Biocompatible cellulose nanocrystal-based Trojan horse enables targeted delivery of nano-Au radiosensitizers to triple negative breast cancer cells.

A hybrid cellulose-based programmable nanoplatform for applications in precision radiation oncology is described. Here, sugar heads work as tumor targeting moieties and steer the precise delivery of radiosensitizers, i.e. gold nanoparticles (AuNPs) into triple negative breast cancer (TNBC) cells. This "Trojan horse" approach promotes a specific and massive accumulation of radiosensitizers in TNBC cells, thus avoiding the fast turnover of small-sized AuNPs and the need for high doses of AuNPs for treatment. Application of X-rays resulted in a significant increase of the therapeutic effect while delivering the same dose, showing the possibility to use roughly half dose of X-rays to obtain the same radiotoxicity effect. These data suggest that this hybrid nanoplatform acts as a promising tool for applications in enhancing cancer radiotherapy effects with lower doses of X-rays.

CdSe/ZnS Quantum Rods (QRs) and Phenyl Boronic Acid BODIPY as Efficient Förster Resonance Energy Transfer (FRET) Donor-Acceptor Pair.

The reversibility of the covalent interaction between boronic acids and 1,2- or 1,3-diols has put the spotlight on this reaction for its potential in the development of sensors and for the fishing of bioactive glycoconjugates. In this work, we describe the investigation of this reaction for the reversible functionalization of the surface of CdSe/ZnS Quantum Rods (QRs). With this in mind, we have designed a turn-off Förster resonance energy transfer (FRET) system that ensures monitoring the extent of the reaction between the phenyl boronic residue at the meso position of a BODIPY probe and the solvent-exposed 1,2-diols on QRs' surface. The reversibility of the corresponding boronate ester under oxidant conditions has also been assessed, thus envisioning the potential sensing ability of this system.

Unveiling Liquid-Phase Exfoliation of Graphite and Boron Nitride Using Fluorescent Dyes Through Combined Experiments and Simulations.

Liquid-phase exfoliation (LPE) in aqueous solutions provides a simple, scalable, and green approach to produce 2D materials. By combining atomistic simulations with exfoliation experiments, the interaction between a surfactant and a 2D layer at the molecular scale can be better understood. In this work, two different dyes, corresponding to rhodamine B base (Rbb) and to a phenylboronic acid BODIPY (PBA-BODIPY) derivative, are employed as dispersants to exfoliate graphene and hexagonal boron nitride (hBN) through sonication-assisted LPE. The exfoliated 2D sheets, mostly as few-layers, exhibit good quality and high loading of dyes. Using molecular dynamics (MD) simulations, the binding free energies are calculated and the arrangement of both dyes on the layers are predicted. It has been found that the dyes show a higher affinity toward hBN than graphene, which is consistent with the higher yields of exfoliated hBN. Furthermore, it is demonstrated that the adsorption behavior of Rbb molecules on graphene and hBN is quite different compared to PBA-BODIPY.

Shaping Silver Nanoparticles' Size through the Carrier Composition: Synthesis and Antimicrobial Activity.

The increasing resistance of bacteria to conventional antibiotics represents a severe global emergency for human health. The broad-spectrum antibacterial activity of silver has been known for a long time, and silver at the nanoscale shows enhanced antibacterial activity. This has prompted research into the development of silver-based nanomaterials for applications in clinical settings. In this work, the synthesis of three different silver nanoparticles (AgNPs) hybrids using both organic and inorganic supports with intrinsic antibacterial properties is described. The tuning of the AgNPs' shape and size according to the type of bioactive support was also investigated. Specifically, the commercially available sulfated cellulose nanocrystal (CNC), the salicylic acid functionalized reduced graphene oxide (rGO-SA), and the commercially available titanium dioxide (TiO2) were chosen as organic (CNC, rGO-SA) and inorganic (TiO2) supports. Then, the antimicrobial activity of the AgNP composites was assessed on clinically relevant multi-drug-resistant bacteria and the fungus Candida albicans. The results show how the formation of Ag nanoparticles on the selected supports provides the resulting composite materials with an effective antibacterial activity.

Simple engineering of hybrid cellulose nanocrystal-gold nanoparticles results in a functional glyconanomaterial with biomolecular recognition properties.

Cellulose nanocrystal and gold nanoparticles are assembled, in a unique way, to yield a novel modular glyconanomaterial whose surface is then easily engineered with one or two different headgroups, by exploiting a robust click chemistry route. We demonstrate the potential of this approach by conjugating monosaccharide headgroups to the glyconanomaterial and show that the sugars retain their binding capability to C-type lectin receptors, as also directly visualized by cryo-TEM.

Graphene Oxide-BODIPY Conjugates as Highly Fluorescent Materials.

Covalent functionalization of graphene oxide (GO) with boron dipyrromethenes (BODIPYs) was achieved through a facile synthesis, affording two different GO-BODIPY conjugates where the main difference lies in the nature of the spacer and the type of bonds between the two components. The use of a long but flexible spacer afforded strong electronic GO-BODIPY interactions in the ground state. This drastically altered the light absorption of the BODIPY structure and impeded its selective excitation. In contrast, the utilisation of a short, but rigid spacer based on boronic esters resulted in a perpendicular geometry of the phenyl boronic acid BODIPY (PBA-BODIPY) with respect to the GO plane, which enables only minor electronic GO-BODIPY interactions in the ground state. In this case, selective excitation of PBA-BODIPY was easily achieved, allowing to investigate the excited state interactions. A quantitative ultrafast energy transfer from PBA-BODIPY to GO was observed. Furthermore, due to the reversible dynamic nature of the covalent GO-PBA-BODIPY linkage, some PBA-BODIPY is free in solution and, hence, not quenched from GO. This resulted in a weak, but detectable fluorescence from the PBA-BODIPY that will allow to exploit GO-PBA-BODIPY for slow release and imaging purposes.

Ball milled glyco-graphene oxide conjugates markedly disrupted Pseudomonas aeruginosa biofilms.

The engineering of the surface of nanomaterials with bioactive molecules allows controlling their biological identity thus accessing functional materials with tuned physicochemical and biological profiles suited for specific applications. Then, the manufacturing process, by which the nanomaterial surface is grafted, has a significant impact on their development and innovation. In this regard, we report herein the grafting of sugar headgroups on a graphene oxide (GO) surface by exploiting a green manufacturing process that relies on the use of vibrational ball mills, a grinding apparatus in which the energy is transferred to the reacting species through collision with agate spheres inside a closed and vibrating vessel. The chemical composition and the morphology of the resulting glyco-graphene oxide conjugates (glyco-GO) are assessed by the combination of a series of complementary advanced techniques (i.e. UV-vis and Raman spectroscopy, transmission electron microscopy, and Magic Angle Spinning (MAS) solid-state NMR (ssNMR) providing in-depth insights into the chemical reactivity of GO in a mechanochemical route. The conjugation of monosaccharide residues on the GO surface significantly improves the antimicrobial activity of pristine GO against P. aeruginosa. Indeed, glyco-GO conjugates, according to the monosaccharide derivatives installed into the GO surface, affect the ability of sessile cells to adhere to a polystyrene surface in a colony forming assay. Scanning electron microscopy images clearly show that glyco-GO conjugates significantly disrupt an already established P. aeruginosa biofilm.

Glyco-Coated CdSe/ZnS Quantum Dots as Nanoprobes for Carbonic Anhydrase IX Imaging in Cancer Cells.

The bioimaging of cancer cells by the specific targeting of overexpressed biomarkers is an approach that holds great promise in the identification of selective diagnostic tools. Tumor-associated human carbonic anhydrase (hCA) isoforms IX and XII have been considered so far as well-defined biomarkers, with their expression correlating with cancer progression and aggressiveness. Therefore, the availability of highly performant fluorescent tools tailored for their targeting and able to efficiently visualize such key targets is in high demand. We report here on the design and synthesis of a kind of quantum dot (QD)-based fluorescent glyconanoprobe coated with a binary mixture of ligands, which, according to the structure of the terminal domains, impart specific property sets to the fluorescent probe. Specifically, monosaccharide residues ensured the dispersibility in the biological medium, CA inhibitor residues provided specific targeting of membrane-anchored hCA IX overexpressed on bladder cancer cells, and the quantum dots imparted the optical/fluorescence properties.

Novel Synthetic Approach to Heteroatom Doped Polycyclic Aromatic Hydrocarbons: Optimizing the Bottom-Up Approach to Atomically Precise Doped Nanographenes.

The success of the rational bottom-up approach to nanostructured carbon materials and the discovery of the importance of their doping with heteroatoms puts under the spotlight all synthetic organic approaches to polycyclic aromatic hydrocarbons. The construction of atomically precise heteroatom doped nanographenes has evidenced the importance of controlling its geometry and the position of the doping heteroatoms, since these parameters influence their chemical-physical properties and their applications. The growing interest towards this research topic is testified by the large number of works published in this area, which have transformed a once "fundamental research" into applied research at the cutting edge of technology. This review analyzes the most recent synthetic approaches to this class of compounds.

Metal-Free Antibacterial Additives Based on Graphene Materials and Salicylic Acid: From the Bench to Fabric Applications.

The custom functionalization of a graphene surface allows access to engineered nanomaterials with improved colloidal stability and tailored specific properties, which are available to be employed in a wide range of applications ranging from materials to life science. The high surface area and their intrinsic physical and biological properties make reduced graphene oxide and graphene oxide unique materials for the custom functionalization with bioactive molecules by exploiting different surface chemistries. In this work, preparation (on the gram scale) of reduced graphene oxide and graphene oxide derivatives functionalized with the well-known antibacterial agent salicylic acid is reported. The salicylic acid functionalities offered a stable colloidal dispersion and, in addition, homogeneous absorption on a sample of textile manufacture (i.e., cotton fabrics), as shown by a Raman spectroscopy study, thus providing nanoengineered materials with significant antibacterial activity toward different strains of microorganisms. Surprisingly, graphene surface functionalization also ensured resistance to detergent washing treatments as verified on a model system using the quartz crystal microbalance technique. Therefore, our findings paved the way for the development of antibacterial additives for cotton fabrics in the absence of metal components, thus limiting undesirable side effects.

Combining cross-coupling reaction and Knoevenagel condensation in the synthesis of glyco-BODIPY probes for DC-SIGN super-resolution bioimaging.

Lectins are involved in a wide range of carbohydrate mediated recognition processes. Therefore, the availability of highly performant fluorescent tools tailored for lectin targeting and able to efficiently track events related to such key targets is in high demand. We report here on the synthesis of the glyco-BODIPYs 1 and 2, based on the efficient combination of a Heck-like cross coupling and a Knoevenagel condensation, which revealed efficient in addressing lectins. In particular, glyco-BODIPY 1 has two glycosidase stable C-mannose residues, which act as DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) targeting modules. By using live-cell fluorescence microscopy, we proved that BODIPY-mannose 1 was efficiently taken up by immune cells expressing DC-SIGN receptors. Super-resolution stimulated emission depletion (STED) microscopy further revealed that the internalized 1 localized in membranes of endosomes, proving that 1 is a reliable tool also in STED applications. Of note, glyco-BODIPY 1 contains an aryl-azido group, which allows further functionalization of the glycoprobe with bioactive molecules, thus paving the way for the use of 1 for tracking lectin-mediated cell internalization in diverse biological settings.

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY.

Mechanochemistry is an emerging and reliable alternative to conventional solution (batch) synthesis of complex molecules under green and solvent-free conditions. In this regard, we report here on the conjugation of a dextran polysaccharide with a fluorescent probe, a phenylboronic acid (PBA)-functionalized boron dipyrromethene (BODIPY) applying the ball milling approach. The ball milling formation of boron esters between PBA BODIPY and dextran proved to be more efficient in terms of reaction time, amount of reactants, and labelling degree compared to the corresponding solution-based synthetic route. PBA-BODIPY dextran assembles into nanoparticles of around 200 nm by hydrophobic interactions. The resulting PBA-BODIPY dextran nanoparticles retain an apolar interior as proved by pyrene fluorescence, suitable for the encapsulation of hydrophobic drugs with high biocompatibility while remaining fluorescent.

Multiwalled Carbon Nanotubes for Combination Therapy: a Biodistribution and Efficacy Pilot Study.

A drug delivery system (DDS) for combined therapy, based on a short oxidized multiwalled carbon nanotube, is reported. It was prepared exploiting a synthetic approach which allowed loading of two drugs, doxorubicin and metformin, the targeting agent biotin and a radiolabeling tag, to enable labeling with Ga-68 or Cu-64 in order to perform an extensive biodistribution study by PET/CT. The DDS biodistribution profile changes with different administration methods. Once administered at therapeutic doses, the DDS showed a marginal beneficial effect on 4T1 tumor bearing mice, a syngeneic and orthotopic model of triple negative breast cancer, with survival extended by 1 week and 2 days in 20% of the mice. This is encouraging given the aggressiveness of the 4T1 tumor. Furthermore our DDS was well tolerated, ruling out concerns regarding the toxicity of carbon nanotubes.

Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies.

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (68Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.

Combined therapies with nanostructured carbon materials: there is room still available at the bottom.

The progress of the chemistry of carbon nanotubes (CNT) and graphene derivatives [mainly graphene oxide (GO)] has produced a number of technologically advanced drug delivery systems (DDS) that have been used in the field of nanomedicine, mostly in studies related to oncology. However, such a demanding field of research requires continuous improvements in terms of efficiency, selectivity and versatility. The loading of two, or more, bioactive components on the same nanoparticle offers new possibilities for treating cancer, efficiently addressing issues related both to biodistribution and pharmacokinetics. Nanostructured carbon materials (NCM), with their high surface area, their efficient cellular membrane crossing and their chemical versatility are ideal candidates for easy hetero-decoration and exploitation as advanced DDS. This review describes the achievements obtained in this area focusing on those studies in which two or more active components were loaded onto the DDS.

Nanostructured carbon materials decorated with organophosphorus moieties: synthesis and application.

A new synthetic approach for the production of carbon nanomaterials (CNM) decorated with organophosphorus moieties is presented. Three different triphenylphosphine oxide (TPPO) derivatives were used to decorate oxidized multiwalled carbon nanotubes (ox-MWCNTs) and graphene platelets (GPs). The TPPOs chosen bear functional groups able to react with the CNMs by Tour reaction (an amino group), nitrene cycloaddition (an azido group) or CuAAC reaction (one terminal C-C triple bond). All the adducts were characterized by FTIR, Raman spectroscopy, TEM, XPS, elemental analysis and ICP-AES. The cycloaddition of nitrene provided the higher loading on ox-MWCNTs and GPs as well, while the Tour approach gave best results with nanotubes (CNTs). Finally, we investigated the possibility to reduce the TPPO functionalized CNMs to the corresponding phosphine derivatives and applied one of the materials produced as heterogeneous organocatalyst in a Staudinger ligation reaction.