Luminescent Alendronic Acid-Conjugated Micellar Nanostructures for Potential Application in the Bone-Targeted Delivery of Cholecalciferol.

Vitamin D, an essential micronutrient crucial for skeletal integrity and various non-skeletal physiological functions, exhibits limited bioavailability and stability in vivo. This study is focused on the development of polyethylene glycol (PEG)-grafted phospholipid micellar nanostructures co-encapsulating vitamin D3 and conjugated with alendronic acid, aimed at active bone targeting. Furthermore, these nanostructures are rendered optically traceable in the UV-visible region of the electromagnetic spectrum via the simultaneous encapsulation of vitamin D3 with carbon dots, a newly emerging class of fluorescents, biocompatible nanoparticles characterized by their resistance to photobleaching and environmental friendliness, which hold promise for future in vitro bioimaging studies. A systematic investigation is conducted to optimize experimental parameters for the preparation of micellar nanostructures with an average hydrodynamic diameter below 200 nm, ensuring colloidal stability in physiological media while preserving the optical luminescent properties of the encapsulated carbon dots. Comprehensive chemical-physical characterization of these micellar nanostructures is performed employing optical and morphological techniques. Furthermore, their binding affinity for the principal inorganic constituent of bone tissue is assessed through a binding assay with hydroxyapatite nanoparticles, indicating significant potential for active bone-targeting. These formulated nanostructures hold promise for novel therapeutic interventions to address skeletal-related complications in cancer affected patients in the future.

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases.

Extracellular vesicles (EVs), acting as inherent nanocarriers adept at transporting a range of different biological molecules such as proteins, lipids, and genetic material, exhibit diverse functions within the gastroenteric tract. In states of normal health, they participate in the upkeep of systemic and organ homeostasis. Conversely, in pathological conditions, they significantly contribute to the pathogenesis of gastrointestinal diseases (GIDs). Isolating EVs from patients' biofluids facilitates the discovery of new biomarkers that have the potential to offer a rapid, cost-effective, and non-invasive method for diagnosing and prognosing specific GIDs. Furthermore, EVs demonstrate considerable therapeutic potential as naturally targeted physiological carriers for the intercellular delivery of therapeutic cargo molecules or as nanoscale tools engineered specifically to regulate physio-pathological conditions or disease progression. Their attributes including safety, high permeability, stability, biocompatibility, low immunogenicity, and homing/tropism capabilities contribute to their promising clinical therapeutic applications. This review will delve into various examples of EVs serving as biomarkers or nanocarriers for therapeutic cargo in the context of GIDs, highlighting their clinical potential for both functional and structural gastrointestinal conditions. The versatile and advantageous properties of EVs position them as promising candidates for innovative therapeutic strategies in advancing personalized medicine approaches tailored to the gastroenteric tract, addressing both functional and structural GIDs.

Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to some metabolic disorders, such as central obesity and type 2 diabetes (T2D). Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, may have therapeutic roles in MASLD associated with T2D. This study aims to investigate the molecular mechanisms underlying the effectiveness of semaglutide on MASLD in terms of progression from liver steatosis to fibrosis. We characterized exosomes from ten patients with type 2 diabetes (T2D) before (T0) and after 12 months (T12) of treatment with once-weekly subcutaneous semaglutide. Six of ten patients were considered responders to therapy (R) based on MASLD severity downgrading by at least one class according to a validated ultrasonographic (US) score. Normal hepatocytes (HEPA-RG) and stellate (LX-2) cells were challenged with exosomes from R and NR patients, isolated before and after 12 months of therapy. Exosomes from both R and NR patients isolated at T0 significantly affected LX-2 viability. After 12 months of treatment, only those isolated from R patients restored cell viability, whereas those from NR patients did not. No effects were observed on HEPA-RG cells. Exosomes at T12 from R but not from NR patients significantly decreased the production of α-SMA, a marker of LX-2 activation, a liver stellate cell model, and ph-SMAD2 and CTGF, involved in fibrosis processes. TGF-ß1 was not modulated by the exosomes of R and NR patients. As a downstream effect, Vimentin, Collagen 1A1, and Fibronectin extracellular matrix components were also downregulated, as measured by droplets digital PCR. In conclusion, these results shed light on the potential effectiveness of semaglutide in improving liver fibrosis in MASLD.

The oleic/palmitic acid imbalance in exosomes isolated from NAFLD patients induces necroptosis of liver cells via the elongase-6/RIP-1 pathway.

Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression. Aim of the study was to highlight the PA/OA imbalance within circulating exosomes, the subsequent intracellular alterations, and the impact on NALFD. Liver cells were challenged with exosomes isolated from both healthy subjects and NAFLD patients. The exosomal PA/OA ratio was artificially modified, and biological effects were evaluated. A NAFLD-derived exosomal PA/OA imbalance impacts liver cell cycle and cell viability. OA-modified NAFLD-derived exosomes restored cellular viability and proliferation, whereas the inclusion of PA into healthy subjects-derived exosomes negatively affected cell viability. Moreover, while OA reduced the phosphorylation and activation of the necroptosis marker, Receptor-interacting protein 1 (phospho-RIP-1), PA induced the opposite outcome, alongside increased levels of stress fibers, such as vimentin and fibronectin. Administration of NAFLD-derived exosomes led to increased expression of Elongase 6 (ELOVL6), Stearoyl-CoA desaturase 1 (SCD1), Tumor necrosis factor α (TNF-α), Mixed-lineage-kinase-domain-like-protein (MLKL) and RIP-1 in the hepatocytes, comparable to mRNA levels in the hepatocytes of NAFLD patients reported in the Gene Expression Omnibus (GEO) database. Genetic and pharmacological abrogation of ELOVL6 elicited a reduced expression of downstream molecules TNF-α, phospho-RIP-1, and phospho-MLKL upon administration of NAFLD-derived exosomes. Lastly, mice fed with high-fat diet exhibited higher phospho-RIP-1 than mice fed with control diet. Targeting the Elongase 6-RIP-1 signaling pathway offers a novel therapeutic approach for the treatment of the NALFD-induced exosomal PA/OA imbalance.

Encapsulation of MCC950 in Liposomes Decorated with Anti-Frizzled 1 Improves Drug Bioavailability and Effectiveness in Fatty Liver Disease.

Inflammasome activation plays a crucial role in the progression to more severe stages of non-alcoholic fatty liver disease (NAFLD), representing a promising therapeutic target. MCC950 is a small molecule acting as a potent and specific inhibitor of the canonical and non-canonical activation of the NLRP3 inflammasome, but its short plasmatic half-life limits its use. Herein, we report, for the first time, the encapsulation of MCC950 in poly(ethylene glycol) (PEG) liposomes (LPs) that are specifically functionalized with an antibody against Frizzled 1 (FZD1), a g-coupled protein involved in the WNT pathway and overexpressed on inflammasome-activated macrophages. MCC950, encapsulated into PEG-LP formulations conjugated with an anti-FZD1 antibody, inhibits the NLRP3 inflammasome activation at concentrations 10 times lower than that of the free drug in THP-1 cells. Luminescent carbon dots (CDs) were also co-encapsulated with MCC950 in LPs to obtain optically traceable nanoformulations that have proved the enhanced ability of the targeted LPs to be internalized into THP-1 cells with respect to their nontargeted counterparts. Our results suggest that MCC950 encapsulation into targeted LPs represents a valuable strategy to achieve reformulation of the NLRP3 inhibitor, able to significantly curtail the threshold of MCC950 doses for inhibiting inflammasome activation, thus offering a new therapeutic approach.

The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel-mediated resistance in gastric cancer cell lines.

Introduction: Paclitaxel (PTX) interferes with microtubule architecture by binding to ß-tubulin, thereby blocking progression at the G2/M phase and inducing apoptosis. This study aimed to investigate molecular processes underlying PTX-mediated resistance in gastric cancer (GC) cells. Methods: PTX-mediated resistance involves many processes, and in this work some of the factors involved in the resistance mechanism were identified by comparing two GC lines with PTX induced resistance to their sensitive counterparts. Results: Thus, the key feature of PTX-resistant cells was the overexpression of pro-angiogenic factors such as VEGFA, VEGFC, and Ang2, known to support tumor cell growth. A second relevant change detected in PTX-resistant lines was the elevated level of TUBßIII, a tubulin isoform that opposes microtubule stabilization. A third identified factor contributing to PTX-resistance was P-glycoprotein (P-gp), a transporter responsible for chemotherapy efflux from the cells, highly expressed in PTX-resistant lines. Discussion: These findings were in line with a greater sensitivity of resistant cells to treatment with both Ramucirumab and Elacridar. Ramucirumab significantly reduced the expression of angiogenic molecules and TUBßIII, while Elacridar restored the access of chemotherapy, recovering its anti-mitotic and pro-apoptotic effects. Finally, this study highlighted the role played by exosomes in spreading factors responsible for resistance in the tumor microenvironment.

Synthesis and Characterization of SPIONs Encapsulating Polydopamine Nanoparticles and Their Test for Aqueous Cu2+ Ion Removal.

The removal of pollutants, such as heavy metals, aromatic compounds, dyes, pesticides and pharmaceuticals, from water is still an open challenge. Many methods have been developed and exploited for the purification of water from contaminants, including photocatalytic degradation, biological treatment, adsorption and chemical precipitation. Absorption-based techniques are still considered among the most efficient and commonly used approaches thanks to their operational simplicity. In recent years, polydopamine-coated magnetic nanoparticles have emerged for the uptake of heavy metals in water treatment, since they combine specific affinity towards pollutants and magnetic separation capacity. In this context, this work focuses on the synthesis of polydopamine (PDA)-coated Super Paramagnetic Iron Oxide Nanoparticles (PDA@SPIONs) as adsorbents for Cu2+ ions, designed to serve as functional nanostructures for the removal of Cu2+ from water by applying a magnetic field. The synthetic parameters, including the amount of SPIONs and PDA, were thoroughly investigated to define their effects on the nanostructure features and properties. Subsequently, the ability of the magnetic nanostructures to bind metal ions was assessed on Cu2+-containing solutions. A systematic investigation of the prepared functional nanostructures was carried out by means of complementary spectroscopic, morphological and magnetic techniques. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) measurements were performed in order to estimate the Cu2+ binding ability. The overall results indicate that these nanostructures hold great promise for future bioremediation applications.

Assembling Near-Infrared Dye on the Surface of Near-Infrared Silica-Coated Copper Sulphide Plasmonic Nanoparticles.

Functionalization of colloidal nanoparticles with organic dyes, which absorb photons in complementary spectral ranges, brings a synergistic effect for harvesting additional light energy. Here, we show functionalization of near-infrared (NIR) plasmonic nanoparticles (NPs) of bare and amino-group functionalized mesoporous silica-coated copper sulphide (Cu2-xS@MSS and Cu2-xS@MSS-NH2) with specific tricarbocyanine NIR dye possessing sulfonate end groups. The role of specific surface chemistry in dye assembling on the surface of NPs is demonstrated, depending on the organic polar liquids or water used as a dispersant solvent. It is shown that dye binding to the NP surfaces occurs with different efficiency, but mostly in the monomer form in polar organic solvents. Conversely, the aqueous medium leads to different scenarios according to the NP surface chemistry. Predominant formation of the disordered dye monomers occurs on the bare surface of mesoporous silica shell (MSS), whereas the amino-group functionalized MSS accepts dye predominantly in the form of dimers. It is found that the dye-NP interaction overcomes the dye-dye interaction, leading to disruption of dye J-aggregates in the presence of the NPs. The different organization of the dye molecules on the surface of silica-coated copper sulphide NPs provides tuning of their specific functional properties, such as hot-band absorption and photoluminescence.

Plasma-Derived Exosomes from NAFLD Patients Modulate the Cannabinoid Receptors' Expression in Cultured HepaRG Cells.

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors' expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.

Au nanoparticles decorated nanographene oxide-based platform: Synthesis, functionalization and assessment of photothermal activity.

A novel hybrid nanocomposite formed of carboxylated Nano Graphene Oxide (c-NGO), highly densely decorated by monodisperse citrate-coated Au nanoparticles (c-NGO/Au NPs), is synthesized and thoroughly characterized for photothermal applications. A systematic investigation of the role played by the synthetic parameters on the Au NPs decoration of the c-NGO platform is performed, comprehensively studying spectroscopic and morphological characteristics of the achieved nanostructures, thus elucidating their still not univocally explained synthesis mechanism. Remarkably, the Au NPs coating density of the c-NGO sheets is much higher than state-of-the-art systems with analogous composition prepared with different approaches, along with a higher NPs size dispersion. A novel theoretical approach for estimating the average number of NPs per sheet, combining DLS and TEM results, is developed. The assessment of the c-NGO/Au NPs photothermal activity is performed under continuous wave (CW) laser irradiation, at 532 nm and 800 nm, before and after functionalization with PEG-SH. c-NGO/Au NPs composite behaves as efficient photothermal agent, with a light into heat conversion ability higher than that of the single components. The c-NGO/Au NPs compatibility for photothermal therapy is assessed by in vitro cell viability tests, which show no significant effects of c-NGO/Au NPs, as neat and PEGylated, on cell metabolic activity under the investigated conditions. These results demonstrate the great potential held by the prepared hybrid nanocomposite for photothermal conversion technologies, indicating it as particularly promising platform for photothermal ablation of cancer cells.

Understanding the Effect of the Synthetic Method and Surface Chemistry on the Properties of CsPbBr3 Nanoparticles.

Over the last decade, the attractive properties of CsPbBr3 nanoparticles (NPs) have driven ever-increasing progress in the development of synthetic procedures to obtain high-quality NPs at high concentrations. Understanding how the properties of NPs are influenced by the composition of the reaction mixture in combination with the specific synthetic methodology is crucial, both for further elucidating the fundamental characteristics of this class of materials and for their manufacturing towards technological applications. This work aims to shed light on this aspect by synthesizing CsPbBr3 NPs by means of two well-assessed synthetic procedures, namely, hot injection (HI) and ligand-assisted reprecipitation (LARP) in non-polar solvents, using PbBr2 and Cs2CO3 as precursors in the presence of already widely investigated ligands. The overall goal is to study and compare the properties of the NPs to understand how each synthetic method influences the NPs' size and/or the optical properties. Reaction composition and conditions are purposely tuned towards the production of nanocubes with narrow size distribution, high emission properties, and the highest achievable concentration. As a result, the formation of bulk crystals as precipitate in LARP limits the achievement of a highly concentrated NP solution. The size of the NPs obtained by LARP seems to be poorly affected by the ligands' nature and the excess bromide, as consequence of bromide-rich solvation agents, effectively results in NPs with excellent emission properties. In contrast, NPs synthesized by HI exhibit high reaction yield, diffusion growth-controlled size, and less striking emission properties, probably ascribed to a bromide-deficient condition.

NIR-Absorbing Mesoporous Silica-Coated Copper Sulphide Nanostructures for Light-to-Thermal Energy Conversion.

Plasmonic nanostructures, featuring near infrared (NIR)-absorption, are rising as efficient nanosystems for in vitro photothermal (PT) studies and in vivo PT treatment of cancer diseases. Among the different materials, new plasmonic nanostructures based on Cu2-xS nanocrystals (NCs) are emerging as valuable alternatives to Au nanorods, nanostars and nanoshells, largely exploited as NIR absorbing nanoheaters. Even though Cu2-xS plasmonic properties are not linked to geometry, the role played by their size, shape and surface chemistry is expected to be fundamental for an efficient PT process. Here, Cu2-xS NCs coated with a hydrophilic mesoporous silica shell (MSS) are synthesized by solution-phase strategies, tuning the core geometry, MSS thickness and texture. Besides their loading capability, the silica shell has been widely reported to provide a more robust plasmonic core protection than organic molecular/polymeric coatings, and improved heat flow from the NC to the environment due to a reduced interfacial thermal resistance and direct electron-phonon coupling through the interface. Systematic structural and morphological analysis of the core-shell nanoparticles and an in-depth thermoplasmonic characterization by using a pump beam 808 nm laser, are carried out. The results suggest that large triangular nanoplates (NPLs) coated by a few tens of nanometers thick MSS, show good photostability under laser light irradiation and provide a temperature increase above 38 °C and a 20% PT efficiency upon short irradiation time (60 s) at 6 W/cm2 power density.

Polydopamine-Coated Magnetic Iron Oxide Nanoparticles: From Design to Applications.

Magnetic iron oxide nanoparticles have been extensively investigated due to their applications in various fields such as biomedicine, sensing, and environmental remediation. However, they need to be coated with a suitable material in order to make them biocompatible and to add new functionalities on their surface. This review is intended to give a comprehensive overview of recent advantages and applications of iron oxide nanoparticles coated by polydopamine film. The synthesis method of magnetic nanoparticles, their functionalization with bioinspired materials and (in particular) with polydopamine are discussed. Finally, some interesting applications of polydopamine-coated magnetic iron oxide nanoparticles will be pointed out.

Exosomal FZD-7 Expression Is Modulated by Different Lifestyle Interventions in Patients with NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition characterized from hypertriglyceridemia and hepatic fat accumulation, in the absence of alcohol intake. NAFLD starts as steatosis (NAFL), and the continued injury relative to the toxic fat induces inflammation, steatohepatitis (NASH), and HCC. One of the factors determining liver degeneration during the evolution of NAFLD is a modification of Wnt/Frizzled (FZD) signaling. In particular, an inhibition of Wnt signaling and an overexpression of a specific FZD receptor protein, namely, the FZD7, have been observed in NAFLD. Actually, the prognosis and the follow-up of NAFLD is not easy, and the liver biopsy is the gold standard for an accurate detection of liver fibrosis. In this study, the modulation of the FZD7 expression levels in plasma-derived exosomes of NAFLD-affected patients, before and after specific lifestyle interventions, were experimentally evaluated by Western blotting analysis. The experimental data were analyzed by an accurate statistical study that indicated, in the exosomes derived from plasma of NAFLD patients with moderate or severe steatosis, an average expression level of FZD7 that was significantly higher than healthy subjects at baseline; conversely, the values were normalized after 90 days of specific lifestyle interventions. The overall results suggested that the FZD7 delivered by exosomes represents a good candidate as a new and effective biomarker for diagnosis and prognosis of NAFLD.

Magnetic implants in vivo guiding sorafenib liver delivery by superparamagnetic solid lipid nanoparticles.

HYPOTHESIS: Solid lipid nanoparticles (SLNs), co-encapsulating superparamagnetic iron oxide nanoparticles and sorafenib, have been exploited for magnetic-guided drug delivery to the liver. Two different magnetic configurations, both comprising two small magnets, were under-skin implanted to investigate the effect of the magnetic field topology on the magnetic SLNP accumulation in liver tissues. A preliminary simulation analysis was performed to predict the magnetic field topography for each tested configuration. EXPERIMENTS: SLNs were prepared using a hot homogenization approach and characterized using complementary techniques. Their in vitro biological behavior was assessed in HepG-2 liver cancer cells; wild-type mice were used for the in vivo study. The magnet configuration that resulted in a higher magnetic targeting efficiency was investigated by evaluating the iron content in homogenated murine liver tissues. FINDINGS: SLNs, characterized by an average size smaller than 200 nm, retained their superparamagnetic behavior and relevant molecular resonance imaging properties as negative contrast agents. The evaluation of iron accumulation in the liver tissues was consistent with the magnetic induction profile of each magnet configuration, concurring with the results predicted by simulation analysis and obtained by measurements in living mice.

Luminescent PLGA Nanoparticles for Delivery of Darunavir to the Brain and Inhibition of Matrix Metalloproteinase-9, a Relevant Therapeutic Target of HIV-Associated Neurological Disorders.

Human immunodeficiency virus (HIV) can independently replicate in the central nervous system (CNS) causing neurocognitive impairment even in subjects with suppressed plasma viral load. The antiretroviral drug darunavir (DRV) has been approved for therapy of HIV-infected patients, but its efficacy in the treatment of HIV-associated neurological disorders (HAND) is limited due to the low penetration through the blood-brain barrier (BBB). Therefore, innovations in DRV formulations, based on its encapsulation in optically traceable nanoparticles (NPs), may improve its transport through the BBB, providing, at the same time, optical monitoring of drug delivery within the CNS. The aim of this study was to synthesize biodegradable polymeric NPs loaded with DRV and luminescent, nontoxic carbon dots (C-Dots) and investigate their ability to permeate through an artificial BBB and to inhibit in vitro matrix metalloproteinase-9 (MMP-9) that represents a factor responsible for the development of HIV-related neurological disorders. Biodegradable poly(lactic-co-glycolic) acid (PLGA)-based nanoformulations resulted characterized by an average hydrodynamic size less than 150 nm, relevant colloidal stability in aqueous medium, satisfactory drug encapsulation efficiency, and retained emitting optical properties in the visible region of the electromagnetic spectrum. The assay on the BBB artificial model showed that a larger amount of DRV was able to cross BBB when incorporated in the PLGA NPs and to exert an enhanced inhibition of matrix metalloproteinase-9 (MMP-9) expression levels with respect to free DRV. The overall results reveal the great potential of this class of nanovectors of DRV for an efficacious treatment of HANDs.

Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer.

Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.

High Surface Area Mesoporous Silica Nanoparticles with Tunable Size in the Sub-Micrometer Regime: Insights on the Size and Porosity Control Mechanisms.

Mesoporous silica nanostructures (MSNs) attract high interest due to their unique and tunable physical chemical features, including high specific surface area and large pore volume, that hold a great potential in a variety of fields, i.e., adsorption, catalysis, and biomedicine. An essential feature for biomedical application of MSNs is limiting MSN size in the sub-micrometer regime to control uptake and cell viability. However, careful size tuning in such a regime remains still challenging. We aim to tackling this issue by developing two synthetic procedures for MSN size modulation, performed in homogenous aqueous/ethanol solution or two-phase aqueous/ethyl acetate system. Both approaches make use of tetraethyl orthosilicate as precursor, in the presence of cetyltrimethylammonium bromide, as structure-directing agent, and NaOH, as base-catalyst. NaOH catalyzed syntheses usually require high temperature (>80 °C) and large reaction medium volume to trigger MSN formation and limit aggregation. Here, a successful modulation of MSNs size from 40 up to 150 nm is demonstrated to be achieved by purposely balancing synthesis conditions, being able, in addition, to keep reaction temperature not higher than 50 °C (30 °C and 50 °C, respectively) and reaction mixture volume low. Through a comprehensive and in-depth systematic morphological and structural investigation, the mechanism and kinetics that sustain the control of MSNs size in such low dimensional regime are defined, highlighting that modulation of size and pores of the structures are mainly mediated by base concentration, reaction time and temperature and ageing, for the homogenous phase approach, and by temperature for the two-phase synthesis. Finally, an in vitro study is performed on bEnd.3 cells to investigate on the cytotoxicity of the MNSs.

A Possible Role of FZD10 Delivering Exosomes Derived from Colon Cancers Cell Lines in Inducing Activation of Epithelial-Mesenchymal Transition in Normal Colon Epithelial Cell Line.

Exosomes belong to the family of extracellular vesicles released by every type of cell both in normal and pathological conditions. Growing interest in studies indicates that extracellular vesicles, in particular, the fraction named exosomes containing lipids, proteins and nucleic acid, represent an efficient way to transfer functional cargoes between cells, thus combining all the other cell-cell interaction mechanisms known so far. Only a few decades ago, the involvement of exosomes in the carcinogenesis in different tissues was discovered, and very recently it was also observed how they carry and modulate the presence of Wnt pathway proteins, involved in the carcinogenesis of gastrointestinal tissues, such as Frizzled 10 protein (FZD10), a membrane receptor for Wnt. Here, we report the in vitro study on the capability of tumor-derived exosomes to induce neoplastic features in normal cells. Exosomes derived from two different colon cancer cell lines, namely the non-metastatic CaCo-2 and the metastatic SW620, were found to deliver, in both cases, FZD10, thus demonstrating the ability to reprogram normal colonic epithelial cell line (HCEC-1CT). Indeed, the acquisition of specific mesenchymal characteristics, such as migration capability and expression of FZD10 and markers of mesenchymal cells, was observed. The exosomes derived from the metastatic cell line, characterized by a level of FZD10 higher than the exosomes extracted from the non-metastatic cells, were also more efficient in stimulating EMT activation. The overall results suggest that FZD10, delivered by circulating tumor-derived exosomes, can play a relevant role in promoting the CRC carcinogenesis and propagation.