Search

This work shows the synthesis of a drug delivery system made of casein nanoparticles able to host hydrophobic molecules and be functionalized with aptamers targeting the epidermal growth factor receptor.

Polyhydroxybutyrate (PHB) is a non-toxic polyhydroxyalkanoate polymer produced by several microorganisms, widely used as a biological substitute for plastics derived from fossil hydrocarbons. In this work, PHB polymer has been tested in an animal model for colorectal cancer. In the animal model, PHB has been able to reduce the number of polyps by 48,1%, and the tumoral extension area by 58,1%. Also, PHB induces a selective increase in beneficial gut bacterial taxons in this animal model, and a selective reduction in pro-inflammatory taxons, demonstrating its value as a nutraceutical compound. This antitumor effect is caused by gut production of 3-hydroxybutyrate and butyrate. In this animal model, 3-hydroxybutyrate is also observed in plasma and in brain tissue, after PHB consumption, making PHB supplementation interesting as a bioactive compound in other extraintestinal conditions, as 3-hydroxybutyrate has been reported to enhance brain and cognitive function, cardiac performance, appetite suppression and diabetes. Therefore, PHB could be postulated as an interesting non-polysaccharide antitumor prebiotic, paving the way towards its future use in functional foods.

Ultrathin gold nanowires (AuNWs) have shown great potential toward applications in flexible electronics. However, they suffer from high surface instability that consequently limits their applicability for solution-processed composite materials. To overcome this limitation, we show for the first time how a synthetic thiolated small-molecule ligand such as ethyl 11-(4-mercaptobenzamido) undecanoate can stabilize the AuNW surface enabling their manipulation in solution-processed composite manufacturing techniques. As a proof of concept, we show how such stabilized NWs can be formulated into a PDMS matrix and spin-coated to afford stretchable elastomeric strips capable of sensing mechanical deformation with loading as low as 0.03 wt %.

Hybrid hydrogels made of chemically modified pectin, gelatin and xanthan gum have been formulated and processed through a double crosslinking step, aimed at wound healing applications. The formulation of hybrid hydrogels finds its cornerstone in the possibility to create a supportive environment for cell adhesion and proliferation, ensuring the transport of nutrients via porous structures, together with mechanical properties closely comparable to the native tissue. The hydrogels present a good swelling behavior, resistance to dissolution and fragmentation in simulated biological environment (PBS 1× and DMEM) for up to 20 days and the porous structure, as pictured via scanning electron microscopy, has been foreseen to help cell migration and the exchange of biomolecules. Rheological characterization showed desired mechanical features, while the biocompatibility has been assessed via live/dead assay on murine fibroblasts. Finally, the hybrid hydrogels have also been proved suitable for mechanical extrusion, demonstrating the possibility of cell encapsulation in the future perspective of 3D bioprinting applications.

In recent years, the interest regarding the use of proteins as renewable resources has deeply intensified. The strongest impact of these biomaterials is clear in the field of smart medicines and biomedical engineering. Zein, a vegetal protein extracted from corn, is a suitable biomaterial for all the above-mentioned purposes due to its biodegradability and biocompatibility. The controlled drug delivery of small molecules, fabrication of bioactive membranes, and 3D assembly of scaffold for tissue regeneration are just some of the topics now being extensively investigated and reported in the literature. Herein, we review the recent literature on zein as a biopolymer and its applications in the biomedical world, focusing on the different shapes and sizes through which it can be manipulated.

We report on the fabrication and electro-mechanical characterization of a nanocomposite system exhibiting anisotropic electrical response under the application of tactile compressive stresses (5 kPa) at low frequencies (0.1-1 Hz). The nanocomposite is based on a chemically cross-linked gel incorporating a highly conductive ionic liquid and surface functionalized barium titanate (BaTiO

Presently, a plenty of concerns related to the environment are due to the overuse of petroleum-based chemicals and products; the synthesis of functional materials, starting from the natural sources, is the current trend in research. The interest for nanocellulose has recently increased in a huge range of fields, from the material science to the biomedical engineering. Nanocellulose gained this leading role because of several reasons: its natural abundance on this planet, the excellent mechanical and optical features, the good biocompatibility and the attractive capability of undergoing surface chemical modifications. Nanocellulose surface tuning techniques are adopted by the high reactivity of the hydroxyl groups available; the chemical modifications are mainly performed to introduce either charged or hydrophobic moieties that include amination, esterification, oxidation, silylation, carboxymethylation, epoxidation, sulfonation, thiol- and azido-functional capability. Despite the several already published papers regarding nanocellulose, the aim of this review involves discussing the surface chemical functional capability of nanocellulose and the subsequent applications in the main areas of nanocellulose research, such as drug delivery, biosensing/bioimaging, tissue regeneration and bioprinting, according to these modifications. The final goal of this review is to provide a novel and unusual overview on this topic that is continuously under expansion for its intrinsic sophisticated properties.

Herein we report the synthesis of cellulose nanocrystals covalently bound to a model chemotherapeutic drug (DOXO) via a novel spacer arm, which acts both as linker and as selective releasing agent. The carbamate linkage present in the linker, shows stability in aqueous environments for a wide range of conditions and can only be hydrolyzed in the presence of cells, freeing the active drug, with unmodified chemotherapeutic properties.

This study investigates the effect of PD1 blockade on the therapeutic efficacy of novel doxorubicin-loaded temperature-sensitive liposomes. Herein, we report photothermally-activated, low temperature-sensitive magnetoliposomes (mLTSL) for efficient drug delivery and magnetic resonance imaging (MRI). The mLTSL were prepared by embedding small nitrodopamine palmitate (NDPM)-coated iron oxide nanoparticles (IO NPs) in the lipid bilayer of low temperature-sensitive liposomes (LTSL), using lipid film hydration and extrusion. Doxorubicin (DOX)-loaded mLTSL were characterized using dynamic light scattering, differential scanning calorimetry, electron microscopy, spectrofluorimetry, and atomic absorption spectroscopy. Photothermal experiments using 808 nm laser irradiation were conducted. In vitro photothermal DOX release studies and cytotoxicity was assessed using flow cytometry and resazurin viability assay, respectively. In vivo DOX release and tumor accumulation of mLTSL(DOX) were assessed using fluorescence and MR imaging, respectively. Finally, the therapeutic efficacy of PD1 blockade in combination with photothermally-activated mLTSL(DOX) in CT26-tumor model was evaluated by monitoring tumor growth, cytokine release and immune cell infiltration in the tumor tissue. Interestingly, efficient photothermal heating was obtained by varying the IO NPs content and the laser power, where on-demand burst DOX release was achievable in vitro and in vivo. Moreover, our mLTSL exhibited promising MR imaging properties with high transverse r2 relaxivity (333 mM-1 s-1), resulting in superior MR imaging in vivo. Furthermore, mLTSL(DOX) therapeutic efficacy was potentiated in combination with anti-PD1 mAb, resulting in a significant reduction in CT26 tumor growth via immune cell activation. Our study highlights the potential of combining PD1 blockade with mLTSL(DOX), where the latter could facilitate chemo/photothermal therapy and MRI-guided drug delivery.

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive group of breast cancers. The lack of specific actionable targets makes chemotherapy the main treatment for TNBC patients. However, chemotherapy has limited success due to scarce bioavailability, severe systemic side effects and drug resistance. Polymeric nanoparticles (PNPs) may efficiently deliver in vivo therapeutics to tumors when conjugated to specific targeting agents. Potential agents for targeting tumor cells are aptamers: short, single-stranded oligonucleotides that interact at high affinity with their targets. Here, we report the characterization of new multifunctional nanovectors consisting of safe and biodegradable PNPs, highly specific TNBC aptamers as delivery agents and artificial small interfering RNA (siRNA) as drug payload, designed to suppress programmed cell death-ligand 1 (PD-L1) expression, a major feature of immune evasion in cancer cells. We efficiently entrapped siRNA-PD-L1 into PNPs. To enable active targeting, siPD-L1-PNPs were functionalized with TN145-aptamer, which we previously generated by cell-SELEX and shown to bind with nanomolar affinity to TNBC cells distinguishing them from both normal breast cells and non-TNBC breast cancer cells. TN145 aptamer actively internalizes into target cells, thus representing a good candidate to deliver a therapeutic payload. We show that the aptamer-decorated nanovectors efficiently deliver fluorescein-labeled siRNA into TNBC MDA-MB-231 and BT-549 cells, as assessed by confocal microscopy. Unconjugated nanovectors or conjugated with scrambled aptamers were used as controls. Non-TNBC BT-474 and MCF7 breast cancer cells, were used to exclude unspecific binding. Importantly, a 30-min incubation of TN145-conjugated nanovectors on target cells, at a siPD-L1 concentration of 1 nM, results in stronger PD-L1 silencing than that achieved by siPD-L1 delivered via a commercial transfection reagent. Furthermore, TN145-PNPs loaded with both siPD-L1 and cisplatin were generated and the efficacy of combined treatment was tested on tumor cells and tumor and immune cell co-cultures. Chemotherapy, including cisplatin, has been reported to induce PD-L1 enrichment in TNBC cells, hence an aptamer-targeted nanosystem enabling the synergistic effect of siRNA that directly knocks down PD-L1 expression on tumor cells with a powerful chemotherapeutic drug could be the future way to eradicate TNBC cells. Citation Format: Lisa Agnello, Simona Camorani, Silvia Tortorella, Annachiara d’Argenio, Roberto Nilo, Monica Fedele, Antonella Zannetti, Mauro Comes Franchini, Laura Cerchia. Nano-immunotherapy in TNBC: Aptamer-based nanoparticles for PD-L1 siRNA delivery to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 367.

Background Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC. Methods Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses. Results We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs. Conclusions Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.

Photoacoustic (PA) imaging is indeed one of the most promising bioimaging techniques for theranostics applications in humans, allowing for the visualization of blood vessels and melanomas with high spatial resolution. However, in order to overcome the endogenous contrast arising from interfering endogenous species such as haemoglobin and melanin, specific contrast agents need to be developed, allowing PAI to successfully identify targeted contrast in the range of wavelengths in which interference from the biomatrix is minimized. This has been first performed by small molecule dyes, which, however, suffer from some important limitations such as low hydrophilicity and short circulation times. For this reason, scientific research has recently directed its efforts towards the development of nanostructured contrast agents capable of providing efficient PA contrast at low concentrations with low toxicity and high biocompatibility. The principal nanostructures are based on (1) metal and semiconducting nanoparticles, amongst which variously shaped nano-gold plays the main role, (2) carbon nanomaterials, such as carbon nanotubes and graphene, and (3) conjugated polymer nanoparticles. In this review, the principal characteristics of this class of materials are reported and greater focus is directed towards in vivo studies. A detailed analysis is performed on various physical-chemical parameters that define the PA response of reported contrast agents, like absorption coefficients and photoacoustic efficiencies. By comparing the experimental data, this review provides a comprehensive tool for the evaluation of new nanostructured contrast agents for PA imaging.

Gold nanorods assisted photothermal therapy (GNR-PTT) is a new cancer treatment technique that has shown promising potential for bladder cancer treatment. The position of the bladder cancer at different locations along the bladder wall lining can potentially affect the treatment efficacy since laser is irradiated externally from the skin surface. The present study investigates the efficacy of GNR-PTT in the treatment of bladder cancer in mice for tumours growing at three different locations on the bladder, i.e., Case 1: closest to skin surface, Case 2: at the bottom half of the bladder, and Case 3: at the side of the bladder. Investigations were carried out numerically using an experimentally validated framework for optical-thermal simulations. An in-silico approach was adopted due to the flexibility in placing the tumour at a desired location along the bladder lining. Results indicate that for the treatment parameters considered (laser power 0.3 W, GNR volume fraction 0.01% v/v), only Case 1 can be used for an effective GNR-PTT. No damage to the tumour was observed in Cases 2 and 3. Analyses of the thermo-physiological responses showed that the effectiveness of GNR-PTT in treating bladder cancer depends not only on the depth of the tumour from the skin surface, but also on the type of tissue that the laser must pass through before reaching the tumour. In addition, the results are reliant on GNRs with a diameter of 10 nm and an aspect ratio of 3.8 - tuned to exhibit peak absorption for the chosen laser wavelength. Results from the present study can be used to highlight the potential for using GNR-PTT for treatment of human bladder cancer. It appears that Cases 2 and 3 suggest that GNR-PTT, where the laser passes through the skin to reach the bladder, may be unfeasible in humans. While this study shows the feasibility of using GNRs for photothermal ablation of bladder cancer, it also identifies the current limitations needed to be overcome for an effective clinical application in the bladder cancer patients.

A novel highly biocompatible nanosystem made up of a chitosan matrix and filled with magnesium nanoparticles was synthesized using a simple and one-pot strategy, and tested as a promising, well-tolerated tool for photothermal therapy. Moreover, in vivo a proof of concept on hepatocarcinoma-bearing mice is presented.

The interest for biodegradable electronic devices is rapidly increasing for application in the field of wearable electronics, precision agriculture, biomedicine, and environmental monitoring. Energy storage devices integrated on polymeric substrates are of particular interest to enable the large-scale on field use of complex devices. This work presents a novel class of eco-friendly supercapacitors based on biodegradable poly(3-hydroxybutyrrate) PHB, ionic liquids, and cluster-assembled gold electrodes. By electrochemical characterization, we demonstrate the possibility of tuning the supercapacitor energetic performance according to the type and amount of the ionic liquid employed. Our devices based on hydrophobic plastic materials are stable under cyclic operation and resistant to moisture exposure.

Photothermal therapy has always been a very attractive anti-cancer strategy, drawing a lot of attention thanks to its excellent performance as a non-invasive and pretty safe technique. Lately, nanostructures have become the main characters of the play of cancer therapy due to their ability to absorb near-infrared radiation and efficient light-to-heat conversion. Here we present the synthesis of polyethylene glycol (PEG)-stabilized hybrid ultrasmall (80% cell viability decrease already after 10 min laser irradiation with a laser power P = 3W/cm2 that was proved to be harmless to the control cells. Moreover, a previous cell viability test had shown that the nanoparticles themselves were reasonably biocompatible: without irradiation cell viability remained high. Herein, we show that our hybrid AuAgNTrs exhibit very exciting potential as nanostructures for hyperthermia cancer therapy, mostly due to their easy synthesis protocol, excellent cell compatibility and promising photothermal features.

We present a modular system for the quantitative characterization of the piezoelectric coefficient of piezoelectric polymers and soft polymeric nanocomposites in the compression mode. Our approach is based on an apparatus providing spectral information on the electro-mechanical response in aselected range of frequencies of compressive loads (10–1200 Hz), with high sensitivity (down to 0.5 pC/N) and automated data acquisition modalities, enabling repeatability and reproducibility of the electro-mechanical characterization in the low-force regime (0.1 N 1.5 N). The system is modular and can be developed to cover the 2 mHz-1.2 kHz frequency range in charge mode and the 2 μHz-1200 Hz in voltage mode. We calibrated and validated the apparatus functionality using a commercial PVDF piezoelectric polymer. The suitability of the system for the quantitative measurements of the piezoelectricity of soft polymeric nanocomposites was then assessed by performing measurements of a novel piezoelectric nanocomposite material. This consisted of a polydimethylsiloxane (PDMS) matrix with embedded BaTiO3 nanoparticles, engineered with functional surface coatings to favor their homogeneous dispersion into the polymer. The proposed system demonstrated to be an effective solution for the systematic characterization of the electro-mechanical conversion properties of soft piezoelectric materials in view of soft robotics and energy harvesting applications.

Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors with high morbidity and mortality that have remained mostly unchanged over the past decades. The epidermal growth factor receptor (EGFR) is often overexpressed and activated in these tumors and strongly contributes to their pathogenesis. Still, EGFR-targeted therapies such as monoclonal antibodies and kinase inhibitors have demonstrated only limited improvements in the clinical outcome of this disease. Here, we take advantage of the extraordinary affinity of EGF for its cognate receptor to specifically target magnetite-containing nanoparticles to HNSCC cells and mediate, in vitro, their cellular upload. On the basis of this, we show efficient accumulation, in vivo, of such nanoparticles in subcutaneous xenograft tumor tissues in sufficient amounts to be able to mediate visualization by magnetic resonance imaging. Overall, our EGF-coated nanosystem may warrant, in the near future, novel and very efficient theranostic approaches to HNSCC.

Polymeric nanoparticles (PNPs) may efficiently deliver in vivo therapeutics to tumors when conjugated to specific targeting agents. Gint4.T aptamer specifically recognizes platelet-derived growth factor receptor β and can cross the blood-brain barrier (BBB). We synthesized Gint4.T-conjugated PNPs able of high uptake into U87MG glioblastoma (GBM) cells and with astonishing EC50 value (38 pM) when loaded with a PI3K-mTOR inhibitor. We also demonstrated in vivo BBB passage and tumor accumulation in a GBM orthotopic model.

Gene therapy based on small interfering RNA (siRNA) has emerged as an exciting new therapeutic approach. In this work, incorporation of PEI into poly(d,l-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-b-PEG) particles has been shown to be quite effective in the development of corresponding gene delivery systems, and encapsulation of magnetic nanoparticles as an MRI contrast agent, resulted in unique theranostic nanoparticles.

We report on the fabrication and electro-mechanical characterization of a nanocomposite system exhibiting anisotropic electrical response under the application of tactile compressive stresses (5 kPa) at low frequencies (0.1-1 Hz). The nanocomposite is based on a chemically cross-linked gel incorporating a highly conductive ionic liquid and surface functionalized barium titanate (BaTiO 3 ) ferroelectric nanoparticles. The system was engineered to respond to mechanical stimulations by combining piezoionic and piezoelectric activity, generating electric charge due to a redistribution of the mobile ions across the polymer matrix and to the presence of the electrically polarized ceramic nanoparticles, respectively. The nanocomposite response was characterized in a quasi-static regime using a custom-designed apparatus. The results obtained showed that the combination of both piezo-effects led to output voltages up to 8 mV and anisotropy in the response. This allows to discriminate the sample orientation with respect to the load direction by monitoring the phase and amplitude modulation of the output signal. The integration of cluster-assembled gold electrodes produced by Supersonic Cluster Beam Deposition (SCBD) was also performed, enabling to enhance the charge transduction efficiency by a factor of 10, compared to the bare nanocomposite. This smart piezoionic/piezoelectric nanocomposite represents an interesting solution for the development of soft devices for discriminative touch sensing and objects localization in physically unstructured environments.

Erica Locatelli,1,* Yan Li,2,* Ilaria Monaco,1 Wei Guo,3 Mirko Maturi,1 Luca Menichetti,4 Paolo Armanetti,4 Robert C Martin,2 Mauro Comes Franchini1 1Department of Industrial Chemistry “Toso Montanari”, Bologna, Italy; 2Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA; 3Department of Hematology, The First Hospital of Jilin University, Changchun, China; 4Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy *These authors contributed equally to this work Introduction and purpose: Cancer stem cells (CSCs) present a higher capacity to evade being killed by cancer agents and developing chemoresistance, thus leading to failure of conventional anticancer therapeutics. Nanomaterials specifically designed for targeting and treating not only tumor cells, but also CSCs, may encompass therapeutic and diagnostic tools, thus successfully eradicating the tumor. Materials and methods: Polymeric micelles simultaneously loaded with gold nanorods (GNRs) and Adriamycin were prepared and used as a novel therapeutic and diagnostic weapon. Epithelial cell adhesion molecule (EpCAM) is an important CSC surface marker and has been exploited in this work as an active targeting agent. Photoacoustic imaging was applied for GNR individuation and tissue recognition. Results: The nanosystem was demonstrated to be able to elicit effective targeting of cancer cells and cause their killing, in particular under laser ablation. Moreover, ex vivo photoacoustic imaging is able to clearly identify tumor regions thanks to GNR’s contrast. Conclusion: The nanosystem can be considered a powerful and promising theranostic weapon for hepatocellular carcinoma treatment. Keywords: gold nanorods, drug delivery, photoacoustic imaging, photothermal therapy, EpCAM, cancer stem cells

Lysolipid-containing thermosensitive liposomes (LTSL) have gained attention for triggered release of chemotherapeutics. Superparamagnetic iron oxide nanoparticles (SPION) offers multimodal imaging and hyperthermia therapy opportunities as a promising theranostic agent. Combining LTSL with SPION may further enhance their performance and functionality of LTSL. However, a major challenge in clinical translation of nanomedicine is the poor scalability and complexity of their preparation process. Exploiting the nature of self-assembly, nanoprecipitation is a simple and scalable technique for preparing liposomes. Herein, we developed a novel SPION-incorporated lysolipid-containing thermosensitive liposome (mLTSL10) formulation using nanoprecipitation. The formulation and processing parameters were carefully designed to ensure high reproducibility and stability of mLTSL10. The effect of solvent, aqueous-to-organic volume ratio, SPION concentration on the mLTSL10 size and dispersity was investigated. mLTSL10 were successfully prepared with a small size (∼100 nm), phase transition temperature at around 42 °C, and high doxorubicin encapsulation efficiency. Indifferent from blank LTSL, we demonstrated that mLTSL10 combining the functionality of both LTSL and SPION can be successfully prepared using a scalable nanoprecipitation approach.

The first one-step synthesis of dumbbell-like gold–iron oxide nanoparticles has been reported here. Surface functionalization with a biocompatible chitosan matrix allowed us to obtain a novel targetable diagnostic and therapeutic tool.

Correction for ‘Phosphorescent bio-based resin for digital light processing (DLP) 3D-printing’ by Mirko Maturi et al., Green Chem., 2020, 22, 6212–6224, DOI: 10.1039/D0GC01983F.

A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 μm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.

Herein we report the synthesis of a resilient nanosystem based on silica-coated magnetic MnFe2O3 nanoparticles conjugated to fluorescein and PEGylated gold nanorods embedded in polymeric micelles (MnFe2O4@SiO2@GNRs@PMs), for magnetic–photoacoustic–optical triple-modality imaging. The magnetic relaxivity of the nanosystem has been evaluated, revealing high r2/r1 ratios that suggest the effectiveness of the nanosystem as the T2-contrast agent. In addition, contrast-based fluorescence imaging has been tested both in vitro and ex vivo, showing that the nanosystem exhibits the suitable optical properties of fluorescein, with contrast intensities comparable with previously reported results. Finally, photoacoustic, due to gold nanorods, performances of the nanosystem have been evaluated, revealing good linearity between concentration and photoacoustic response in the 25–250 nM concentration under irradiation at 690 nm. The results showed a contrast-to-noise ratio (CNR) as high as 60 in a mouse leg subcutaneously injected with the nanosystem. Biocompatibility studies revealed no hemolytic effect induced by the nanoconstruct, revealing the applicability of the studied diagnostic tool for medical studies.

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors.

In this work, iron/silica/gold core-shell nanoparticles (Fe

We report the synthesis, fabrication and characterization of a hybrid hydrogel/cellulose nanocomposite, which exhibits high-performance electro–mechanical underwater actuation and high sensitivity in response to electrical stimuli below the standard potential of water electrolysis. The macromolecular structure of the material is constituted by an electroactive hydrogel, obtained through a photo-polymerization reaction with the use of three vinylic co-monomers: Na-4-vinylbenzenesulfonate, 2-hydroxyethylmethacrylate, and acrylonitrile. Different amounts (from 0.1% to 1.4% w/w) of biodegradable cellulose nanocrystals (CNCs) with sulfonate surface groups, obtained through the acidic hydrolysis of sulphite pulp lapsheets, are physically incorporated into the gel matrix during the synthesis step. Freestanding thin films of the nanocomposites are molded, and their swelling, mechanical and responsive properties are fully characterized. We observed that the embedding of the CNCs enhanced both the material Young's modulus and its sensitivity to the applied electric field in the sub-volt regime (down to 5 mV cm−1). A demonstrator integrating multiple actuators that cooperatively bend together, mimicking the motion of an electro-valve, is also prototyped and tested. The presented nanocomposite is suitable for the development of soft smart components for bio-robotic applications and cells-based and bio-hybrid fluidic devices fabrication.

In this work, iron/silica/gold core–shell nanoparticles (Fe3O4@SiO2@Au NPs) characterized by magnetic and optical properties have been synthesized to obtain a promising theranostic platform. To improve their biocompatibility, the obtained multilayer nanoparticles have been entrapped in polymeric micelles, decorated with folic acid moieties, and tested in vivo for photoacoustic and magnetic resonance imaging detection of ovarian cancer.

New flame retardant organo-modified bentonites, based on nitrogen-containing compounds were synthesized via an ion exchange process starting from pristine bentonite with acidified 6-(4-butylphenyl)−1,3,5-triazine-2,4-diamine (BFTDA) and 11-amino-N-(pyridine-2yl)undecanamide (APUA). The amount of nitrogen rich organic modifier in the obtained organoclays (Bento-BFTDA and Bento-APUA) determined by TGA is around 0.4 mmol/g for both samples. With the aim to study the effect of these additives on a commercial epoxy resin, nanocomposites containing 3 and 5 wt% of the nanofillers were prepared by solventless addition to the epoxy resin formulation. For the sake of comparison similar nanocomposites with plain unmodified bentonite were produced. The nanocomposite's thermo-mechanical properties of all the produced samples were measured and they resulted slightly improved or practically unaffected. Finally, when the flame behavior was assessed in the cone-calorimeter, an encouraging decrease of 17% in the peak heat released rate (pHRR) was obtained at 3 wt% loading level with Bento-APUA. These promising results suggest that the APUA modified organoclay, prepared with low cost reactants and mild reaction conditions, might efficiently act as a flame retardant.

The reactivity of the ynamide tert-butyl N-ethynyl-N-phenylcarbamate (1) in the 1,3-dipolar cycloaddition (1,3-DC) with C-carboxymethyl-N-phenylnitrilimine was investigated. This [3+2] cycloaddition affords the 5-amino pyrazole as a single regioisomer. The obtained cycloadduct has been activated at the 4-position of the pyrazole ring through bromination and subsequently coupled with a phenyl group under Pd catalysis. A detailed computational study has been performed to fully explain the complete regioselectivity observed.

Iron oxide-containing magnetic nanoparticles (MNPs) have certain advantages over currently used contrast agents for tumor imaging by magnetic resonance imaging (MRI) as they offer the possibility of functionalization with ligands and tracers. Functionalized MNPs also may be used for targeted tumor therapy. In the current study nanoparticles (NPs) consisting of recombinant human serum albumin (rHSA) with incorporated hydrophilic (NH4)2Ce(IV)(NO3)6-γ-Fe2O3 particles (CAN maghemite particles) for medical imaging were produced and characterized. For this purpose CAN maghemite particles were incorporated into an rHSA matrix to yield rHSA-NPs. The resulting NPs were analyzed by transmission electron microscopy, photon correlation spectroscopy, and atomic absorption. The sizes of the manufactured NP were 170 ± 10 nm, and the zeta-potential was − 50 ± 3 mV. The NPs remained stable when stored after lyophilization with sucrose 3% [w/v] as a cryoprotector. They showed pro-inflammatory properties without cell and animal toxicity in vivo and were highly contrasting in MRI. In conclusion, this report introduces novel rHSA NP with favorable properties containing iron oxide for detection by MRI.

Weizhong Zhang,1 Xuanyi Li,2 Mauro Comes Franchini,3 Ke Xu,1 Erica Locatelli,3 Robert C Martin,2 Ilaria Monaco,3 Yan Li,2 Shusen Cui11Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of China; 2Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA; 3Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Bologna, ItalyAbstract: We introduced curcumin-loaded nanomicelles into a tendon-healing model to evaluate their effects on tendon healing and adhesion. Three groups consisting of 36 rats underwent rupture and repair of the Achilles tendon. The treatment group received an injection of curcumin-loaded nanomicelles (gold nanorods [GNRs]-1/ curcumin in polymeric nanomicelles [curc@PMs] at a dosage of 0.44 mg curcumin/kg in 0.1 mL saline) into the surgical site and exposed to laser postoperatively at weeks 1, 2, and 3, for three times 10 seconds each, on the surgical site in the rats that underwent tendon rupture and repair, while the other two groups received 0.44 mg curcumin/kg in 0.1 mL saline and 0.1 mL of saline, respectively. The specimens were harvested at 4 weeks and subjected to biomechanical and histological evaluation. The scoring results of tendon adhesion indicated that GNRs-1/curc@PMs group was in the lowest grade of peritendinous adhesions compared to the other groups. Histological assessment further confirmed the preventive effect of GNRs-1/curc@PMs on tendon adhesion. These findings indicated greater tendon strength with less adhesion in the group treated with GNRs-1/curc@PMs combined with laser exposure, and that nanoparticle-based therapy may be applied to prevent adhesion in clinical patients.Keywords: nanorods, peritendinous adhesion, curcumin