2017-2-3, Vittorio, Orazio, Curcio, Manuela, Cojoc, Monica, Goya, Gerardo F., Hampel, Silke, Iemma, Francesca, Dubrovska, Anna, Cirillo, Giuseppe

Nanotechnology can offer different solutions for enhancing the therapeutic efficiency of polyphenols, a class of natural products widely explored for a potential applicability for the treatment of different diseases including cancer. While possessing interesting anticancer properties, polyphenols suffer from low stability and unfavorable pharmacokinetics, and thus suitable carriers are required when planning a therapeutic protocol. In the present review, an overview of the different strategies based on polymeric materials is presented, with the aim to highlight the strengths and the weaknesses of each approach and offer a platform of ideas for researchers working in the field.

2019, Makharza, Sami A., Cirillo, Giuseppe, Vittorio, Orazio, Valli, Emanuele, Voli, Florida, Farfalla, Annafranca, Curcio, Manuela, Iemma, Francesca, Nicoletta, Fiore Pasquale, El-Gendy, Ahmed A., Goya, Gerardo F., Hampel, Silke

Selective vectorization of Cisplatin (CisPt) to Glioblastoma U87 cells was exploited by the fabrication of a hybrid nanocarrier composed of magnetic γ-Fe2 O3 nanoparticles and nanographene oxide (NGO). The magnetic component, obtained by annealing magnetite Fe3 O4 and characterized by XRD measurements, was combined with NGO sheets prepared via a modified Hummer’s method. The morphological and thermogravimetric analysis proved the effective binding of γ-Fe2 O3 nanoparticles onto NGO layers. The magnetization measured under magnetic fields up to 7 Tesla at room temperature revealed superparamagnetic-like behavior with a maximum value of MS = 15 emu/g and coercivity HC ≈ 0 Oe within experimental error. The nanohybrid was found to possess high affinity towards CisPt, and a rather slow fractional release profile of 80% after 250 h. Negligible toxicity was observed for empty nanoparticles, while the retainment of CisPt anticancer activity upon loading into the carrier was observed, together with the possibility to spatially control the drug delivery at a target site. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

2015, Du, Nan, Kiani, Mahdi, Mayr, Christian G., You, Tiangui, Bürger, Danilo, Skorupa, Ilona, Schmidt, Oliver G., Schmidt, Heidemarie

Memristive devices are popular among neuromorphic engineers for their ability to emulate forms of spike-driven synaptic plasticity by applying specific voltage and current waveforms at their two terminals. In this paper, we investigate spike-timing dependent plasticity (STDP) with a single pairing of one presynaptic voltage spike and one post-synaptic voltage spike in a BiFeO3 memristive device. In most memristive materials the learning window is primarily a function of the material characteristics and not of the applied waveform. In contrast, we show that the analog resistive switching of the developed artificial synapses allows to adjust the learning time constant of the STDP function from 25 ms to 125 μs via the duration of applied voltage spikes. Also, as the induced weight change may degrade, we investigate the remanence of the resistance change for several hours after analog resistive switching, thus emulating the processes expected in biological synapses. As the power consumption is a major constraint in neuromorphic circuits, we show methods to reduce the consumed energy per setting pulse to only 4.5 pJ in the developed artificial synapses.

2015, Lin, Gungun, Fomin, Vladimir M., Makarov, Denys, Schmidt, Oliver G.

We apply the technique of supervised discriminant analysis (SDA) for in-flow detection in droplet-based magnetofluidics. Based on the SDA, we successfully discriminate bivariant droplets of different volumes containing different encapsulated magnetic content produced by a GMR-based lab-on-chip platform. We demonstrate that the accuracy of discrimination is superior when the correlation of variables for data training is included to the case when the spatial distribution of variables is considered. Droplets produced with differences in ferrofluid concentration of 2.5 mg/ml and volume of 200 pl have been identified with high accuracy (98 %), indicating the significance of SDA for e.g. the discrimination in magnetic immuno-agglutination assays. Furthermore, the results open the way for the development of a unique magnetofluidic platform for future applications in multiplexed droplet-based barcoding assays and screening.

2015, Mendes, Rafael Gregorio, Koch, Britta, Bachmatiuk, Alicja, Ma, Xing, Sanchez, Samuel, Damm, Christine, Schmidt, Oliver G., Gemming, Thomas, Eckert, Jürgen, Rümmeli, Mark H.

Graphene oxide (GO) has attracted great interest due to its extraordinary potential for biomedical application. Although it is clear that the naturally occurring morphology of biological structures is crucial to their precise interactions and correct functioning, the geometrical aspects of nanoparticles are often ignored in the design of nanoparticles for biological applications. A few in vitro and in vivo studies have evaluated the cytotoxicity and biodistribution of GO, however very little is known about the influence of flake size and cytotoxicity. Herein, we aim at presenting an initial cytotoxicity evaluation of different nano-sized GO flakes for two different cell lines (HeLa (Kyoto) and macrophage (J7742)) when they are exposed to samples containing different sized nanographene oxide (NGO) flakes (mean diameter of 89 and 277 nm). The obtained data suggests that the larger NGO flakes reduce cell viability as compared to smaller flakes. In addition, the viability reduction correlates with the time and the concentration of the NGO nanoparticles to which the cells are exposed. Uptake studies were also conducted and the data suggests that both cell lines internalize the GO nanoparticles during the incubation periods studied.

2017, Kaufmann, Anika, Hampel, Silke, Rieger, Christiane, Kunhardt, David, Schendel, Darja, Füssel, Susanne, Schwenzer, Bernd, Erdmann, Kati

Background: In addition to conventional chemotherapeutics, nucleic acid-based therapeutics like antisense oligodeoxynucleotides (AS-ODN) represent a novel approach for the treatment of bladder cancer (BCa). An efficient delivery of AS-ODN to the urothelium and then into cancer cells might be achieved by the local application of multi-walled carbon nanotubes (MWCNT). In the present study, pristine MWCNT and MWCNT functionalized with hydrophilic moieties were synthesized and then investigated regarding their physicochemical characteristics, dispersibility, biocompatibility, cellular uptake and mucoadhesive properties. Finally, their binding capacity for AS-ODN via hybridization to carrier strand oligodeoxynucleotides (CS-ODN), which were either non-covalently adsorbed or covalently bound to the different MWCNT types, was evaluated. Results: Pristine MWCNT were successfully functionalized with hydrophilic moieties (MWCNT-OH, -COOH, -NH2, -SH), which led to an improved dispersibility and an enhanced dispersion stability. A viability assay revealed that MWCNT-OH, MWCNT-NH2 and MWCNT-SH were most biocompatible. All MWCNT were internalized by BCa cells, whereupon the highest uptake was observed for MWCNT-OH with 40% of the cells showing an engulfment. Furthermore, all types of MWCNT could adhere to the urothelium of explanted mouse bladders, but the amount of the covered urothelial area was with 2-7% rather low. As indicated by fluorescence measurements, it was possible to attach CS-ODN by adsorption and covalent binding to functionalized MWCNT. Adsorption of CS-ODN to pristine MWCNT, MWCNT-COOH and MWCNT-NH2 as well as covalent coupling to MWCNT-NH2 and MWCNT-SH resulted in the best binding capacity and stability. Subsequently, therapeutic AS-ODN could be hybridized to and reversibly released from the CS-ODN coupled via both strategies to the functionalized MWCNT. The release of AS-ODN at experimental conditions (80 °C, buffer) was most effective from CS-ODN adsorbed to MWCNT-OH and MWCNT-NH2 as well as from CS-ODN covalently attached to MWCNT-COOH, MWCNT-NH2 and MWCNT-SH. Furthermore, we could exemplarily demonstrate that AS-ODN could be released following hybridization to CS-ODN adsorbed to MWCNT-OH at physiological settings (37 °C, urine). Conclusions: In conclusion, functionalized MWCNT might be used as nanotransporters in antisense therapy for the local treatment of BCa.

2014, Cirillo, Giuseppe, Hampel, Silke, Spizzirri, Umile Gianfranco, Parisi, Ortensia Ilaria, Picci, Nevio, Iemma, Francesca

The use of biologics, polymers, silicon materials, carbon materials, and metals has been proposed for the preparation of innovative drug delivery devices. One of the most promising materials in this field are the carbon-nanotubes composites and hybrid materials coupling the advantages of polymers (biocompatibility and biodegradability) with those of carbon nanotubes (cellular uptake, stability, electromagnatic, and magnetic behavior). The applicability of polymer-carbon nanotubes composites in drug delivery, with particular attention to the controlled release by composites hydrogel, is being extensively investigated in the present review.

2019, Lerra, L., Farfalla, A., Sanz, B., Cirillo, G., Vittorio, O., Voli, F., Grand, M.L., Curcio, M., Nicoletta, F.P., Dubrovska, A., Hampel, S., Iemma, F., Goya, G.F.

With the aim to obtain a site-specific doxorubicin (DOX) delivery in neuroblastoma SH-SY5Y cells, we designed an hybrid nanocarrier combining graphene oxide (GO) and magnetic iron oxide nanoparticles (MNPs), acting as core elements, and a curcumin–human serum albumin conjugate as functional coating. The nanohybrid, synthesized by redox reaction between the MNPs@GO system and albumin bioconjugate, consisted of MNPs@GO nanosheets homogeneously coated by the bioconjugate as verified by SEM investigations. Drug release experiments showed a pH-responsive behavior with higher release amounts in acidic (45% at pH 5.0) vs. neutral (28% at pH 7.4) environments. Cell internalization studies proved the presence of nanohybrid inside SH-SY5Y cytoplasm. The improved efficacy obtained in viability assays is given by the synergy of functional coating and MNPs constituting the nanohybrids: while curcumin moieties were able to keep low DOX cytotoxicity levels (at concentrations of 0.44–0.88 µM), the presence of MNPs allowed remote actuation on the nanohybrid by a magnetic field, increasing the dose delivered at the target site.

2017, Cimalla, P., Walther, J., Mueller, C., Almedawar, S., Rellinghaus, B., Wittig, D., Ader, M., Karl, M.O., Funk, R.H.W., Brand, M., Koch, E.

In this paper, we present a reliable and robust method for magnetomotive optical coherence tomography (MM-OCT) imaging of single cells labeled with iron oxide particles. This method employs modulated longitudinal and transverse magnetic fields to evoke alignment and rotation of anisotropic magnetic structures in the sample volume. Experimental evidence suggests that magnetic particles assemble themselves in elongated chains when exposed to a permanent magnetic field. Magnetomotion in the intracellular space was detected and visualized by means of 3D OCT as well as laser speckle reflectometry as a 2D reference imaging method. Our experiments on mesenchymal stem cells embedded in agar scaffolds show that the magnetomotive signal in rotational MM-OCT is significantly increased by a factor of ˜3 compared to previous pulsed MM-OCT, although the solenoid's power consumption was 16 times lower. Finally, we use our novel method to image ARPE-19 cells, a human retinal pigment epithelium cell line. Our results permit magnetomotive imaging with higher sensitivity and the use of low power magnetic fields or larger working distances for future three-dimensional cell tracking in target tissues and organs.

2017-10-10, Göttlicher, Markus, Rohnke, Marcus, Moryson, Yannik, Thomas, Jürgen, Sann, Joachim, Lode, Anja, Schumacher, Matthias, Schmidt, Romy, Pilz, Stefan, Gebert, Annett, Gemming, Thomas, Janek, Jürgen

Background: Surface functionalization of orthopedic implants with pharmaceutically active agents is a modern approach to enhance osseointegration in systemically altered bone. A local release of strontium, a verified bone building therapeutic agent, at the fracture site would diminish side effects, which could occur otherwise by oral administration. Strontium surface functionalization of specially designed titanium-niobium (Ti-40Nb) implant alloy would provide an advanced implant system that is mechanically adapted to altered bone with the ability to stimulate bone formation. Methods: Strontium-containing coatings were prepared by reactive sputtering of strontium chloride (SrCl2) in a self-constructed capacitively coupled radio frequency (RF) plasma reactor. Film morphology, structure and composition were investigated by scanning electron microscopy (SEM), time of flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS). High-resolution transmission electron microscopy (HR-TEM) was used for the investigation of thickness and growth direction of the product layer. TEM lamellae were prepared using the focused ion beam (FIB) technique. Bioactivity of the surface coatings was tested by cultivation of primary human osteoblasts and subsequent analysis of cell morphology, viability, proliferation and differentiation. The results are correlated with the amount of strontium that is released from the coating in biomedical buffer solution, quantified by inductively coupled plasma mass spectrometry (ICP-MS). Results: Dense coatings, consisting of SrOxCly, of more than 100 nm thickness and columnar structure, were prepared. TEM images of cross sections clearly show an incoherent but well-structured interface between coating and substrate without any cracks. Sr2+ is released from the SrOxCly coating into physiological solution as proven by ICP-MS analysis. Cell culture studies showed excellent biocompatibility of the functionalized alloy. Conclusions: Ti-40Nb alloy, a potential orthopedic implant material for osteoporosis patients, could be successfully plasma coated with a dense SrOxCly film. The material performed well in in vitro tests. Nevertheless, the Sr2+ release must be optimized in future work to meet the requirements of an effective drug delivery system.