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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.

Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system and the diagnosis is often dismal. GBM pharmacological treatment is strongly limited by its intracranial location beyond the blood–brain barrier (BBB). While Temozolomide (TMZ) exhibits the best clinical performance, still less than 20% crosses the BBB, therefore requiring administration of very high doses with resulting unnecessary systemic side effects. Here, we aimed at designing new negative temperature-responsive gel formulations able to locally release TMZ beyond the BBB. The biocompatibility of a chitosan-β-glycerophosphate-based thermogel (THG)-containing mesoporous SiO2 nanoparticles (THG@SiO2) or polycaprolactone microparticles (THG@PCL) was ascertained in vitro and in vivo by cell counting and histological examination. Next, we loaded TMZ into such matrices (THG@SiO2-TMZ and THG@PCL-TMZ) and tested their therapeutic potential both in vitro and in vivo, in a glioblastoma resection and recurrence mouse model based on orthotopic growth of human cancer cells. The two newly designed anticancer formulations, consisting in TMZ-silica (SiO2@TMZ) dispersed in the thermogel matrix (THG@SiO2-TMZ) and TMZ, spray-dried on PLC and incorporated into the thermogel (THG@PCL-TMZ), induced cell death in vitro. When applied intracranially to a resected U87-MG-Red-FLuc human GBM model, THG@SiO2-TMZ and THG@PCL-TMZ caused a significant reduction in the growth of tumor recurrences, when compared to untreated controls. THG@SiO2-TMZ and THG@PCL-TMZ are therefore new promising gel-based local therapy candidates for the treatment of GBM.

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.

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS). We found that the integrin α5β1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (

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.

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.

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.

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.

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.

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

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

Aim: Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer. Materials & methods: Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents – the drug alisertib and silver nanoparticles – were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP‑2, a receptor overexpressed by brain cancer cells. Results: The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma–astrocytoma epithelial‑like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs’ biodistribution in healthy animals and their effect on tumor reduction in tumor‑bearing mice were studied using PNPs radiolabeled with 99mTc. Conclusion: Tumor reduction was achieved in vivo when using silver/alisertib@PNPs–chlorotoxin., JRC.I.4-Nanobiosciences

Magnetic nanoparticles have become important tools for imaging a wide range of diseases, improving drug delivery and applying hyperthermic treatment. Iron oxide based nanoparticles have been widely examined, unlike cobalt ferrite based ones. Herein, monodisperse and stable CoFe2O4 nanoparticles have been produced, coated and further stabilized using ethyl 12-(hydroxyamino)-12-oxododecanoate, poly(lactic-co-glycolic acid) and bovine serum albumin. The final product, NBRh1, was fully characterized and has been directly radiolabeled with 99mTc using SnCl1 as the reducing agent in high yields. In vitro stability and hyperthermic properties of 99mTC-NBRh1 were encouraging for further application in low frequencies hyperthermia and biomagnetic applications. In vivo evaluation followed after injection in healthy mice. The planar and SPECT imaging data as well as the biodistribution results were in accordance, showing high liver and spleen uptake as expected starting almost immediately after administration. In conclusion the preliminary results for nanoparticles bearing a cobalt ferrite core justify further investigations towards potential hyperthermic applications, drug transportation and liver or spleen imaging.

The catalytic asymmetric inverse-electron-demand (IED) [4+2] cycloaddition of various salicylaldehyde-derived N-arylimines with electron-rich alkenes in the presence of chiral BINOL-derived phosphoric acid catalysts has been studied with the aim of obtaining optically active 4-aminobenzopyran derivatives. Dienophiles such as 2,3-dihydro-2H-furan, benzyl N-vinylcarbamate and 2-vinylindole have been employed.

1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile imines with substituted acetylenes bearing thiol or sulfone groups were studied. The sulfur controls the regiochemistry of the reaction, and this protocol was applied to the synthesis of ring-fused thieno[2,3-c]pyrazoles.

1,3-Dipolar cycloaddition of C-aryl-N-aryl- and C-carboxymethyl-N-aryl-nitrile imines with functionalized acetylenes have been studied. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Under scandium triflate catalysis a reversal in the regiochemistry was observed, especially in the case of C-carboxymethyl-N-aryl-nitrile imines.

The use of hard and/or soft nanoparticles for therapy, collectively called nanomedicine, has great potential in the battle against cancer. Major research efforts are underway in this area leading to development of new drug delivery approaches and imaging techniques. Despite this progress, the vast majority of patients who are affected by cancer today sadly still need surgical intervention, especially in the case of solid tumors. An important perspective for researchers is therefore to provide even more powerful tools to the surgeon for pre- and post-operative approaches. In this context, image-guided surgery, in combination with nanotechnology, opens a new strategy to win this battle. In this perspective, we will analyze and discuss the recent progress with nanoparticles of both metallic and biomaterial composition, and their use to develop powerful systems to be applied in image-guided surgery.

Some N-Boc ynamides bearing a terminal ester or aryl group are treated with azides to produce the desired triazoles with complete regiocontrol.

The cyanobis(dibenzylamino)borane-mediated transformation of chiral aldehydes into the corresponding α-amino nitriles is described. Starting from these compounds short synthetic routes can be envisaged for obtaining diastereomerically pure functionalized 1,2-diamines and hydroxylated α-amino acids that are of interest as core key units of biologically active substances or as potential ligands for asymmetric catalysis. The stereochemical outcome of the aminative cyanation reaction is discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The synthesis of levetiracetam and its enantiomer by deracemization of (±)-2-bromobutyric acid using either ( S )- or ( R )- N -phenylpantolactam as chiral auxiliaries, followed by S N 2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described.

Several new ligands featuring a rigid three ring skeleton have been prepared for the first time following a modular approach. Chirality has been introduced by use of an oxazoline moiety fused with a cyclopenta[b]thiophene backbone. The efficiency and stereochemical impact of these ligands on the copper-catalyzed enantioselective addition of Et2Zn to chalcone was examined and enantiomeric excesses up to 79% were achieved using the ligand (R,R)-16 substituted with a methyl group at the cyclopenta moiety. Computational and ESI-mass spectral studies show that these new compounds behave as monodentate ligands towards Cu+. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Enantiomerically pure central and planar chiral ferrocenyl cyanohydrins have been used for the synthesis of previously unreported 5-ferrocenyl-oxazolines and a 5-ferrocenyl-thiazoline where the central chirality lies on the carbon bearing the oxygen or the sulfur atom. The epimerization at C 5 of the oxazoline ring has also been investigated.

Enantiopure fluorinated isoxazolidines and amino polyols were obtained from the 1,3-dipolar cycloaddition of allylic fluorides and Z-α-phenyl-N-methylnitrone under environment-friendly conditions.

A synthesis of ferrocenyl-oxazolines is described using an iodide-mediated ring expansion of N-ferrocenoyl-aziridine-2-carboxylic esters. The ring enlargements take place with full stereocontrol, namely net retention of configuration. Modification of the ester function by a Grignard reaction leads to three new types of ferrocenyl-oxazoline carbinol ligands, which were used as chiral ligands in the asymmetric addition of diethylzinc to benzaldehyde (e.e.s ranging from 46 to 62%). The planar chiral ferrocenyl-oxazoline carbinol ligand gave a very good result (e.e. 90%) in the palladium-catalyzed allylic substitution of 1,3-diphenyl prop-2-enylacetate with dimethyl malonate.

Rac-N-substituted pantolactams (5) are readily obtained in medium to good yields by reaction of rac-pantolactone (1) with primary amines under acid catalysis, whether at 250°C in a pressure reactor or under microwave irradiation. It appears that the amine can react with pantolactone at the carbonyl carbon atom to give a hydroxyamide (3) in a reversible way and at the methylene carbon atom to give a γ-amino acid (4). The last one on dehydration would give the corresponding pantolactam (5).

A new protocol is described for the stereocontrolled synthesis of pseudo-C(2)-symmetric core units of interest as candidates for HIV protease inhibition. Addition of unbranched and branched organolithium reagents to cyanohydrins from l-phenylalaninal and l-isoleucinal, followed by in situ reduction of the intermediate imines and CHT deprotection under MW irradiation, led to 1,3-diamino alcohols 6a and 8a as the major products in satisfactory to good yields. The first preparation of a previously unreported pseudo-C(2)-symmetric triamino derivative was accomplished expeditiously via high-yielding nitro-Mannich addition of the silylnitronate, from 2-phenyl-1-nitroethane, to the PMP imine derived from l-phenylalaninal. Reduction of the nitro group in the moderately unstable nitro diamine adduct, followed by chromatographic separation of the required diastereoisomer and CHT debenzylation under MW irradiation, led to the 2-PMP-protected triamine 19 isolated as a bis(sulfonamide).

Indoles (II) and (V) bearing Michael acceptors at the 4-position are used in enantioselective organocatalytic cascade reactions with enals (III) and (VI).

Jennifer Vandooren,1 Nele Berghmans,1 Chris Dillen,1 Ilse Van Aelst,1 Isabelle Ronsse,1 Liron Limor Israel,2 Ina Rosenberger,3 Jörg Kreuter,3 Jean-Paul Lellouche,2 Shulamit Michaeli,4 Erica Locatelli,5 Mauro Comes Franchini,5 Miren K Aiertza,6 Laura Sánchez-Abella,6 Iraida Loinaz,6 Dylan R Edwards,7 Louis Shenkman,8 Ghislain Opdenakker1 1Rega Institute for Medical Research, University of Leuven, Leuven, Belgium; 2Department of Chemistry and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 3Institut für Pharmazeutische Technologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany; 4The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 5Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy; 6New Materials Department, Fundación CIDETEC, San Sebastián, Spain; 7School of Biological Sciences, University of East Anglia, Norwich, UK; 8Tel Aviv University, Ramat Aviv, Tel Aviv, Israel Abstract: The need for test systems for nanoparticle biocompatibility, toxicity, and inflammatory or adaptive immunological responses is paramount. Nanoparticles should be free of microbiological and chemical contaminants, and devoid of toxicity. Nevertheless, in the absence of contamination, these particles may still induce undesired immunological effects in vivo, such as enhanced autoimmunity, hypersensitivity reactions, and fibrosis. Here we show that artificial particles of specific sizes affect immune cell recruitment as tested in a dermal air pouch model in mice. In addition, we demonstrate that the composition of nanoparticles may influence immune cell recruitment in vivo. Aside from biophysical characterizations in terms of hydrodynamic diameter, zeta potential, concentration, and atomic concentration of metals, we show that – after first-line in vitro assays – characterization of cellular and molecular effects by dermal air pouch analysis is straightforward and should be included in the quality control of nanoparticles. We demonstrate this for innate immunological effects such as neutrophil recruitment and the production of immune-modulating matrix metalloproteases such as MMP-9; we propose the use of air pouch leukocytosis analysis as a future standard assay. Keywords: nanoparticles, biocompatibility, toxicity, air pouch, immunologyA Letter to theEditor has been received and published for this article.

The reactions of thioferrocenoylsilanes with organolithium reagents, dienes and reducing agents which afford α-silyl sulphides, dihydrothiopyranes and α-silyl ferrocenyl thiols, respectively, have been investigated. α-Silyl sulphides were further functionalised through carbodesilylation with aldehydes. We also report the synthesis of a new planar chiral thioferrocenoylsilane that gave good diastereomeric excess in the reaction with t-butyllithium, lithium lutidine and 2,3-dimethylbuta-1,3-diene. The 1,1′-bis-thioferrocenoylsilane, too unstable to be isolated, was trapped in situ with dienes.

Organomanganese halides and organomanganates prepared by transmetalation of organolithium and Grignard reagents add smoothly to the carbonyl moiety of acylsilanes and of substituted aldehydes bearing a chiral center at the a-position affording the desired alcohols in good to excellent yields and with essentially no undesired products from enolization. Comparison of the stereochemical outcome with that observed for other organometallic species, outlines the capability of organomanganese reagents to induce uniformly good diastereoselectivities, in a number of cases significantly higher than reported previously for these reactions. The key role displayed by the R3Si group in promoting high 1,2-asymmetric induction, clearly emerges in the comparison of acylsilane 12 with the corresponding aldehyde 13. The sense of the Cram:anti-Cram selectivity depends upon the nature of the carbonyl reagents engaged in these reactions. © 2001 Elsevier Science B.V. All rights reserved.