Search

Nano-/microplastics (NP) is a human-made emerging contaminant with worldwide occurrence. The small size (below one micrometer), the different chemical nature and the persistence make NP to potential hazards with suspect probability of tissue penetration and inflammation or as accumulator for toxins. A strategy to stop the spill of novel NP is the remediation from waste water or rivers as prominent distributors. We have developed core–shell superparamagnetic iron oxide nanoparticles (SPIONs) that attract NP and glue them to larger agglomerates which then can be removed from water by applying an external magnetic field. The shell molecules provide two interaction motifs towards NP. The tuned surface potential of the functionalized SPIONs attract complementary charged NP efficiently and the n-alkyl chain is dedicated to preferential interaction towards organic NP rather than inorganic particles. Structural analytics and molecular dynamics simulation support the proposed concept. Systematic remediation experiments with different NP (chemical structures, sizes and mixtures), from different waters – including river water – and with different SPION core materials indicate a universal validity of the concept, with best remediation performance for mixed NP. We suggest a method for broadband remediation of various NP with simple materials and processes, which both have the potential to be up-scaled.

Nanomedicine is at a crossroads: with relatively few success stories in terms of clinical translation despite more and more research on increasingly sophisticated nanomaterials, it is important to consider whether we are on the right track. Indeed, it is crucial that we address the fact that while considerable efforts are being made to overcome barriers to translation from the bench to the clinic, scientists are still struggling to decipher fundamental aspects of nanomaterial interactions with biological systems. We believe that a key to the successful adoption of nanomedicines in oncology and beyond lies in a deeper understanding of underlying biological processes and in decoding interactions between engineered nanomaterials and biological systems. Here we provide an overview of progress in nanomedicine during the past 5 years.

According to the World Health Organization, cancer is the second most important cause of death in Europe. Due to its manifold manifestations, it is not possible to treat all patients according to a uniform scheme. However, all solid tumors have one thing in common: independent of the tumor’s molecular subgroup and the treatment protocol, the immune status of the tumor, especially the amount of tumor infiltrating lymphocytes (TILs), is important for the patient’s clinical outcome – the higher the number of TILs, the better the outcome. For this reason it seems desirable to increase the number of TILs. One way to accumulate T cells in the tumor area is to make them magnetizable and attract them with an external magnetic field. Magnetization can be achieved by superparamagnetic iron oxide nanoparticles (SPIONs) which can be bound to the cells’ surface or internalized into the cells. For this study, SPIONs with different coatings were synthesized and incubated with immortalized mouse T lymphocytes. SPIONs only stabilized with lauric acid (LA) coated in situ or afterwards showed high toxicity. Addition of an albumin layer increased the biocompatibility but reduced cellular uptake. To increase the cellular uptake the albumin coated particles were aminated, leading to both higher uptake and toxicity, dependent on the degree of amination. In the presence of an externally applied magnetic field, T cells loaded with selected types and amounts of SPIONs were guidable. With this promising pilot study we already can demonstrate that it is possible to attract SPION bearing T cells by an external magnet. To sum up, biocompatibility and uptake of SPIONs by T cells are opposing events. Thus, for the functionalization of T cells with SPIONs the balance between uptake and toxicity must be evaluated carefully.

Magnetic particle imaging (MPI) is a tomographic imaging method to determine the spatial distribution of magnetic nanoparticles (MNP) within a defined volume. To evaluate the imaging capabilities of existing MPI scanners, their sensitivity and image resolution limits have to be analyzed. Therefore, precisely defined structures (phantoms) with various tracer concentrations are required to enable comparative studies between existing MPI systems. To support the development of capable MPI phantoms, we developed a method to incorporate different commercially available MNP into a long-term stable synthetic polymer with an iron concentration of up to 200 mmol/l. The properties of each type of polymer matrix embedded MNP were tested by magnetic particle spectroscopy (MPS). For shaping the particle loaded polymer to a phantom, we used 3-D printed molds with a structure cross section of 2 × 2 mm2. The particle loads within the phantoms were then imaged using MPI. The particle-loaded polymer is very suitable for preparation of measurement phantoms that could be visualized by MPI. Repeated shore hardness and MPS measurements up to one year did not reveal any changes in the mechanical and magnetic properties of the used material. In conclusion, we developed long-term stable measurement phantoms for magnetic particle imaging. Further work will focus on more detailed particle loaded structures in phantoms and water based polymers with a more homogeneous particle distribution.

The complex interplay of single wrist bones acting in combination with their ligamentous connections is still not fully understood. In this regard various theories exist, divisible in columnar and ring/row theories. The object of this study was to examine the mobility of the individual carpal bones as well as the ulna and metacarpals relative to each other in wrists of cadaveric hands using CT scans.The regular wrist mobility of a total of 21 cadaveric hands was examined by CT imaging in neutral position, radial/ulnar abduction as well as wrist flexion and extension. The data were evaluated as 3D models by using a standardized global coordinate system and object coordinate systems. Rotation and translation of each carpal bone as well as radius/ulna and all metacarpal bones were evaluated.The principal motion took place in the carpus between the radius and the proximal carpal row followed by the midcarpal joint and the carpometacarpal joints and not mainly between the individual bones of a row. The scaphoid moves out of its row aggregate mainly during flexion and adapts to the motion of the distal carpal row. The trapezium and first metacarpal bones play a specific role detached from the remaining bones.With this study, a better understanding of the motion of the individual bones of the carpus, the metacarpals and the radius/ulna is shown. The study supports the row theory, where most motion takes place between the individual rows and not between the carpal bones, leaving the scaphoid and the first ray in a special role between the rows.

Innovative strategies fighting cancer by inducing anti-tumor responses from the immune system are urgently needed. Amongst others, chemotherapeutics from the class of the anthracyclines have been shown to induce death of cancer cells with immunogenic features and triggering immunogenic anti-tumor responses. However, the patient's immune system often becomes severely impaired by the unspecific action of these cytotoxic drugs in systemic chemotherapy, preventing any effective immune reactions. To reduce systemic side effects and to accumulate the drug exclusively in the tumor region, we developed an iron oxide nanoparticle-based system for the magnetically targeted delivery of mitoxantrone to the tumor, which has previously proven its long-term therapeutic efficacy in tumor bearing rabbits. Here, we show in vitro that superparamagnetic iron oxide nanoparticles (SPIONs), loaded with the chemotherapeutic drug mitoxantrone, are able to induce cell death with immunogenic features and concomitant maturation of dendritic cells, comparable to the free drug, whereas unloaded nanoparticles are very biocompatible. We conclude that the targeted delivery of mitoxantrone to the tumor region might be a promising possibility to selectively modulate the tumor microenvironment and to locally stimulate immune responses against the tumor. Thus, SPIONs can be used as a platform to specifically bring immunogenic cell death inducers (e.g. mitoxantrone, hypericin, doxorubicin) to the tumor region by sparing the immune system from their toxic effects.

Aminoferrocene-based prodrugs are activated in cancer cells by reactive oxygen species (ROS). They were shown to exhibit high cytotoxicity towards a variety of cancer cell lines and primary cancer cells, but remain not toxic towards non-malignant cells. However, these prodrugs have rather high lipophilicity leading to relatively low water solubility. In particular, an n-octanol/water partition coefficient for the best aminoferrocene-based prodrug (2) was found to be 4.51±0.03. Though the approaches for decreasing lipophilicity are straightforward and include the addition of polar residues to the drug structure, these modifications also lead to dramatic decrease of cell permeability and, correspondingly, lower the activity of the drug. Therefore, a delicate balance of polar and unpolar groups should be found to reduce lipophilicity without compromising the useful drug properties. In this study we optimized an N-alkyl substituent, which is a key element responsible for the stabilization of the aminoferrocene drug released in cancer cells from prodrug 2. We found that an N-propargyl residue is an optimal replacement for the N-benzyl fragment. In particular, such a substitution (prodrug 7a) leads to reduction of prodrug lipophilicity down to logP=3.78±0.05, improvement of its water solubility, decrease of its propensity towards aggregation and dramatic increase of its ROS-generating properties. Finally, we demonstrated that the optimized prodrug strongly suppresses growth of Guerin's carcinoma (T8) in vivo at the dose of 30mg/kg.

A rational use of superparamagnetic iron oxide nanoparticles (SPIONs) in drug delivery, diagnostics, and other biomedical applications requires deep understanding of the molecular drug adsorption/desorption mechanisms for proper design of new pharmaceutical formulations. The adsorption and desorption of the cytostatic Mitoxantrone (MTO) to lauric acid-albumin hybrid coated particles SPIONs (SEONLA−HSA) was studied by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), surface titration, release experiments and small-angle neutron and X-ray scattering. Such MTO-loaded nanoparticles have shown very promising results in in vivo animal models before, while the exact binding mechanism of the drug was unknown. SEONLA−HSA formulations have shown better stability under drug loading in comparison with uncoated nanoparticle and sustainable drug release to compare with protein solution. Adsorption of MTO to SEONLA−HSA leads to decreasing of absolute value of zeta potential and repulsive interaction among particles, which points to the location of separate molecules of MTO on the outer surface of LA-HSA shell.

Nearly one fourth of all deaths worldwide are attributable to cardiovascular diseases (CVD), including stroke and ischemic heart disease. In spite of the steady progress in cardiovascular diagnostics and therapy, the CVD prevalence continues to rise on a global scale. Persisting efforts in the fields of bio-engineering and tissue engineering, in parallel with improved understanding of disease mechanisms, have shifted the focus of research towards improved approaches to vascular regeneration, based on degradable biomaterials for temporary rather than permanent grafting. Utilizing advanced bioplotting techniques in order to combine cells, natural hydrogels and fibers, the production of tailored 3D vessel constructs that promote the regeneration of native tubular tissues has now become achievable. In this paper, we review the most promising biomaterials and additive manufacturing approaches to fabricate novel vascular constructs. In addition, we discuss the progress and the remaining challenges in the field.

Various nanoparticle systems have been developed for medical applications in recent years. For constant improvement of efficacy and safety of nanoparticles, a close interdisciplinary interplay between synthesis, physicochemical characterizations and toxicological investigations is urgently needed. Based on combined toxicological data, we follow a “safe-by design” strategy for our superparamagnetic iron oxide nanoparticles (SPION). Using complementary interference-free toxicological assay systems, we initially identified agglomeration tendencies in physiological fluids, strong uptake by cells and improvable biocompatibility of lauric acid (LA)-coated SPIONs (SPION LA ). Thus, we decided to further stabilize those particles by an artificial protein corona consisting of serum albumin. This approach finally lead to increased colloidal stability, augmented drug loading capacity and improved biocompatibility in previous in vitro assays. Here, we show in whole blood ex vivo and on isolated red blood cells (RBC) that a protein corona protects RBCs from hemolysis by SPIONs.

The transfer of substances via the blood-placenta barrier is tightly regulated and critical for the fetus and the expecting mother. In case of necessary medical interventions during pregnancy a comprehensive knowledge about the interaction of the drugs with this barrier is indispensable. Therefore well-engineered test systems are needed and valuable transport systems are helpful. We developed an in vitro microfluidic blood-placenta barrier system consisting of the human trophoblast cell line BeWo and human primary placental pericytes. The integrity and stability of the model was verified by a permeability assay and immunocytochemistry. As potential drug carriers magnetic nanoparticles with various coatings were applied and their ability to pass the barrier was quantified by magnetic particle spectroscopy. We could demonstrate that up to 4% of negatively charged nanoparticles pass the barrier in a time-dependent manner.

The global burden of atherothrombotic diseases continues to grow. Worldwide, 17.9 million deaths per year are caused by cardiovascular diseases (CVD). According to WHO estimates, this number is expected to grow to more than 23.6 million by 2030. To achieve a more effective primary prevention of cardiovascular morbidity and mortality, the development of new diagnostic and therapeutic strategies is required. Nanomedicine offers a unique platform for novel approaches to the diagnosis and therapy of CVD. In particular iron oxide-based magnetic nanoparticles, a class of nanosized agents with superparamagnetic properties, are considered a promising tool in management of cardiovascular patients. Their possible applications range from plaque imaging and thrombus detection to the targeted drug-delivery, stent endothelialisation and blood vessel regeneration. This paper summarizes recent advances in the implementation of magnetic nanoparticles to diagnosis and treatment of cardiovascular disorders.

In this work we present a new formulation of superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic drug targeting. The particles were reproducibly synthesized from current good manufacturing practice (cGMP) - grade substances. They were surface coated using fatty acids as anchoring molecules for human serum albumin. We comprehensively characterized the physicochemical core-shell structure of the particles using sophisticated methods. We investigated biocompatibility and cellular uptake of the particles using an established flow cytometric method in combination with microwave-plasma assisted atomic emission spectroscopy (MP-AES). The cytotoxic drug mitoxantrone was adsorbed on the protein shell and we showed that even in complex media it is slowly released with a close to zero order kinetics. We also describe an in vitro proof-of-concept assay in which we clearly showed that local enrichment of this SPION-drug conjugate with a magnet allows site-specific therapeutic effects.

Nanoparticles have belonged to various fields of biomedical research for quite some time. A promising site-directed application in the field of nanomedicine is drug targeting using magnetic nanoparticles which are directed at the target tissue by means of an external magnetic field. Materials most commonly used for magnetic drug delivery contain metal or metal oxide nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs consist of an iron oxide core, often coated with organic materials such as fatty acids, polysaccharides or polymers to improve colloidal stability and to prevent separation into particles and carrier medium [1]. In general, magnetite and maghemite particles are those most commonly used in medicine and are, as a rule, well-tolerated. The magnetic properties of SPIONs allow the remote control of their accumulation by means of an external magnetic field. Conjugation of SPIONs with drugs, in combination with an external magnetic field to target the nanoparticles (so-called "magnetic drug targeting", MDT), has additionally emerged as a promising strategy of drug delivery. Magnetic nanoparticle-based drug delivery is a sophisticated overall concept and a multitude of magnetic delivery vehicles have been developed. Targeting mechanism-exploiting, tumor-specific attributes are becoming more and more sophisticated. The same is true for controlled-release strategies for the diseased site. As it is nearly impossible to record every magnetic nanoparticle system developed so far, this review summarizes interesting approaches which have recently emerged in the field of targeted drug delivery for cancer therapy based on magnetic nanoparticles.

The availability of cell growth-supporting materials for regenerative medicine is limited. Here, we aimed to improve the attachment and growth of endothelial cells (HUVECs) and fibroblasts on electrospun poly(e-caprolactone) (PCL) mats with different fiber diameters and on newly-established PCL and silk fibroin (PCL/SF) blended fibers obtained by using benign solvents (mixture of acetic acid and formic acid) for electrospinning. PCL mats were produced in two different average fiber diameters, namely micro and nano range. The electrospinning method was optimized to produce PCL/SF blended fibers. Morphology (F-actin), viability (calcein) and metabolic activity (WST-8 assay) of HUVECs and fibroblasts cultured in 2D on the mats of different fiber size and composition were compared. Subsequently, cylindrical PCL/SF scaffolds were produced and colonized with cells using 3D radial magnetic cell seeding. Both PCL and PCL/SF nanofibers provided better support for initial cell adhesion (day 1) compared with PCL microfibers. At day 7, the highest metabolic activity in HUVECs and fibroblasts was observed on PCL/SF mats. Microscopic studies confirmed that on day 7, the best support for cell growth was observed on PCL/SF. Tubular PCL/SF scaffolds were successfully colonized using magnetic nanoparticles and 3D radial magnetic cell seeding. Taken together, the fibers obtained by blending SF with PCL combine the mechanical benefits of PCL with improved biological functionality of SF. Electrospun PCL/SF nanofibers represent a promising material to produce both flat and 3D structures with potential for enhanced cell attachment and tissue regeneration.

Magnetic targeting is considered a promising method to accumulate the nanoparticles at the sites of atherosclerotic lesions, but little is known about the biological effects of magnetic nanoparticles on the vascular wall. Here, we investigated endothelial cell growth and vitality upon treatment with SPION (0–60 mg/mL) using two complementing methods: real-time cell analysis and live-cell microscopy. Moreover, the uptake of circulating superparamagnetic iron oxide nanoparticles (SPIONs) was assessed in an in vitro model of arterial bifurcations. At the tested concentrations, SPIONs were well tolerated and had no major influence on endothelial cell growth. Our results further showed a uniform distribution of endothelial SPION uptake independent of channel geometry or hemodynamic conditions: In the absence of magnetic force, no increase in accumulation of SPIONs at non-uniform shear stress region at the outer walls of bifurcation was observed. Application of external magnet allowed enhanced accumulation of SPIONs at the regions of non-uniform shear stress. Increased uptake of SPIONs at non-uniform shear stress region was well tolerated by endothelial cells (ECs) and did not affect endothelial cell viability or attachment. These findings indicate that magnetic targeting can constitute a promising and safe technique for the delivery of imaging and therapeutic nanoparticles to atherosclerotic lesions.

To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies.This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

The aim of magnetic drug targeting (MDT) in cancer therapy is to concentrate chemotherapeutics to a tumor region while simultaneously the overall dose is reduced. This can be achieved with coated superparamagnetic nanoparticles bound to a chemotherapeutic agent. These particles are applied intra arterially close to the tumor region and focused to the tumor by a strong external magnetic field. The interaction of the particles with the field gradient leads to an accumulation in the region of interest (i.e. tumor). The particle enrichment and thereby the drug-load in the tumor during MDT has been proven by several analytical and imaging methods. Moreover, in pilot studies we investigated in an experimental in vivo tumor model the effectiveness of this approach. Complete tumor regressions without any negative side effects could be observed.

Tumors grown on animals and treated with magnetic drug targeting and magnetic hyperthermia have been analyzed by microcomputed X-ray tomography to study the three-dimensional nanoparticle distribution. The measurements have been performed in two laboratories, with a polychromatic X-ray cone beam as well as with monochromatic parallel beam. Due to the poor resolution in the first case, the distribution of the magnetic nanoparticles can be studied only qualitatively. With the polychromatic beam semi-quantitative results can be achieved. In this paper, the results from both methods are presented and compared.

Magnetic nanoparticles have been investigated for biomedical applications for more than 30 years. The development of biocompatible nanosized drug delivery systems for specific targeting of therapeutics is imminent in medical research, especially for treating cancer and vascular diseases. We used drug-labeled magnetic iron oxide nanoparticles, which were attracted to an experimental tumor in rabbits with an external magnetic field (magnetic drug targeting, MDT). Aim of this study was to detect and quantify the biodistribution of the magnetic nanoparticles by magnetorelaxometry. The study shows higher amount of nanoparticles in the tumor after intraarterial application and MDT compared to intravenous administration.

Magnetic drug targeting is a local drug delivery system. Electromicroscopic pictures document the ferrofluid enrichment in the intracellular space in vitro. In vivo experiments were performed in VX2 tumor-bearing rabbits using magnetic nanoparticles bound to mitoxantrone. High-pressure liquid chromatography (HPLC) analyses after magnetic drug targeting showed an increasing concentration of the chemotherapeutic agent in the tumor region compared to regular systemic chemotherapy.

Ferrofluids coated with starch polymers can be used as biocompatible carriers. Bound to medical drugs, such magnetic particles can be enriched in a desired body compartment using an external magnetic field. In the present study, we confirm the enrichment of ferrofluids in tumor tissue using histological investigations and conventional imaging techniques, i.e. X-ray and MRI.