A novel human detoxification system based on nanoscale bioengineering and magnetic separation techniques.

We describe the conceptual approach, theoretical background and preliminary experimental data of a proposed platform technology for specific and rapid decorporation of blood-borne toxins from humans. The technology is designed for future emergent in-field or in-hospital detoxification of large numbers of biohazard-exposed victims; for example, after radiological attacks. The proposed systems is based on nanoscale technology employing biocompatible, superparamagnetic nanospheres, which are functionalized with target-specific antitoxin receptors, and freely circulate within the human blood stream after simple intravenous injection. Sequestration of the blood-borne toxins onto the nanosphere receptors generates circulating nanosphere-toxin complexes within a short time interval; mathematical modeling indicates prevailing of unbound nanosphere receptors over target toxin concentrations at most therapeutic injection dosages. After a toxin-specific time interval nanosphere-toxin complexes are generated within the blood stream and, after simple arterial or venous access, the blood is subsequently circulated via a small catheter through a portable high gradient magnetic separator device. In this device, the magnetic toxin complexes are retained by a high gradient magnetic field and the detoxified blood is then returned back to the blood circulation (extracorporeal circulation). Our preliminary in vitro experiments demonstrate >95% first pass capture efficiency of magnetic spheres within a prototype high gradient magnetic separation device. Further, based on the synthesis of novel hydrophobic magnetite nanophases with high magnetization ( approximately 55 emu/g), the first biodegradable magnetic nanospheres at a size range of approximately 280 nm and functionalized with PEG-maleimide surface groups for specific antibody attachment are described here. In future applications, we envision this technology to be suitable for emergent, in-field usage for acutely biohazard exposed victims as both the injectable toxin-binding magnetic spheres and the separator device are made to be portable, light-weight, zero-power, and self- or helper-employed. Details of the technology are presented and the state-of-knowledge and research is discussed.

[1]  C Papadimitriou,et al.  The efficiency of tumor cell purging using immunomagnetic CD34+ cell separation systems , 1997, Bone Marrow Transplantation.

[2]  Donald Garlotta,et al.  A Literature Review of Poly(Lactic Acid) , 2001 .

[3]  R D Swartz,et al.  Preservation of plasma volume during hemodialysis depends on dialysate osmolality. , 1982, American journal of nephrology.

[4]  D. Shah,et al.  A large-scale magnetic separator for selective cell separations with paramagnetic microbeads. , 1990, Artificial organs.

[5]  Y Li,et al.  PEGylated PLGA nanoparticles as protein carriers: synthesis, preparation and biodistribution in rats. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[6]  Ruxandra Gref,et al.  Protein encapsulation within polyethylene glycol-coated nanospheres. I. Physicochemical characterization. , 1998, Journal of biomedical materials research.

[7]  H. Métivier,et al.  Experimental approaches to improve the available chelator treatments for Np decorporation , 1998 .

[8]  M. Slavik,et al.  Rapid detection of Salmonella typhimurium in chicken carcass wash water using an immunoelectrochemical method. , 2000, Journal of food protection.

[9]  A Göpferich,et al.  Polyanhydride degradation and erosion. , 2002, Advanced drug delivery reviews.

[10]  J. Plumas,et al.  Preparation of purified lymphoma cells suitable for therapy. , 2004, Cytotherapy.

[11]  M Dueser,et al.  Multistage magnetic and electrophoretic extraction of cells, particles and macromolecules. , 2000, Advances in biochemical engineering/biotechnology.

[12]  S. M. Moghimi Re-establishing the long circulatory behaviour of poloxamine-coated particles after repeated intravenous administration: applications in cancer drug delivery and imaging. , 1999, Biochimica et biophysica acta.

[13]  Nuray Karapinar,et al.  Magnetic separation of ferrihydrite from wastewater by magnetic seeding and high-gradient magnetic separation , 2003 .

[14]  A. Hasan,et al.  The use of 99Tcm-DTPA aerosol and caesium iodide mini-scintillation detectors in the assessment of lung injury during cardiopulmonary bypass surgery. , 1997, Nuclear medicine communications.

[15]  G. Stradling Decorporation of actinides: a review of recent research , 1998 .

[16]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[17]  R. Arshady,et al.  Microspheres for biomedical applications: preparation of reactive and labelled microspheres. , 1993, Biomaterials.

[18]  Zahi A Fayad,et al.  Recombinant HDL-like nanoparticles: a specific contrast agent for MRI of atherosclerotic plaques. , 2004, Journal of the American Chemical Society.

[19]  Jin Chen,et al.  New technology of pulsating high gradient magnetic separation , 1998 .

[20]  A. Rosengart,et al.  Physicochemical characteristics of magnetic microspheres containing tissue plasminogen activator , 2007 .

[21]  R. D. Pascoe,et al.  Influence of path length and slurry velocity on the removal of iron from kaolin using a high gradient magnetic separator , 2002 .

[22]  J. Beneš,et al.  The isolation of caesium-137 from liquid radioactive fall-out , 1963 .

[23]  J D Slack,et al.  Acute hemodynamic effects and blood pool kinetics of polystyrene microspheres following intravenous administration. , 1981, Journal of pharmaceutical sciences.

[24]  Michael D. Kaminski,et al.  Preparation and characterization of hydrophobic superparamagnetic magnetite gel , 2006 .

[25]  N. Okamoto,et al.  Separation of carp (Cyprinus carpio L.) thrombocytes by using a monoclonal antibody, and their aggregation by collagen. , 1997, Veterinary immunology and immunopathology.

[26]  J. Watson,et al.  High purity, recovery, and selection of human blood cells with a novel high gradient magnetic separator. , 1996, Journal of hematotherapy.

[27]  Dehong Chen,et al.  Polycaprolactone microparticles and their biodegradation , 2000 .

[28]  C T Laurencin,et al.  Biodegradable polyphosphazenes for drug delivery applications. , 2003, Advanced drug delivery reviews.

[29]  G. Bifulco,et al.  Comparative study on biocompatibility and absorption times of three absorbable monofilament suture materials (Polydioxanone, Poliglecaprone 25, Glycomer 631). , 2000, British journal of plastic surgery.

[30]  H. El-Shall,et al.  Interaction of PLGA nanoparticles with human blood constituents. , 2005, Colloids and surfaces. B, Biointerfaces.

[31]  J Szebeni,et al.  Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. , 2003, Progress in lipid research.

[32]  M. D. Butterworth,et al.  Development of Systems for Targeting the Regional Lymph Nodes for Diagnostic Imaging: In Vivo Behaviour of Colloidal PEG-Coated Magnetite Nanospheres in the Rat Following Interstitial Administration , 2001, Pharmaceutical Research.

[33]  V. Volf Treatment of incorporated transuranium elements : a report sponsored by WHO and the IAEA , 1978 .

[34]  P. Couvreur,et al.  Polyalkylcyanoacrylate nanoparticles as carriers for granulocyte-colony stimulating factor (G-CSF). , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[35]  M. Portaccio,et al.  The α1-antitrypsin/elastase Complex as an Experimental Model for Hemodialysis in Acute Catabolic Renal Failure, Extracorporeal Blood Circulation and Cardiocirculatory Bypass , 2002 .

[36]  M C Yang,et al.  In vitro characterization of the occurrence of hemolysis during extracorporeal blood circulation using a mini hemodialyzer. , 2000, ASAIO journal.

[37]  M. Šafaříková,et al.  Separation of magnetic affinity biopolymer adsorbents in a Davis tube magnetic separator , 2001, Biotechnology Letters.

[38]  Patrick J. Gaffney,et al.  Quantitative “magnetic resonance immunohistochemistry” with ligand‐targeted 19F nanoparticles , 2004 .

[39]  P. Laroche,et al.  [Modeling of cutaneous radio-contamination: effects of washings by soap and by solutions of DTPA]. , 1997, Annales pharmaceutiques francaises.

[40]  V. Torchilin,et al.  Biodegradable long-circulating polymeric nanospheres. , 1994, Science.

[41]  J.H.P. Watson,et al.  Magnetic separator with transversally magnetised disk permanent magnets , 2002 .

[42]  J L Riley,et al.  Large-scale production of CD4+ T cells from HIV-1-infected donors after CD3/CD28 costimulation. , 1998, Journal of hematotherapy.

[43]  G. Bengtsson,et al.  Stability of Prussian blue bound to anion-exchange resin beads for radiocaesium reduction in foodstuffs , 1997 .

[44]  Paulo A. Augusto,et al.  Magnetic shielding: application to a new magnetic separator and classifier , 2004 .