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 Parkinson’s 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 - 200 nm. 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.

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Exosomes have recently come into focus as “natural nanoparticles” for use as drug delivery vehicles. Our objective was to assess the feasibility of an exosome-based drug delivery platform for a potent chemotherapeutic agent, paclitaxel (PTX), to treat MDR cancer. Herein, we developed and compared different methods of loading exosomes released by macrophages with PTX (exoPTX), and characterized their size, stability, drug release, and in vitro antitumor efficacy. Reformation of the exosomal membrane upon sonication resulted in high loading efficiency and sustained drug release. Importantly, incorporation of PTX into exosomes increased cytotoxicity more than 50 times in drug resistant MDCKMDR1 (Pgp+) cells. Next, our studies demonstrated a nearly complete co-localization of airway-delivered exosomes with cancer cells in a model of murine Lewis Lung Carcinoma pulmonary metastases, and a potent anticancer effect in this mouse model. We conclude that exoPTX holds significant potential for the delivery of various chemotherapeutics to treat drug resistant cancers.

Polymer nanomaterials have sparked a considerable interest as vehicles used for diagnostic and therapeutic agents; research in nanomedicine has not only become a frontier movement but is also a revolutionizing drug delivery field. A common approach for building a drug delivery system is to incorporate the drug within the nanocarrier that results in increased solubility, metabolic stability, and improved circulation time. With this foundation, nanoparticles with stealth properties that can circumvent RES and other clearance and defense mechanisms are the most promising. However, recent developments indicate that select polymer nanomaterials can implement more than only inert carrier functions by being biological response modifiers. One representative of such materials is Pluronic block copolymers that cause various functional alterations in cells. The key attribute for the biological activity of Pluronics is their ability to incorporate into membranes followed by subsequent translocation into the cells and affecting various cellular functions, such as mitochondrial respiration, ATP synthesis, activity of drug efflux transporters, apoptotic signal transduction, and gene expression. As a result, Pluronics cause drastic sensitization of MDR tumors to various anticancer agents, enhance drug transport across the blood brain and intestinal barriers, and causes transcriptional activation of gene expression both in vitro and in vivo. Collectively, these studies suggest that Pluronics have a broad spectrum of biological response modifying activities which make it one of the most potent drug targeting systems available, resulting in a remarkable impact on the emergent field of nanomedicine.

Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Comprised of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell–cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells. In addition, exosomes can be amended through their parental cells to express a targeting moiety on their surface, or supplemented with desired biological activity. Development and validation of exosome-based drug delivery systems are the focus of this review. Different techniques of exosome isolation, characterization, drug loading, and applications in experimental disease models and clinic are discussed. Exosome-based drug formulations may be applied to a wide variety of disorders such as cancer, various infectious, cardiovascular, and neuro-degenerative disorders. Overall, exosomes combine benefits of both synthetic nanocarriers and cell-mediated drug delivery systems while avoiding their limitations.

Micellization of poly(oxyethylene-6-oxypropylene-6-oxyethylene) triblock copolymers (Pluronic polymers F68, P85, and F108) in aqueous solutions was studied, and critical micellization concentrations (cmc) were determined using surface tension measurements and fluorescent probes (pyrene, l,6-diphenyl-l,3,5-hexatriene). The dependence of cmc on temperature was observed, and critical micellization temperatures characterizing temperature-dependent transitions of Pluronic unimers to multimolecular micelles were measured. The molecular characteristics of P85 and F108 micelles including their dimensions, molecular masses and surfactant aggregation numbers were determined using lightscattering and ultracentrifugation techniques. Depending on the type of Pluronic, the micelles had an average hydrodynamic diameter ranging from about 15 to about 35 nm, a molecular mass of about 200 kDa and aggregation numbers ranging from one to several dozens. The partitioning of fluorescent probes between aqueous and micellar phases was analyzed within the frame of a pseudophase model, and the partitioning coefficients were determined using the fluorescence data. The results are compared with previous reports and are discussed in relationship to the application of block copolymer micelles as microcontainers for drug delivery.

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Solubilization of highly hydrophobic drugs with carriers that are non-toxic, non-immunogenic and well-defined remains a major obstacle in pharmaceutical sciences. Well defined amphiphilic di- and triblock copolymers based on poly(2-oxazolines) were prepared and used for the solubilization of Paclitaxel (PTX) and other water-insoluble drugs. Probing the polymer micelles in water with the fluorescence probe pyrene, an unusual high polar microenvironment of the probe was observed. This coincides with an extraordinary large loading capacity for PTX of 45 wt.% active drug in the formulation as well as high water solubility of the resulting formulation. Physicochemical properties of the formulations, ease of preparation and stability upon lyophilization, low toxicity and immunogenicity suggest that poly(2-oxazoline)s are promising candidates for the delivery of highly challenging drugs. Furthermore, we demonstrate that PTX is fully active and provides superior tumor inhibition as compared to the commercial micellar formulation.