Marina Sokolsky

Exosomes as drug delivery vehicles for Parkinson's disease therapy

Exosomes are naturally occurring nanosized vesicles that have attracted considerable attention as drug delivery vehicles in the past few years. Exosomes are comprised of natural lipid bilayers with the abundance of adhesive proteins that readily interact with cellular membranes. We posit that exosomes secreted by monocytes and macrophages can provide an unprecedented opportunity to avoid entrapment in mononuclear phagocytes (as a part of the host immune system), and at the same time enhance delivery of incorporated drugs to target cells ultimately increasing drug therapeutic efficacy. In light of this, we developed a new exosomal-based delivery system for a potent antioxidant, catalase, to treat Parkinsons disease (PD). Catalase was loaded into exosomes ex vivo using different methods: the incubation at room temperature, permeabilization with saponin, freeze-thaw cycles, sonication, or extrusion. The size of the obtained catalase-loaded exosomes (exoCAT) was in the range of 100-200nm. A reformation of exosomes upon sonication and extrusion, or permeabilization with saponin resulted in high loading efficiency, sustained release, and catalase preservation against proteases degradation. Exosomes were readily taken up by neuronal cells in vitro. A considerable amount of exosomes was detected in PD mouse brain following intranasal administration. ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD. Overall, exosome-based catalase formulations have a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders.

Towards nanomedicines of the future: Remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields

The paper describes the concept of magneto-mechanical actuation of single-domain magnetic nanoparticles (MNPs) in super-low and low frequency alternating magnetic fields (AMFs) and its possible use for remote control of nanomedicines and drug delivery systems. The applications of this approach for remote actuation of drug release as well as effects on biomacromolecules, biomembranes, subcellular structures and cells are discussed in comparison to conventional strategies employing magnetic hyperthermia in a radio frequency (RF) AMF. Several quantitative models describing interaction of functionalized MNPs with single macromolecules, lipid membranes, and proteins (e.g. cell membrane receptors, ion channels) are presented. The optimal characteristics of the MNPs and an AMF for effective magneto-mechanical actuation of single molecule responses in biological and bio-inspired systems are discussed. Altogether, the described studies and phenomena offer opportunities for the development of novel therapeutics both alone and in combination with magnetic hyperthermia.

Theranostic multimodal potential of magnetic nanoparticles actuated by non-heating low frequency magnetic field in the new-generation nanomedicine

The scope of this review involves one of the most promising branches of new-generation biomedicine, namely magnetic nanotheranostics using remote control of functionalized magnetic nanoparticles (f-MNPs) by means of alternating magnetic fields (AMFs). The review is mainly focused on new approach which utilizes non-heating low frequency magnetic fields (LFMFs) for nanomechanical actuation of f-MNPs. This approach is compared to such traditional ones as magnetic resonance imaging (MRI) and radio-frequency (RF) magnetic hyperthermia (MH) which utilize high frequency heating AMF. The innovative principles and specific models of non-thermal magnetomechanical actuation of biostructures by MNP rotational oscillations in LFMF are described. The discussed strategy allows biodistribution monitoring in situ, delivering drugs to target tissues and releasing them with controlled rate, controlling biocatalytic reaction kinetics, inducing malignant cell apoptosis, and more. Optimization of both LFMF and f-MNP parameters may lead to dramatic improvement of treatment efficiency, locality, and selectivity on molecular or cellular levels and allow implementing both drug and drugless, i.e., pure nanomechanical therapy, in particular cancer therapy. The optimal parameters within this approach differ significantly from those used in MH or MRI because of the principal difference in the f-MNP actuation modes. It is shown that specifically designed high gradient, steady magnetic field enables diagnostic and therapeutic LFMF impact localization in the deep tissues within the area ranging from a millimeter to a few centimeters and 3D scanning of affected region, if necessary.

Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption

Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact.