Abstract
Hospitals routinely treat patients suffering from overdoses of drugs or other toxic chemicals as a result of illicit drug consumption, suicide attempts or accidental exposures. However, for many life-threatening situations, specific antidotes are not available and treatment is largely based on emptying the stomach, administering activated charcoal or other general measures of intoxication support. A promising strategy for managing such overdoses is to inject nanocarriers that can extract toxic agents from intoxicated tissues. To be effective, the nanocarriers must remain in the blood long enough to sequester the toxic components and/or their metabolites, and the toxin bound complex must also remain stable until it is removed from the bloodstream. Here, we discuss the principles that govern the use of injectable nanocarriers in biodetoxification and review the pharmacological performance of a number of different approaches.
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Watson, W. A. et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 23, 589–666 (2005).
Mokhlesi, B., Leiken, J. B., Murray, P. & Corbridge, T. C. Adult toxicology in critical care - Part I: general approach to the intoxicated patient. Chest 123, 577–592 (2003).
Zimmerman, J. L. Poisonings and overdoses in the intensive care unit: general and specific management issues. Crit. Care Med. 31, 2794–2801 (2003).
Babu Dhanikula, A., Lafleur, M. & Leroux, J. C. Characterization and in vitro evaluation of spherulites as sequestering vesicles with potential application in drug detoxification. Biochim. Biophys. Acta 1758, 1787–1796 (2006).
Breyer-Pfaff, U. The metabolic fate of amitriptyline, nortiptyline and amitriptylinoxide in man. Drug Metab. Rev. 36, 723–746 (2004).
Allen, T. M. & Cullis, P. R. Drug delivery systems: entering the mainstream. Science 303, 1818–1822 (2004).
Yamaoka, T., Tabata, Y. & Ikada, Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 83, 601–606 (1994).
Moghimi, S. M., Hunt, A. C. & Murray, J. C. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53, 283–318 (2001).
Olson, K. R. Poisoning and drug overdose. (Lange Medical Books / McGraw-Hill, New York, 2007).
Rossi, J. & Leroux, J. C. in Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery (ed. K. M. Wasan) 88–123 (John Wiley & Sons, Hoboken, 2006).
Morey, T. E. et al. Treatment of local anesthetic-induced cardiotoxicity using drug scavenging nanoparticles. Nano Lett. 4, 757–759 (2004).
Jovanovic, A. V., Underhill, R. S., Bucholz, T. L. & Duran, R. S. Oil core and silica shell nanocapsules: toward controlling the size and the ability to sequester hydrophobic compounds. Chem. Mater. 17, 3375–3383 (2005).
Varshney, M. et al. Pluronic microemulsions as nanoreservoirs for extraction of bupivacaine from normal saline. J. Am. Chem. Soc. 126, 5108–5112 (2004).
Lee, D. W. & Baney, R. H. Oligochitosan derivatives bearing electron-deficient aromatic rings for adsorption of amitryptiline: implications for drug detoxification. Biomacromolecules 5, 1310–1315 (2004).
Walde, P. & Ichikawa, S. Enzymes inside lipid vesicles: preparation, reactivity and applications. Biomol. Eng. 18, 143–177 (2001).
Cullis, P. R. et al. Influence of pH gradients on the transbilayer transport of drugs, lipids, peptides and metal ions into large unilamellar vesicles. Biochim. Biophys. Acta 1331, 187–211 (1997).
Leung, P. et al. Encapsulation of thiosulfate:cyanide sulfurtransferase by mouse erythrocytes. Toxicol. Appl. Pharmacol. 83, 101–107 (1986).
Pei, L., Petrikovics, I. & Way, J. L. Antagonism of the lethal effects of paraoxon by carrier erythrocytes containing phosphotriesterase. Fundam. Appl. Toxicol. 28, 209–214 (1995).
Petrikovics, I. et al. Antagonism of paraoxon intoxication by recombinant phosphotriesterase encapsulated within sterically stabilized liposomes. Toxicol. Appl. Pharmacol. 156, 56–63 (1999).
Petrikovics, I. et al. Comparing therapeutic and prophylactic protection against the lethal effect of paraoxon. Toxicol. Sci. 77, 258–262 (2004).
Petrikovics, I. et al. Long circulating liposomes encapsulating organophosphorus acid anhydrolase in diisopropylfluorophosphate antagonism. Toxicol. Sci. 57, 16–21 (2000).
Mayer, L. D., Reamer, J. & Bally, M. B. Intravenous pretreatment with empty pH gradient liposomes alters the pharmacokinetics and toxicity of doxorubicin through in vivo active drug encapsulation. J. Pharm. Sci. 88, 96–102 (1999).
Babu Dhanikula, A., Lamontagne, D. & Leroux, J. C. Rescue of amitriptyline-intoxicated hearts with nanosized vesicles. Cardiovasc. Res. 74, 480–486 (2007).
Simard, P., Hoarau, D., Khalid, M. N., Roux, E. & Leroux, J. C. Preparation and in vivo evaluation of PEGylated spherulite formulations. Biochim. Biophys. Acta 1715, 37–48 (2005).
Blank, M. L., Cress, E. A., Byrd, B. L., Washburn, L. C. & Snyder, F. Liposomal encapsulated Zn-DTPA for removing intracellular 169Yb. Health Phys. 39, 913–920 (1980).
Rahman, Y. E., Rosenthal, M. W. & Cerny, E. A. Intracellular plutonium: removal by liposome-encapsulated chelating agents. Science 180, 300–302 (1973).
Phan, G. et al. Pharmacokinetics of DTPA entrapped in conventional and long-circulating liposomes of different size for plutonium decorporation. J. Controlled Release 110, 177–188 (2005).
Phan, G. et al. Enhanced decorporation of plutonium by DTPA encapsulated in small PEG-coated liposomes. Biochimie 88, 1843–1849 (2006).
Weinberg, G. L., VadeBoncouer, T., Ramaraju, G. A., Garcia-Amaro, M. F. & Cwik, M. J. Pretreatment of resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 88, 1071–1075 (1998).
Weinberg, G. L., Ripper, R., Feinstein, D. L. & Hoffman, W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg. Anesth. Pain Med. 28, 198–202 (2003).
Rosenblatt, M. A., Abel, M., Fischer, G. W., Itzkovich, C. J. & Eisenkraft, J. B. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 105, 217–221 (2007).
Foxall, G., McCahon, R., Lamb, J., Hardman, J. G. & Bedforth, N. M. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anesthesia 62, 516–518 (2007).
Babu Dhanikula, A. et al. Long circulating lipid nanocapsules for drug detoxification. Biomaterials 28, 1248–1257 (2007).
Joncheray, T. J. et al. Electrochemical and spectroscopic characterization of organic compound uptake in silica core-shell nanocapsules. Langmuir 22, 8684–8689 (2006).
Underhill, R. S. et al. Oil-filled silica nanocapsules for lipophilic drug uptake: implications for drug detoxification therapy. Chem. Mater. 14, 4919–4925 (2002).
Jovanovic, A. V. et al. Surface modification of silica core-shell nanocapsules: biomedical implications. Biomacromolecules 7, 945–949 (2006).
Mertz, C. J. et al. In vitro studies of functionalized magnetic nanospheres for selective removal of a simulant biotoxin. J. Magn. Magn. Mater. 293, 572–577 (2005).
Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6, 688–701 (2006).
Bateman, D. N. Digoxin-specific antibody fragments. Toxicol. Rev. 23, 135–143 (2004).
Bom, A. et al. A novel concept of reversing neuromuscular blok: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew. Chem. Int. Edn 41, 266–270 (2002).
Sorgenfrei, I. F. et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex. Anesthesiology 104, 667–674 (2006).
Naguib, M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth. Analg. 104, 575–581 (2007).
Lee, D. W. et al. Aromatic-aromatic interaction of amitriptyline: implication of overdosed drug detoxification. J. Pharm. Sci. 94, 373–381 (2005).
Discher, D. E. & Eisenberg, A. Polymer vesicles. Science 297, 967–973 (2002).
O'Reilly, R. K., Hawker, C. J. & Wooley, K. L. Cross-linked block copolymer micelles: functional nanostructures of great potential and versatility. Chem. Soc. Rev. 35, 1068–1083 (2006).
Mayes, A. G. & Whitecombe, M. J. Synthetic strategies for the generation of molecularly imprinted organic polymers. Adv. Drug Deliv. Rev. 57, 1742–1778 (2005).
Jones, M. C. et al. Self-assembled nanocages for hydrophilic guest molecules. J. Am. Chem. Soc. 128, 14599–14605 (2006).
Lacy, C. F., Armstrong, L. L., Goldman, M. P. & Lance, L. L. Drug Information Handbook edn 14 (Lexi-Comp, Hudson, 2006).
Phan, G. et al. Targeting of diethylene triamine pentaacetic acid encapsulated in liposomes to rat liver: an effective strategy to prevent bone deposition and increase urine elimination of plutonium in rats. Int. J. Radiat. Biol. 80, 413–422 (2004).
Fallon, M. S. & Chauhan, A. Sequestration of amitriptyline by liposomes. J. Colloid Interface Sci. 300, 7–19 (2006).
Wang, L. et al. A biocompatible method of decorporation: bisphosphonate-modified magnetite nanoparticles to remove uranyl ions from blood. J. Am. Chem. Soc. 128, 13358–13359 (2006).
Suy, K. et al. Effective reversal of moderate rocuronium- or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant binding agent. Anesthesiology 106, 283–288 (2007).
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The Canada Research Chair program and the Natural Sciences and Engineering Research Council of Canada (NanoIP program) are acknowledged for their financial support.
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Leroux, JC. Injectable nanocarriers for biodetoxification. Nature Nanotech 2, 679–684 (2007). https://doi.org/10.1038/nnano.2007.339
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DOI: https://doi.org/10.1038/nnano.2007.339
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