nanoparticles do not cause platelet aggregation or impair basal monocyte function. Moreover, in vitro biocompatibility assays show a dose-dependent cellular uptake while maintaining high cell viability values and cell cycle progression without causing cellular oxidative stress. Taken together, the results suggest that the FSP-SPIONs-DMSA optimized in this work could be a worthy alternative with the benefit of a large-scale production aimed at industrialization for biomedical applications.

Antiadherent AgBDC Metal-Organic Framework Coating for Escherichia coli Biofilm Inhibition.

Surface microbial colonization and its potential biofilm formation are currently a major unsolved problem, causing almost 75% of human infectious diseases. Pathogenic biofilms are capable of surviving high antibiotic doses, resulting in inefficient treatments and, subsequently, raised infection prevalence rates. Antibacterial coatings have become a promising strategy against the biofilm formation in biomedical devices due to their biocidal activity without compromising the bulk material. Here, we propose for the first time a silver-based metal-organic framework (MOF; here denoted AgBDC) showing original antifouling properties able to suppress not only the initial bacterial adhesion, but also the potential surface contamination. Firstly, the AgBDC stability (colloidal, structural and chemical) was confirmed under bacteria culture conditions by using agar diffusion and colony counting assays, evidencing its biocide effect against the challenging E. coli, one of the main representative indicators of Gram-negative resistance bacteria. Then, this material was shaped as homogeneous spin-coated AgBDC thin film, investigating its antifouling and biocide features using a combination of complementary procedures such as colony counting, optical density or confocal scanning microscopy, which allowed to visualize for the first time the biofilm impact generated by MOFs via a specific fluorochrome, calcofluor.

Achievements in Mesoporous Bioactive Glasses for Biomedical Applications.

Nowadays, mesoporous bioactive glasses (MBGs) are envisaged as promising candidates in the field of bioceramics for bone tissue regeneration. This is ascribed to their singular chemical composition, structural and textural properties and easy-to-functionalize surface, giving rise to accelerated bioactive responses and capacity for local drug delivery. Since their discovery at the beginning of the 21st century, pioneering research efforts focused on the design and fabrication of MBGs with optimal compositional, textural and structural properties to elicit superior bioactive behavior. The current trends conceive MBGs as multitherapy systems for the treatment of bone-related pathologies, emphasizing the need of fine-tuning surface functionalization. Herein, we focus on the recent developments in MBGs for biomedical applications. First, the role of MBGs in the design and fabrication of three-dimensional scaffolds that fulfil the highly demanding requirements for bone tissue engineering is outlined. The different approaches for developing multifunctional MBGs are overviewed, including the incorporation of therapeutic ions in the glass composition and the surface functionalization with zwitterionic moieties to prevent bacterial adhesion. The bourgeoning scientific literature on MBGs as local delivery systems of diverse therapeutic cargoes (osteogenic/antiosteoporotic, angiogenic, antibacterial, anti-inflammatory and antitumor agents) is addressed. Finally, the current challenges and future directions for the clinical translation of MBGs are discussed.

La Farmacia en pequeño: Aproximación al mundo de los nanomateriales en sus aplicaciones farmacéuticas / Small Pharmacy: Approach to the world of nanomaterials in their pharmaceutical applications

En las últimas décadas el desarrollo de resistencias bacterianas y sus implicaciones terapéuticas se ha convertido en una de las principales amenazas en la Salud Mundial. Se habla incluso de la aparición de una nueva “era postantibiótica” en la que el tratamiento antimicrobiano será inútil, dado el carácter multirresistente de numerosos microorganismos. La nanotecnología ha irrumpido con mucho éxito en el tratamiento de diversas enfermedades (principalmente el cáncer), llegando a una nueva concepción en los sistemas terapéuticos con un gran impacto tecnológico. En este sentido, este discurso se centra en el empleo de los nanomateriales en el tratamiento de la infección ósea mediante tres vertientes. Entre ellas las nanopartículas de sílice mesoporosa, capaces de dirigirse específicamente a las bacterias y/o al biofilm, liberar de manera controlada distintos fármacos, aumentando así su eficacia terapéutica y reduciendo los efectos secundarios. Sin duda, la nanotecnología parece tener un gran potencial para superar la problemática en el tratamiento de las infecciones y revolucionar tanto la prevención como el tratamiento de estas infecciones bacterianas, que serán discutidas en el discurso de ingreso. (AU)

In recent decades, the development of bacterial resistance and its therapeutic implications has become one of the main threats to global health. There is even talk of the emergence of a new “post-antibiotic era” in which antimicrobial treatment will be useless, given the multi-resistant nature of many microorganisms. Nanotechnology has broken with great success in the treatment of different diseases (mainly cancer), reaching a new conception in therapeutic systems with a great technological impact. In this sense, this talking focuses on the use of nanomaterials in the treatment of bone infection in three approaches. These include mesoporous silica nanoparticles, capable of specifically targeting bacteria and biofilm, releasing different drugs in a controlled manner, thus increasing their therapeutic efficacy and reducing side effects. Certainly, nanotechnology seems to have great potential to overcome the problem in the treatment of infections and revolutionise both the prevention and treatment of these bacterial infections, and these will be discussed in the introductory speech. (AU)

Commemorative Issue in Honor of Professor María Vallet Regí: 20 Years of Silica-Based Mesoporous Materials.

This Special Issue entitled "Commemorative Issue in Honor of Professor María Vallet-Regí: 20 Years of Silica-Based Mesoporous Materials" arises from the initiative of the editorial team of Pharmaceutics to pay homage to Professor Maria Vallet-Regí for her ground-breaking pioneering scientific contribution to the field of silica-based mesoporous materials for biomedical applications [...].

Superparamagnetic Iron Oxide Nanoparticles Decorated Mesoporous Silica Nanosystem for Combined Antibiofilm Therapy.

A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from a unique magnetic-responsive nanocarrier for a combination therapy against biofilm. The design of the nanosystem is based on antibiotic-loaded mesoporous silica nanoparticles (MSNs) externally functionalized with a thermo-responsive polymer capping layer, and decorated in the outermost surface with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are able to generate heat upon application of an alternating magnetic field (AMF), reaching the temperature needed to induce a change in the polymer conformation from linear to globular, therefore triggering pore uncapping and the antibiotic cargo release. The microbiological assays indicated that exposure of E. coli biofilms to 200 µg/mL of the nanosystem and the application of an AMF (202 kHz, 30 mT) decreased the number of viable bacteria by 4 log10 units compared with the control. The results of the present study show that combined hyperthermia and antibiotic treatment is a promising approach for the effective management of biofilm-associated infections.

Incorporation of Superparamagnetic Iron Oxide Nanoparticles into Collagen Formulation for 3D Electrospun Scaffolds.

Nowadays, there is an ever-increasing interest in the development of systems able to guide and influence cell activities for bone regeneration. In this context, we have explored for the first time the combination of type-I collagen and superparamagnetic iron oxide nanoparticles (SPIONs) to design magnetic and biocompatible electrospun scaffolds. For this purpose, SPIONs with a size of 12 nm were obtained by thermal decomposition and transferred to an aqueous medium via ligand exchange with dimercaptosuccinic acid (DMSA). The SPIONs were subsequently incorporated into type-I collagen solutions to prove the processability of the resulting hybrid formulation by means of electrospinning. The optimized method led to the fabrication of nanostructured scaffolds composed of randomly oriented collagen fibers ranging between 100 and 200 nm, where SPIONs resulted distributed and embedded into the collagen fibers. The SPIONs-containing electrospun structures proved to preserve the magnetic properties of the nanoparticles alone, making these matrices excellent candidates to explore the magnetic stimuli for biomedical applications. Furthermore, the biological assessment of these collagen scaffolds confirmed high viability, adhesion, and proliferation of both pre-osteoblastic MC3T3-E1 cells and human bone marrow-derived mesenchymal stem cells (hBM-MSCs).

Nanoantibiotics Based in Mesoporous Silica Nanoparticles: New Formulations for Bacterial Infection Treatment.

This review focuses on the design of mesoporous silica nanoparticles for infection treatment. Written within a general context of contributions in the field, this manuscript highlights the major scientific achievements accomplished by professor Vallet-Regí's research group in the field of silica-based mesoporous materials for drug delivery. The aim is to bring out her pivotal role on the envisage of a new era of nanoantibiotics by using a deep knowledge on mesoporous materials as drug delivery systems and by applying cutting-edge technologies to design and engineer advanced nanoweapons to fight infection. This review has been divided in two main sections: the first part overviews the influence of the textural and chemical properties of silica-based mesoporous materials on the loading and release of antibiotic molecules, depending on the host-guest interactions. Furthermore, this section also remarks on the potential of molecular modelling in the design and comprehension of the performance of these release systems. The second part describes the more recent advances in the use of mesoporous silica nanoparticles as versatile nanoplatforms for the development of novel targeted and stimuli-responsive antimicrobial nanoformulations for future application in personalized infection therapies.

A versatile multicomponent mesoporous silica nanosystem with dual antimicrobial and osteogenic effects.

In this manuscript, we propose a simple and versatile methodology to design nanosystems based on biocompatible and multicomponent mesoporous silica nanoparticles (MSNs) for infection management. This strategy relies on the combination of antibiotic molecules and antimicrobial metal ions into the same nanosystem, affording a significant improvement of the antibiofilm effect compared to that of nanosystems carrying only one of these agents. The multicomponent nanosystem is based on MSNs externally functionalized with a polyamine dendrimer (MSN-G3) that favors internalization inside the bacteria and allows the complexation of multiactive metal ions (MSN-G3-Mn+). Importantly, the selection of both the antibiotic and the cation may be done depending on clinical needs. Herein, levofloxacin and Zn2+ ion, chosen owing to both its antimicrobial and osteogenic capability, have been incorporated. This dual biological role of Zn2+ could have and adjuvant effect thought destroying the biofilm in combination with the antibiotic as well as aid to the repair and regeneration of lost bone tissue associated to osteolysis during infection process. The versatility of the nanosystem has been demonstrated incorporating Ag+ ions in a reference nanosystem. In vitro antimicrobial assays in planktonic and biofilm state show a high antimicrobial efficacy due to the combined action of levofloxacin and Zn2+, achieving an antimicrobial efficacy above 99% compared to the MSNs containing only one of the microbicide agents. In vitro cell cultures with MC3T3-E1 preosteoblasts reveal the osteogenic capability of the nanosystem, showing a positive effect on osteoblastic differentiation while preserving the cell viability. STATEMENT OF SIGNIFICANCE: A simple and versatile methodology to design biocompatible and multicomponent MSNs based nanosystems for infection management is proposed. These nanosystems, containing two antimicrobial agents, levofloxacin and Zn2+, have been synthetized by external functionalization of MSNs with a polycationic dendrimer (MSNs-G3), which favours its internalization inside the bacteria and lead the complexation with metal ions through the amines of the dendrimer. The nanosystems offer a notable improvement of the antibiofilm effect (above 99%) than both components separately as well as osteogenic capability with positive effect on the osteoblastic differentiation and preserved cell viability.

Impact of the antibiotic-cargo from MSNs on Gram-positive and Gram-negative bacterial biofilms.

Mesoporous silica nanoparticles (MSNs) are promising drug nanocarriers for infection treatment. Many investigations have focused on evaluating the capacity of MSNs to encapsulate antibiotics and release them in a controlled fashion. However, little attention has been paid to determine the antibiotic doses released from these nanosystems that are effective against biofilm during the entire release time. Herein, we report a systematic and quantitative study of the direct effect of the antibiotic-cargo released from MSNs on Gram-positive and Gram-negative bacterial biofilms. Levofloxacin (LVX), gentamicin (GM) and rifampin (RIF) were separately loaded into pure-silica and amino-modified MSNs. This accounts for the versatility of these nanosystems since they were able to load and release different antibiotic molecules of diverse chemical nature. Biological activity curves of the released antibiotic were determined for both bacterial strains, which allowed to calculate the active doses that are effective against bacterial biofilms. Furthermore, in vitro biocompatibility assays on osteoblast-like cells were carried out at different periods of times. Albeit a slight decrease in cell viability was observed at the very initial stage, due to the initial burst antibiotic release, the biocompatibility of these nanosystems is evidenced since a recovery of cell viability was achieved after 72 h of assay. Biological activity curves for GM released from MSNs exhibited sustained patterns and antibiotic doses in the 2-6 µg/mL range up to 100 h, which were not enough to eradicate biofilm. In the case of LVX and RIF first-order kinetics featuring an initial burst effect followed by a sustained release above the MIC up to 96 h were observed. Such doses reduced by 99.9% bacterial biofilm and remained active up to 72 h with no emergence of bacterial resistance. This pioneering research opens up promising expectations in the design of personalized MSNs-based nanotherapies to treat chronic bone infection.

Bacteria as Nanoparticles Carrier for Enhancing Penetration in a Tumoral Matrix Model.

One of the major concerns in the application of nanocarriers in oncology is their scarce penetration capacity in tumoral tissues, which drastically compromises the effctivity. Living organisms as cells and bacteria present the capacity to navigate autonomously following chemical gradients being able to penetrate deeply into dense tissues. In the recent years, the possibility to employ these organisms for the transportation of therapeutic agents and nanocarriers attached on their membrane or engulfed in their inner space have received huge attention. Herein, based on this principle, a new approach to deliver drug loaded nanoparticles achieving high penetration in tumoral matrices is presented. In this case, Escherichia coli (E. coli) bacteria wall is decorated with azide groups, whereas alkyne-strained groups are incorporated on the surface of mesoporous silica nanoparticles loaded with a potent cytotoxic compound, doxorubicin. Both functional groups form stable triazole bonds by click-type reaction allowing the covalent grafting of nanoparticles on living bacteria. Thus, the motility and penetration capacity of bacteria, which carried nanoparticles are evaluated in a 3D tumoral matrix model composed by a dense collagen extracellular matrix with HT1080 human fibrosarcome cells embedded. The results confirmed that bacteria are able to transport the nanoparticles crossing a thick collagen layer being able to destroy almost 80% of the tumoral cells located underneath. These findings envision a powerful strategy in nanomedicine applied for cancer treatment by allowing a homogeneous distribution of therapeutic agents in the malignancy.

Biomaterials against Bone Infection.

Chronic bone infection is considered as one of the most problematic biofilm-related infections. Its recurrent and resistant nature, high morbidity, prolonged hospitalization, and costly medical care expenses have driven the efforts of the scientific community to develop new therapies to improve the standards used today. There is great debate on the management of this kind of infection in order to establish consistent and agreed guidelines in national health systems. The scientific research is oriented toward the design of anti-infective biomaterials both for prevention and cure. The properties of these materials must be adapted to achieve better anti-infective performance and good compatibility, which allow a good integration of the implant with the surrounding tissue. The objective of this review is to study in-depth the antibacterial biomaterials and the strategies underlying them. In this sense, this manuscript focuses on antimicrobial coatings, including the new technological advances on surface modification; scaffolding design including multifunctional scaffolds with both antimicrobial and bone regeneration properties; and nanocarriers based on mesoporous silica nanoparticles with advanced properties (targeting and stimuli-response capabilities).

Strontium-releasing mesoporous bioactive glasses with anti-adhesive zwitterionic surface as advanced biomaterials for bone tissue regeneration.

HYPOTHESIS: The treatment of bone fractures still represents a challenging clinical issue when complications due to impaired bone remodelling (i.e. osteoporosis) or infections occur. These clinical needs still require a radical improvement of the existing therapeutic approach through the design of advanced biomaterials combining the ability to promote bone regeneration with anti-adhesive properties able to minimise unspecific biomolecules adsorption and bacterial adhesion. Strontium-containing mesoporous bioactive glasses (Sr-MBG), which are able to exert a pro-osteogenic effect by releasing Sr2+ ions, have been successfully functionalised to provide mixed-charge (NH3⊕/COO⊝) surface groups with anti-adhesive abilities. EXPERIMENTS: Sr-MBG have been post-synthesis modified by co-grafting hydrolysable short chain silanes containing amino (aminopropylsilanetriol) and carboxylate (carboxyethylsilanetriol) moieties to achieve a zwitterionic zero-charge surface. The final system was then characterised in terms of textural-structural properties, bioactivity, cytotoxicity, pro-osteogenic and anti-adhesive capabilities. FINDINGS: After zwitterionization the in vitro bioactivity was maintained, as well as the ability to release Sr2+ ions which are capable of inducing a mineralization process. Irrespective of their size, Sr-MBG particles did not exhibit any cytotoxicity in pre-osteoblastic MC3T3-E1 up to the concentration of 75 µg/mL. Finally, the zwitterionic Sr-MBGs showed a significant reduction of serum protein adhesion with respect to the pristine ones. These results open promising future expectations in the design of nanosystems which combine pro-osteogenic and anti-adhesive properties.

Nanomaterials as Promising Alternative in the Infection Treatment.

Both the prevalence of antibiotic resistance and the increased biofilm-associated infections are boosting the demand for new advanced and more effective treatment for such infections. In this sense, nanotechnology offers a ground-breaking platform for addressing this challenge. This review shows the current progress in the field of antimicrobial inorganic-based nanomaterials and their activity against bacteria and bacterial biofilm. Herein, nanomaterials preventing the bacteria adhesion and nanomaterials treating the infection once formed are presented through a classification based on their functionality. To fight infection, nanoparticles with inherent antibacterial activity and nanoparticles acting as nanovehicles are described, emphasizing the design of the carrier nanosystems with properties targeting the bacteria and the biofilm.

Antibacterial Nanostructured Ti Coatings by Magnetron Sputtering: From Laboratory Scales to Industrial Reactors.

Based on an already tested laboratory procedure, a new magnetron sputtering methodology to simultaneously coat two-sides of large area implants (up to ~15 cm2) with Ti nanocolumns in industrial reactors has been developed. By analyzing the required growth conditions in a laboratory setup, a new geometry and methodology have been proposed and tested in a semi-industrial scale reactor. A bone plate (DePuy Synthes) and a pseudo-rectangular bone plate extracted from a patient were coated following the new methodology, obtaining that their osteoblast proliferation efficiency and antibacterial functionality were equivalent to the coatings grown in the laboratory reactor on small areas. In particular, two kinds of experiments were performed: Analysis of bacterial adhesion and biofilm formation, and osteoblasts-bacteria competitive in vitro growth scenarios. In all these cases, the coatings show an opposite behavior toward osteoblast and bacterial proliferation, demonstrating that the proposed methodology represents a valid approach for industrial production and practical application of nanostructured titanium coatings.

Concanavalin A-targeted mesoporous silica nanoparticles for infection treatment.

The ability of bacteria to form biofilms hinders any conventional treatment for chronic infections and has serious socio-economic implications. For this purpose, a nanocarrier capable of overcoming the barrier of the mucopolysaccharide matrix of the biofilm and releasing its loaded-antibiotic within this matrix would be desirable. Herein, we developed a new nanosystem based on levofloxacin (LEVO)-loaded mesoporous silica nanoparticles (MSN) decorated with the lectin concanavalin A (ConA). The presence of ConA promotes the internalization of this nanosystem into the biofilm matrix, which increases the antimicrobial efficacy of the antibiotic hosted within the mesopores. This nanodevice is envisioned as a promising alternative to conventional treatments for infection by improving the antimicrobial efficacy and reducing side effects. STATEMENT OF SIGNIFICANCE: The present study is focused on finding an adequate therapeutic solution for the treatment of bone infection using nanocarriers that are capable of overcoming the biofilm barrier by increasing the therapeutic efficacy of the loaded antibiotic. For this purpose, we present a nanoantibiotic that increases the effectiveness of levofloxacin to destroy the biofilm formed by the model bacterium E. coli. This work opens new lines of research in the treatment of chronic infections based on nanomedicines.

Zinc oxide nanocrystals as a nanoantibiotic and osteoinductive agent.

In this paper we aim to analyse the behaviour of ZnO nanocrystals (ZnO NCs), prepared with a new synthetic approach and not embedded in any composite matrix, for bone implant applications in vitro. In particular, we have developed a novel, fast and reproducible microwave-assisted synthesis, to obtain highly-crystalline, round-shaped ZnO NCs of 20 nm in diameter as an extremely-stable colloidal solution in ethanol. The nanocrystals were also partially chemically functionalized by anchoring amino-propyl groups to the ZnO surface (ZnO-NH2 NCs). Thus, the role of both ZnO NC concentration and surface chemistry were tested in terms of biocompatibility towards pre-osteoblast cells, promotion of cell proliferation and differentiation, and also in terms of antimicrobial activity against Gram positive and negative bacteria, such as Escherichia coli and Staphylococcus aureus, respectively. The results suggest that ZnO-NH2 NCs is the most promising candidate to solve infectious disease in bone implants and at the same time promote bone tissue proliferation, even at high concentrations. Although further investigations are needed to clarify the mechanism underlying the inhibition of biofilm formation and to investigate the role of the ZnO-NH2 NCs in in vivo assays, we demonstrated that fine and reproducible control over the chemical and structural parameters in ZnO nanomaterials can open up new horizons in the use of functionalized ZnO NCs as a highly biocompatible and osteoinductive nanoantibiotic agent for bone tissue engineering.

Advances in mesoporous silica nanoparticles for targeted stimuli-responsive drug delivery: an update.

INTRODUCTION: Mesoporous silica nanoparticles (MSNs) are outstanding nanoplatforms for drug delivery. Herein, the most recent advances to turn MSN-based carriers into minimal side effect drug delivery agents are covered. AREAS COVERED: This review summarizes the scientific advances dealing with MSNs for targeted and stimuli-responsive drug delivery since 2015. Delivery aspects to diseased tissues together with approaches to obtain smart MSNs able to respond to internal or external stimuli and their applications are here described. Special emphasis is done on the combination of two or more stimuli on the same nanoplatform and on combined drug therapy. EXPERT OPINION: The use of MSNs in nanomedicine is a promising research field because they are outstanding platforms for treating different pathologies. This is possible thanks to their structural, chemical, physical and biological properties. However, there are certain issues that should be overcome to improve the suitability of MSNs for clinical applications. All materials must be properly characterized prior to their in vivo evaluation; furthermore, preclinical in vivo studies need to be standardized to demonstrate the MSNs clinical translation potential.

Mixed-charge pseudo-zwitterionic mesoporous silica nanoparticles with low-fouling and reduced cell uptake properties.

The design of drug delivery systems needs to consider biocompatibility and host body recognition for an adequate actuation. In this work, mesoporous silica nanoparticles (MSNs) surfaces were successfully modified with two silane molecules to provide mixed-charge brushes (-NH3⊕/-PO3⊝) and well evaluated in terms of surface properties, low-fouling capability and cell uptake in comparison to PEGylated MSNs. The modification process consists in the simultaneous direct-grafting of hydrolysable short chain amino (aminopropyl silanetriol, APST) and phosphonate-based (trihydroxy-silyl-propyl-methyl-phosphonate, THSPMP) silane molecules able to provide a pseudo-zwitterionic nature under physiological pH conditions. Results confirmed that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN display a significant reduction of serum protein adhesion and macrophages uptake with respect to pristine MSNs. In the case of ZMSNs, this reduction is up to a 70-90% for protein adsorption and c.a. 60% for cellular uptake. This pseudo-zwitterionic modification has been focused on the aim of local treatment of bacterial infections through the synergistic effect between the inherent antimicrobial effect of mixed-charge system and the levofloxacin antibiotic release profile. These findings open promising future expectations for the effective treatment of bacterial infections through the use of mixed-charge pseudo-zwitterionic MSNs furtive to macrophages and with antimicrobial properties. STATEMENT OF SIGNIFICANCE: Herein a novel antimicrobial mixed-charge pseudo-zwitterionic MSNs based system with low-fouling and reduced cell uptake behavior has been developed. This chemical modification has been performed by the simultaneous grafting of short chain organosilanes, containing amino and phosphonate groups, respectively. This nanocarrier has been tested for local infection treatment through the synergy between the antimicrobial effect of mixed-charge brushes and the levofloxacin antibiotic release profile.