Targeted Large-Volume Lymphocyte Removal Using Magnetic Nanoparticles in Blood Samples of Patients with Chronic Lymphocytic Leukemia: A Proof-of-Concept Study.

In the past, our research group was able to successfully remove circulating tumor cells with magnetic nanoparticles. While these cancer cells are typically present in low numbers, we hypothesized that magnetic nanoparticles, besides catching single cells, are also capable of eliminating a large number of tumor cells from the blood ex vivo. This approach was tested in a small pilot study in blood samples of patients suffering from chronic lymphocytic leukemia (CLL), a mature B-cell neoplasm. Cluster of differentiation (CD) 52 is a ubiquitously expressed surface antigen on mature lymphocytes. Alemtuzumab (MabCampath®) is a humanized, IgG1κ, monoclonal antibody directed against CD52, which was formerly clinically approved for treating chronic lymphocytic leukemia (CLL) and therefore regarded as an ideal candidate for further tests to develop new treatment options. Alemtuzumab was bound onto carbon-coated cobalt nanoparticles. The particles were added to blood samples of CLL patients and finally removed, ideally with bound B lymphocytes, using a magnetic column. Flow cytometry quantified lymphocyte counts before, after the first, and after the second flow across the column. A mixed effects analysis was performed to evaluate removal efficiency. p < 0.05 was defined as significant. In the first patient cohort (n = 10), using a fixed nanoparticle concentration, CD19-positive B lymphocytes were reduced by 38% and by 53% after the first and the second purification steps (p = 0.002 and p = 0.005), respectively. In a second patient cohort (n = 11), the nanoparticle concentration was increased, and CD19-positive B lymphocytes were reduced by 44% (p < 0.001) with no further removal after the second purification step. In patients with a high lymphocyte count (>20 G/L), an improved efficiency of approximately 20% was observed using higher nanoparticle concentrations. A 40 to 50% reduction of B lymphocyte count using alemtuzumab-coupled carbon-coated cobalt nanoparticles is feasible, also in patients with a high lymphocyte count. A second purification step did not further increase removal. This proof-of-concept study demonstrates that such particles allow for the targeted extraction of larger amounts of cellular blood components and might offer new treatment options in the far future.

Removal of Circulating Tumor Cells from Blood Samples of Cancer Patients Using Highly Magnetic Nanoparticles: A Translational Research Project.

The count of circulating tumor cells (CTCs) has been associated with a worse prognosis in different types of cancer. Perioperatively, CTCs detach due to mechanical forces. Diagnostic tools exist to detect and isolate CTCs, but no therapeutic technique is currently available to remove CTCs in vivo from unprocessed blood. The aim of this study was to design and test new magnetic nanoparticles to purify whole blood from CTCs. Novel magnetic carbon-coated cobalt (C/Co) nanoparticles conjugated with anti-epithelial cell adhesion molecule (EpCAM) antibodies were synthesized, and their antifouling and separation properties were determined. The newly developed C/Co nanoparticles showed excellent separation and antifouling properties. They efficiently removed tumor cells that were added to healthy subjects' blood samples, through an anti-EpCAM antibody interaction. The nanoparticles did not interact with other blood components, such as lymphocytes or the coagulation system. In blood samples of carcinoma patients suffering from metastatic disease, on average, ≥68% of CTCs were removed. These nanoparticles could prompt the development of a blood purification technology, such as a dialysis-like device, to perioperatively remove CTCs from the blood of cancer patients in vivo and potentially improve their prognosis.

Ecotoxicological Assessment of DNA-Tagged Silica Particles for Environmental Tracing.

Environmental tracers are chemical species that move with a fluid and allow us to understand its origin and material transport properties. DNA-based materials have been proposed and used for tracing due to their potential for multitracing with high specificity and sensitivity. For large-scale applications of this new material it is of interest to understand its impact on the environment. We therefore assessed the ecotoxicity of sub-micron silica particles with and without encapsulated DNA in the context of surface and underground tracing of natural waterflows using standard ecotoxicity assays according to ISO standards. Acute toxicity tests were performed with Daphnia magna (48 h), showing no effect on mobility at tracer concentrations below 300 ppm. Chronic ecotoxicological potential was tested with Raphidocelis subcapitata (green algae) (72 h) and Ceriodaphnia species (7 d) with no effect observed at realistic exposure scenario concentrations for both silica particles with and without encapsulated DNA. These results suggest that large-scale environmental tracing with DNA-tagged silica particles in the given exposure scenarios has a low impact on aquatic species with low trophic levels such as select algae and planktonic crustaceans.

Preparation of Functionalized Carbon-Coated Cobalt Nanoparticles with Sulfonated Arene Derivatives, a Study on Surface Functionalization and Stability.

The functionalization of magnetic nanoparticles has been an important field in the last decade due to the versatile applications in catalysis and biomedicine. Generally, a high degree of functionalities on the surface of the nanoparticles is desired. In this study, covalent functionalization of various aromatic sulfonic acids on carbon-coated cobalt nanoparticles are investigated on surface functionalization yield and stability. The nanoparticles are prepared via covalent linkage of an in situ generated diazonium on the graphene-like surface. Adsorption and wash experiments were performed to confirm a covalent bonding of the naphthalene derivatives on the nanoparticle surface. With an increased number of sulfonic acid groups on the aromatic compound a significantly lower loading is observed on the corresponding functionalized nanoparticles. This can be counteracted by a change of nitrite species. With this method, nanoparticles with a high number of sulfonic acid groups can be produced.

Low molecular weight glycerol derived coatings on magnetic nanoparticles: role of initiator, temperature, rate of monomer addition, enhanced biocompatibility and stability.

Biocompatible polymer coatings for magnetic nanoparticles have shown to drastically increase their usability towards biomedical applications. The coatings imprint characteristics such as stability, resistance to non-specific adsorption and tolerance in complex media for biomedicine. Herein, a thorough investigation towards the anionic ring-opening polymerization of glycidol on the surface of carbon-coated cobalt nanoparticle was performed. Reaction parameters that influence polymer growth have been investigated. Thereafter, a maximal achievable hyperbranched polyglycidol M w of up to 1148 g mol-1 under optimal reaction conditions was obtained. With this coating, the dispersion stability of the particles could be substantially increased, the non-specific adsorption of proteins could be decreased to 10% while retaining an efficient magnetic separation.

Tailoring the Colloidal Stability, Magnetic Separability, and Cytocompatibility of High-Capacity Magnetic Anion Exchangers.

Extracorporeal blood purification has been applied to artificially support kidney or liver function. However, convection and diffusion based blood purification systems have limited removal rates for high molecular weight and hydrophobic molecules. This limitation is due to the finite volume of infusion and limited membrane permeability, respectively. Adsorption provides an attractive alternative for the removal of higher molecular weight compounds. The use of adsorption resins containing ion exchanging groups to capture specific molecules has become well-established. Instead of stationary adsorption resins, however, ion exchanging polymers may be immobilized on magnetic particles and serve as freely diffusing, mobile, high capacity solid phase of ion exchange chromatography. While small beads with high surface area are attractive in terms of mass transfer and binding, unifying high capturing capacity with rapid and quantitative bead recovery remains an issue. Therefore, most of the current magnetic ion exchangers are based on micron-sized beads or require long times to separate. In addition to unfavorable magnetic recovery rates, the usually poor cytocompatibility limits their applicability in biomedicine. Here, we report on the synthesis and performance of polycationic polymer coated magnetic nanoflowers (MNF) for highly efficacious anion capturing. We demonstrate accurate control over the polymer content and composition on the beads and show its direct influence on colloidal stability, capturing capacity and magnetic separability. We present the removal of clinically relevant targets by capturing bilirubin with capacities 2-fold higher than previous work as well as quantitative heparin removal. Additionally, we illustrate how copolymerization of poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) with poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) leads to improved cytocompatibility of the polymer-coated MNF capturing agents while retaining high capturing capacities. Taken together, we present a nanoparticle/polymer material, which upon future in vivo validation, unifies high binding capacities and magnetic separability for rapid toxin capturing and hence fulfills key requirements of clinical utility.

Biochemical functionality of magnetic particles as nanosensors: how far away are we to implement them into clinical practice?

Magnetic nanosensors have become attractive instruments for the diagnosis and treatment of different diseases. They represent an efficient carrier system in drug delivery or in transporting contrast agents. For such purposes, magnetic nanosensors are used in vivo (intracorporeal application). To remove specific compounds from blood, magnetic nanosensors act as elimination system, which represents an extracorporeal approach. This review discusses principles, advantages and risks on recent advances in the field of magnetic nanosensors. First, synthesis methods for magnetic nanosensors and possibilities for enhancement of biocompatibility with different coating materials are addressed. Then, attention is devoted to clinical applications, in which nanosensors are or may be used as carrier- and elimination systems in the near future. Finally, risk considerations and possible effects of nanomaterials are discussed when working towards clinical applications with magnetic nanosensors.

Oxidized Co-Sn nanoparticles as long-lasting anode materials for lithium-ion batteries.

Herein, we present the synthesis and systematic comparison of Sn- and Co-Sn-based nanoparticles (NPs) as anode materials for lithium-ion batteries. These nanomaterials were produced via inexpensive routes combining wet chemical synthesis and dry mechanochemical methods (ball milling). We demonstrate that oxidized, nearly amorphous CoSn2Ox NPs, in contrast to highly crystalline Sn and CoSn2 NPs, exhibit high cycling stability over 1500 cycles, retaining a capacity of 525 mA h g-1 (92% of the initial capacity) at a high current density of 1982 mA g-1. Moreover, when cycled in full-cell configuration with LiCoO2 as the cathode, such CoSn2Ox NPs deliver an average anodic capacity of 576 mA h g-1 over 100 cycles at a current of 500 mA g-1, with an average discharge voltage of 3.14 V.