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      Nano-antidotes for drug overdose and poisoning.

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          Abstract

          The number of intoxications from xenobiotics--natural or synthetic foreign chemicals, or substances given in higher doses than typically present in humans--has risen tremendously in the last decade, placing poisoning as the leading external cause of death in the United States. This epidemic has fostered the development of antidotal nanomedicines, which we call "nano-antidotes," capable of efficiently neutralizing offending compounds in situ. Although prototype nano-antidotes have shown efficacy in proof-of-concept studies, the gap to clinical translation can only be filled if issues such as the clinical relevance of intoxication models and the safety profile of nano-antidotes are properly addressed. As the unmet medical needs in resuscitative care call for better treatments, this Perspective critically reviews the recent progress in antidotal medicine and emerging nanotechnologies.

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          Most cited references55

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          Nanoparticle-detained toxins for safe and effective vaccination

          Toxoid vaccines—vaccines based on inactivated bacterial toxins— are routinely used to promote antitoxin immunity for the treatment and prevention of bacterial infections 1–4 . Following chemical or heat denaturation, inactivated toxins can be administered to mount toxin-specific immune responses. However, retaining faithful antigenic presentation while removing toxin virulence remains a major challenge and presents a trade-off between efficacy and safety in toxoid development. Here we show a nanoparticle-based toxin-detainment strategy that safely delivers non-disrupted pore-forming toxins for immune processing. Using erythrocyte membrane-coated nanoparticles and staphylococcal α-haemolysin, we demonstrate effective virulence neutralization via spontaneous particle entrapment. As compared to vaccination with heat-denatured toxin, mice vaccinated with the nanoparticle-detained toxin showed superior protective immunity against toxin adverse effects. We find that the non-disruptive detoxification approach benefited the immunogenicity and efficacy of toxoid vaccines. We anticipate the reported study to open new possibilities in the preparation of antitoxin vaccines against the many virulence factors that threaten public health.
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            Clearance of pathological antibodies using biomimetic nanoparticles

            Pathological antibodies have been demonstrated to play a key role in type II immune hypersensitivity reactions, resulting in the destruction of healthy tissues and leading to considerable morbidity for the patient. Unfortunately, current treatments present significant iatrogenic risk while still falling short for many patients in achieving clinical remission. In the present work, we explored the capability of target cell membrane-coated nanoparticles to abrogate the effect of pathological antibodies in an effort to minimize disease burden, without the need for drug-based immune suppression. Inspired by antibody-driven pathology, we used intact RBC membranes stabilized by biodegradable polymeric nanoparticle cores to serve as an alternative target for pathological antibodies in an antibody-induced anemia disease model. Through both in vitro and in vivo studies, we demonstrated efficacy of RBC membrane-cloaked nanoparticles to bind and neutralize anti-RBC polyclonal IgG effectively, and thus preserve circulating RBCs.
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              An extracorporeal blood-cleansing device for sepsis therapy.

              Here we describe a blood-cleansing device for sepsis therapy inspired by the spleen, which can continuously remove pathogens and toxins from blood without first identifying the infectious agent. Blood flowing from an infected individual is mixed with magnetic nanobeads coated with an engineered human opsonin--mannose-binding lectin (MBL)--that captures a broad range of pathogens and toxins without activating complement factors or coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing through a single biospleen unit at up to 1.25 liters per h in vitro. In rats infected with Staphylococcus aureus or Escherichia coli, the biospleen cleared >90% of bacteria from blood, reduced pathogen and immune cell infiltration in multiple organs and decreased inflammatory cytokine levels. In a model of endotoxemic shock, the biospleen increased survival rates after a 5-h treatment.

                Author and article information

                Journal
                Sci Transl Med
                Science translational medicine
                American Association for the Advancement of Science (AAAS)
                1946-6242
                1946-6234
                Jun 03 2015
                : 7
                : 290
                Affiliations
                [1 ] Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
                [2 ] Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland. jleroux@ethz.ch.
                Article
                7/290/290ps14
                10.1126/scitranslmed.3008736
                26041703
                d9cb54f2-cbdb-4d1b-b593-76579cca5c34
                History

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