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Long Project Biodetoxification : Nanocarriers

Long Project Biodetoxification : Nanocarriers. April 27 th 2010 Mary Coan. Outline. Introduction Current Standard Detoxification Methods Administration of an Antidote Gastric Emptying Removal of Toxins Nanocarrier Biodetoxification Liposomes Nanoemulsions Nanoparticles

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Long Project Biodetoxification : Nanocarriers

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  1. Long ProjectBiodetoxification:Nanocarriers April 27th 2010 Mary Coan

  2. Outline • Introduction • Current Standard Detoxification Methods • Administration of an Antidote • Gastric Emptying • Removal of Toxins • Nanocarrier Biodetoxification • Liposomes • Nanoemulsions • Nanoparticles • Macromoleculues Carriers • Future Work • Conclusion Image: http://www.nature.com/nnano/journal/v3/n3/covers/index.html

  3. Introduction • Acute intoxications, either accidental or intentional, constitute a major public health problem worldwide • Due to the cost burden placed onto the hospital, patient, or the public depending on the healthcare system provided • Illicit drug use plays a profoundly large role in number of treated acute intoxication cases • Approximately 40% • Significant number of deaths are due to over the counter drug overdoses • Analgesics • Antidepressants • Sedatives/hypnotics/antipsychotics • Stimulants • Cardiovascular Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image; http://www.topnews.in/health/files/cholesterol-lowering-drugs.jpg

  4. Introduction • Many acute intoxication cases result in life-threatening situations • Typical treatment for conscious patients in these cases consists of • Emptying the stomach • Administering activated charcoal • Gastric emptying • Whole bowel irrigation • Haemodialysis • Correction of electrolyte disturbances • Adminstering I-V fluids • Removal of toxins through extracorporeal procedures Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://eslpod.com/eslpod_blog/wp-content/uploads/2008/02/emergency-1.jpg

  5. Introduction • Some of the listed treatments can be used on the unconscious • Whole bowel irrigation and haemodialysis are generally reserved for eliminating specific life-threatening toxins from the body • Antidotes are rarely available and/or exist Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://pencilsatdawn.wordpress.com/2007/07/14/antidote/

  6. Outline • Introduction • Current Standard Detoxification Methods • Administration of an Antidote • Gastric Emptying • Removal of Toxins • Nanocarrier Biodetoxification • Liposomes • Nanoemulsions • Nanoparticles • Macromoleculues Carriers • Future Work • Conclusion Image: http://best.rutgers.edu/files/imagecache/featured_block_1/testtubes_3.JPG

  7. Current Standard Detoxification Methods:Administration of an Antidote • There are antidotes for specific cases • Organophosphate/Carbamate insecticide • Atropine • Acetaminophen • N-Acetylcysteine (NAC)/Mucomyst® • Narcotic overdose • Naloxone/Narcan® • There are many more antidotes that are specifically for chemical exposure or poisonous bites not for drug overdoses http://www.rphworld.com/viewlink-25090.html Image: http://store.vitaminliving.com/images/uploads/IV_Bag.jpg

  8. Current Standard Detoxification Methods:Administration of an Antidote • All of these antidotes can be given via an IV or shot • Example of a largely used antidote is Narcan® • Non-habit forming and causes no long-term side effects • Sudden reversal of a heroin high can induce vomiting • Supplied to thousands of Heroin addicts by local government programs to reverse a drug overdose • Thousands have been saved since the induction of the program in a select few cities http://www.boston.com/news/local/articles/2007/11/02/addicts_to_receive_overdose_antidote/ Image: http://www.abconlinepharmacy.com/ns/imagem.php?masterid=1299

  9. Current Standard Detoxification Methods: Gastric Emptying • For patients that swallow any poisonous substance, not including alcohol, the following procedure is typically followed: • IV fluids are administered and continued • Activated charcoal is administered • Orally via a black drink, if the patient is awake and alert • Orally through a tube, if the patient is not awake • Adsorbs and eliminates drugs/metabolites that are still present or being secreted in the gastrointestinal track • Observe the patient and administer any anti-vomiting medicine as needed http://www.emedicinehealth.com/activated_charcoal/article_em.htm Image: http://www.krider.com/MPj03211260000%5B1%5D.jpg

  10. Current Standard Detoxification Methods: Gastric Emptying • Whole Bowel Irrigation is also used to remove toxins from the entire gastrointestinal tract (GI tract) • Flushes the GI tract of everything including any ingested toxins • Typically used only for toxins that are not absorbed by activated charcoal • Iron • Lithium • Sustained-release or Enteric-coated Drugs • Both procedures can not remove any of the toxins already absorbed into the patient’s blood stream http://emedicine.medscape.com/article/1413446-overview

  11. Current Standard Detoxification Methods: Gastric Emptying • In the case of Ethanol intoxication Gastric Lavage is used to remove the contents of the stomach • Used in patients that are not vomiting • A tube is passed through the mouth to the stomach followed by sequential administration and removal of small volumes of liquid via suction • Can be used in the cases of Drug related intoxication if used within 1 hour of consumption • Overdoses can lead to the following if the patient is not treated quickly: • Permanent brain/nervous system damage • Comas • Death Image: http://emptyyourcup.com/blog/uploaded/iStock_000003492238Small_9.jpg http://wps.prenhall.com/wps/media/objects/737/755395/gastric_lavage.pdf

  12. Current Standard Detoxification Methods: Removal of Toxins • Many cases an antidote does not exist and the patient did not orally ingest the drug • Only solution is to remove the toxins from the blood stream • Hemodialysis is the only readily available procedure to remove toxins from the blood stream • Removes substances from the patient’s blood by passing the blood through a semi-permeable membrane in a bedside dialysis machine • Suited for drugs or metabolites that are • water soluble • low volume of distribution, generally remains in the blood stream not in the organs • Molecular weight below 500 g/mol • Low plasma protein binding Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  13. Current Standard Detoxification Methods: Removal of Toxins • An emerging strategy for removing toxins from the blood stream • Injected nanosized particulate carriers (< 1 μm) that act as a sink for the toxin • When a toxic dose of a chemical enters a patient’s blood stream, elevation of the patient’s tissue concentrations above the minimum toxic level (MTL), represented by the blue line, occurs • Toxic levels are maintained until the toxic chemical diffuses and/or metabolizes out of the patients tissues (organs) • Resulting in a decrease of tissue concentrations (upper curve) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  14. Current Standard Detoxification Methods: Removal of Toxins • Nanocarriers absorb the toxin from the blood stream and/or the tissue • Allows for the redistribution of the toxic chemical from the peripheral tissues into the blood compartment • Reduces tissue exposure to the toxic compound • By bringing the tissues concentration below the MTL at a faster rate (lower curve) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  15. Current Standard Detoxification Methods: Removal of Toxins • Injected nanocarriers exit the body via the kidneys or the liver • Natural excretion of the nanocarriers is acceptable and preferred • Saves money, time and reduces the patients risk of surgery • Once the toxic chemical is sequestered by the nanocarriers it will not leach back into the body • Nanosized carriers can take on different forms • Liposomes • Nanoemulsions • Nanoparticles • Macromolecules Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image 1: http://media-2.web.britannica.com/eb-media/37/96837-004-AAC9A5BB.jpg ,Image 2: http://www.pharmoscorp.com/development/nanotechnology.html ,Image 3: http://radio-weblogs.com/0105910/images/nanoparticles.jpg , Image 4: http://www.rsc.org/ejga/SM/2008/b807696k-ga.gif

  16. Current Standard Detoxification Methods: Removal of Toxins • Several of the listed nanocarriers can function as detoxifiers • Detoxifiers Properties • High Specific Surface Area • Adjustbale Composition/Surface Porperties • Manipulated to optimize uptake and circulation time. • Nanocarriers used biodetoxification usually share the same characteristics as those used in drug delivery • Except the affinity of the toxic agent to the carrier • should be very high to ensure rapid and efficient removal of toxins from the peripheral tissues. Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  17. Outline • Introduction • Current Standard Detoxification Methods • Administration of an Antidote • Gastric Emptying • Removal of Toxins • Nanocarrier Biodetoxification • Liposomes • Nanoemulsions • Nanoparticles • Macromoleculues Carriers • Future Work • Conclusion http://www.rsc.org/ejga/CP/2010/b914440d-ga.gif

  18. Nanocarrier Biodetoxification • There are several parameters of the toxic chemical to be considered in toxicity reversal • Molecular weight • Ionization constant • Affinity for blood proteins (Vd) • Half-life • Toxicological profile • Presence of active metabolites • Potential toxicity of metabolites Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.3dchem.com/imagesofmolecules/Cocaine.jpg

  19. Nanocarrier Biodetoxification • Most drugs involved in poisoning are weak bases that are characterized by a large Vd • High protein binding and the presence of active metabolites Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  20. Nanocarrier Biodetoxification • Large Vd‘s can complicate the detoxification procedure • Especially in the case of a slow transfer rate of the toxins from the tissues to the blood Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  21. Nanocarrier Biodetoxification • When drugs bind to blood proteins the extraction efficiency is lowered • Less drug is available for capture Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  22. Nanocarrier Biodetoxification • In most laboratory settings • The nanocarrier is administered prior to or within minutes following exposure to the drug • In many cases the intoxicated patient is admitted to a hospital 3-4 hours after the drug has entered the patient’s body • Large amounts of the drug may have been converted into active metabolites • Some drugs are inactive until contact with a certain bodily fluid, e.g. Silvia, Stomach Acid, Other GI fluids, when they become activated • For example, upon oral absorption almost instantaneously 40% of amitriptyline, an antidepressant, is metabolized by the liver into its active demethylated form • Nortriptyline Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  23. Nanocarrier Biodetoxification Schematic representation of the multiple effects of cannabis smoking on basic enzymatic and physiological mechanisms. These effects are mediated by r9-THC and possibly by active metabolites, and lead to the development of functional and metabolic tolerance. Image: http://www.unodc.org/images/odccp/bulletin/bulletin_1973-01-01_1_page003_img003_large.gif

  24. Nanocarrier Biodetoxification • Injectable nanocarriers need to meet a number of criteria including but not limited to: • Innocuousness • Circulation time • Uptake capacity • In order for the injected carrier to be successful • Must remain in the blood stream and/or tissues • Long enough for the toxic agent to be extracted sufficiently from the blood stream and peripheral tissues • Short enough so that the toxic agent isn't leached back into the bloodstream and/or tissues Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  25. Nanocarrier Biodetoxification • The human body’s response to nanocarriers is very similar to colloids • Circulation time of a colloid depends on its hydrodynamic volume, shape and surface properties • Spherical colloids, maximum circulation times are obtained for those with diameters between 50–200 nm • Very small colloids (< 8 nm) are excreted by the kidneys and/or rapidly accumulate in the liver, whereas large particles (> 200 nm) are subjected to major uptake by the spleen Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image 1: http://focus.aps.org/story/v20/st21

  26. Nanocarrier Biodetoxification • Nanocarriers coated with hydrophilic, flexible polymers such as polyethylene glycol (PEG) • Slow down the immune system clearance time • Improve the half-life in blood • Nanocarriers with extracted toxins are generally eliminated from the bloodstream within 24 hr and mostly end up in the liver where the toxic compound is metabolized • Most drugs rarely cause any significant liver damage upon acute poisoning Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.technologyreview.com/read_article.aspx?id=17578&ch=nanotech&a=f

  27. Nanocarrier Biodetoxification • Quickly decreasing tissue concentrations below the toxic threshold requires the drug to ideally be completely and rapidly captured • Oil(lipid)-based nanocarriers • Selected lipids need to highly compatible with the toxin • Many hydrophobic and amphiphilic drugs are poorly soluble in injectable lipids • Large amounts of the nanocarrier dose is required to extract the toxic agent • Infusing high amounts of lipids may be acceptable in the context of detoxification and potentially saving a life • Injecting large doses of nanocarriers (> 1 g/kg or > 5 ml/kg for a typical 20%-lipid emulsion) can slow down the detoxification process • Increases the time during which the nanocarrier is administered Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.biotargeting.eu/images/%28master%29_0001.png

  28. Nanocarrier Biodetoxification • Typically the partition coefficient, or the solubility of two solvents, for the oil phase is the main parameter used to eliminate possible mixtures • For the uptake of toxic agents by oil-based nanostructures this is not the case • Amphiphilic compounds that possess hydrophilic and hydrophobic properties can adsorb at the oil/water interface • Adsorption depends on specific surface area • Depends on particle size • Extraction capacity generally increases with decreasing particle size • For the case of amphiphilic charged drugs • Adsorption at the interface between the nanocarrier and the drug can be enhanced by adding an oppositely charged component to the nanocarrier’s surface that interacts electro-statically with the drug • Chemically modifying the nanocarrier with specific functional groups can increase drug uptake and improve extraction • Example, electron-deficient aromatic rings that bind to compounds with π-electron-rich aromatic rings Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  29. Nanocarrier Biodetoxification • An alternative strategy to optimize extraction is to create an concentration gradient between the inside and outside of the nanocarrier • This can be achieved by encapsulating an enzyme that degrades the toxic agent into water-filled vesicular structures Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  30. Nanocarrier Biodetoxification • Toxins diffuse into the carrier • Are metabolized by the enzymes • Thus more toxic compounds can be pumped into the carrier • This system requires • The toxic agent to freely permeate the vesicle membranes • The entrapped enzyme to remain active for at least a few hours while circulating in the blood Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  31. Nanocarrier Biodetoxification • Optimization of the extraction of ionizable drugs • Including weak bases or acids • Sequesters the toxic agent into nanosized vesicles by creating a transmembrane pH gradient • Similar to the urinary pH manipulation technique • Used by clinicians to accelerate excretion of ionizable drugs from the kidneys • Neutral low-molecular-weight weak acids and bases can permeate vesicle membranes at much faster rates than their ionized forms • This extraction process is very efficient, even for molecules that are highly protein-bound Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  32. Nanocarrier Biodetoxification • If a vesicle exhibits a pH gradient (acidic or basic for weak bases or acids), the unionized compound diffuses down its concentration gradient into the vesicle interior where it is subsequently ionized and trapped • The diffusion of the toxic agent’s neutral form will continue until the interior buffering capacity is overwhelmed Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  33. Nanocarrier Biodetoxification • Several colloidal carriers have been investigated for detoxification applications over the past two decades Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  34. Nanocarrier Biodetoxification • Sizes ranging from a few nanometres (polymers) to half a micrometrer (emulsions in parenteral nutrition) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  35. Outline • Introduction • Current Standard Detoxification Methods • Administration of an Antidote • Gastric Emptying • Removal of Toxins • Nanocarrier Biodetoxification • Liposomes • Nanoemulsions • Nanoparticles • Macromoleculues Carriers • Future Work • Conclusion

  36. Nanocarrier Biodetoxification:Liposomes • Liposomes • Spherical vesicles • Possess one or more concentric phospholipidbilayer membrane(s) • Have been extensively studied for the treatment of intoxications due to organophosphorus agents (OPs) • Toxic agents commonly found in agriculture pesticides Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://media-2.web.britannica.com/eb-media/37/96837-004-AAC9A5BB.jpg

  37. Nanocarrier Biodetoxification:Liposomes • First use of liposomes as antidotes for OPs was a follow-up to the work of Way and co-workers • Resealed red blood cells served as vesicles to encapsulate the enzymes rhodanese and organophosphorus acid anhydrolase (OPAA) • Degrade cyanide and OPs, respectively Cyanide and/or OPs Rhodanese and/or (OPAA) Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Leung, P. et al. Encapsulation of thiosulfate:cyanidesulfurtransferase by mouse erythrocytes. ToxicolAppl. 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).

  38. Nanocarrier Biodetoxification:Liposomes • The approach was later refined by entrapping OPAA in neutral long-circulating PEGylatedliposomes • Liposomes were chosen to replace the red blood cells in Way’s work due to the following factors: • Built from non-human-derived material • Possible large-scale production • Exhibit a greater shelf-life than red blood cells Enviromental SEM image of bilayer construction of several liposomes Image: http://uber-life.net/technology/liposomes.shtml Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Petrikovics, I. et al. Antagonism of paraoxon intoxication by recombinant phosphotriesteraseencapsulated 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).

  39. Nanocarrier Biodetoxification:Liposomes • Replacing the red blood cells with liposomal OPAA in mice resulted in an efficient detoxifier for Ops • However, liposomal OPAA is only effective when administered in prevention cases • Prior to intoxication • Application of lipomal OPAA after injection of OP, resulted in substantial increase of OP-induced mortality • A more probable situation to happen under real conditions of intoxication • Although these data confirmed the therapeutic value of liposomal OPAA, they also revealed how important timing is in reversing intoxications Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Petrikovics, I. et al. Antagonism of paraoxon intoxication by recombinant phosphotriesteraseencapsulated 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).

  40. Nanocarrier Biodetoxification:Liposomes • Previously mentioned, transmembrane pH gradients can help remove low-molecular-weight weak acids or bases from physiological media • Mayer et al. used stealth (long-circulating) liposomes with an internal pH of 4 as the detoxifying nanocarrier • Administered prior to the injection of a toxic dose of the anti-cancer drug doxorubicin • Captured the drug in vivo • Decreased its toxicity • Maintained the drug’s anti-tumor potency • The pH gradient was maintained with a decrease of only “1.5 units over 20 hrs following injection” • Doxorubicin could be sequestered in situ at clinically relevant doses Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, 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).

  41. Nanocarrier Biodetoxification:Liposomes • Mayer’s study showed that pre-treatment with empty liposomes could improve the pharmacokinetic profiles of drugs • Along with their potential as detoxifying agents • pH gradient spherulites were investigated by Dr. BabuDhanikula to counteract an overdose of amitriptyline • A type of multilamellar liposome made from uniformly spaced concentric bilayers • Amitriptyline is a potentially cardiotoxic antidepressant Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, BabuDhanikula, 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 PEGylatedspherulite formulations. Biochim. Biophys. Acta1715, 37–48 (2005).

  42. Nanocarrier Biodetoxification:Liposomes • Isolated hearts were first coated with amitriptyline at a large enough concentration to cause cardio-toxicity • Immediate infusion of pH-gradient spherulites resulted the recovery of the heart rate • Spherulite concentration in this investigation could be readily achieved in vivo Heart-rate recovery after intoxication and addition of a nanocarrier. Overdose of amitriptyline elevates heart rates and brings about deleterious effects on the heart (cardiotoxicity). Isolated rat hearts were infused for 12 min with amitriptyline to cause intoxication and subsequently perfused with pH 7.4 buffer (red squares), pH 7.4 spherulites (black triangles), or pH 3.0 gradient spherulites (green circles) from 15 to 37 min. Perfusion of pH 3.0 gradient spherulites resulted in swift recovery of heart rate to its initial value because the nanocarrier extracted amitriptyline from the heart tissue and the protonated drug was sequestered within the vesicle aqueous core. The black arrows indicate the time during which the difference in heart beats between the pH 3.0 spherulite and pH 7.4 buffer group was statistically significant (p<0.01). Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, BabuDhanikula, A., Lamontagne, D. & Leroux, J. C. Rescue of amitriptyline-intoxicated hearts with nanosized vesicles. Cardiovasc. Res. 74, 480–486 (2007).

  43. Nanocarrier Biodetoxification:Liposomes • Diethylene tri-amine penta-acetic acid (DTPA) is typically used to decontaminate individuals who have been exposed to toxic heavy metals such as ytterbium and plutonium • DTPA is a molecule that binds cations • DTPA-Pu/Yb complexes are stable and soluble • Easily eliminated from the body via urine • Incorporated DTPA in liposomes resulted in • An increase in DTPA’s half-life • Promotes DTPA’s deposition into tissues • Such as the liver and bone where heavy metals tend to accumulate Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  44. Nanocarrier Biodetoxification:Liposomes • Fattal prepared uncoated and PEGylatedliposomes containing DTPA ranging from 100 to 1600 nm • Assessed their Pudecorporation capacities • Encapsulated DTPA resulted in • A 3- to 90-fold decrease in circulation time when compared to small stealth liposomes • Substantial DTPA deposition in the liver regardless of the liposome formulation • Comparatively higher levels of DTPA in the bone compared to the free DTPA • Liposomal DTPA improved the Pu excretion • Reducing the total Pu burden 30 days after toxic exposure • Liposomes have proven to be effective antidotes for amphiphilic compounds that can be inactivated by encapsulated enzymes or actively trapped within their aqueous compartments • But they may not be ideal for highly hydrophobic and poorly or non-ionizable molecules Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339, 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. Biochimie88, 1843–1849 (2006).

  45. Outline • Introduction • Current Standard Detoxification Methods • Administration of an Antidote • Gastric Emptying • Removal of Toxins • Nanocarrier Biodetoxification • Liposomes • Nanoemulsions • Nanoparticles • Macromoleculues Carriers • Future Work • Conclusion NanoEmulsion: http://www.aapspharmscitech.org/articles/pt0804/pt0804104/pt0804104_figure2.jpg

  46. Nanocarrier Biodetoxification:Nanoemulsions • For highly hydrophobic and poorly or non-ionizable molecules • Colloidal systems such as nanoemulsions, where drug uptake mostly relies on a favorable partition coefficient for oil droplets, may be more appropriate than liposomes • Nanoemulsions are nanosized droplets of oil dispersed in an aqueous phase • Ionizable drugs may exhibit a high affinity for oils or oil/water interfaces • Can be extracted by nanoemulsions Image: http://artsci.ucla.edu/biotech177/blog/?p=821 Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  47. Nanocarrier Biodetoxification:Nanoemulsions • Intralipid is a soybean oil-in-water emulsion (~ 430 nm diameter) that is stabilized with egg phosphatidylcholine lipid • Commonly injected as a source of triglycerides for individuals who cannot ingest fats orally • Evaluated as a detoxifier for hydrophobic drugs such as bupivacaine • Local anaesthetic associated with occasional but severe and potentially lethal cardiotoxicity • Infusion of Intralipid immediately after the injection of a lethal dose of bupivacaine increased survival rates significantly in animals • The mechanism is not fully understood due to the low affinity of bupivacaine for Intralipid • The positive effect of the treatment could be partially attributed to the large dose of lipids injected (several grams of triglycerides per kilogram), which favors drug partition to the oil phase Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  48. Nanocarrier Biodetoxification:Nanoemulsions • Effect of pre- and post-dosing of PEGylatedtricaprylin emulsions on the pharmacokinetics and biodistribution of docetaxel were studied • PEGylatedtricaprylin emulsions are triglyceride based emulsions • Docetaxel is a non-ionisable anticancer drug • Injection of the PEGylatedtricaprylin emulsion 20 minutes after docetaxel was administered resulted in a rapid decrease in the drug concentration in the blood pool • After uptake by the emulsion, the drug was mainly redirected to the liver and spleen • These studies illustrate that nanoemulsions can and have extracted drugs that have already been distributed to peripheral tissues Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  49. Nanocarrier Biodetoxification:Nanoemulsions • Emulsions are particularly attractive in the biomedical field • Can be prepared from generally recognized safe experiments • Often face inherent formulation issues arising from thermodynamic instability • Leads to the coalescence of oil droplets over time or their disassembly in the bloodstream • Emulsion long-term stability is limited by difficulties in obtaining dry formulations for prolonged storage • Particularly relevant in the context of detoxification • Turnover is expected to be low Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339

  50. Nanocarrier Biodetoxification:Nanoemulsions • To enhance stability, nanoemulsions can be coated with a hard polymeric shell • Formation of nanocapsules • Resulting in a nanocarrier that is more robust and controls drug uptake kinetics Dr. Jean-Christophe Leroux, "Injectable nanocarriers for biodetoxification" nature nanotechnology | VOL 2 | NOVEMBER 2007 doi:10.1038/nnano.2007.339 Image: http://www.uni-bielefeld.de/chemie/ac1/images/HAOFig.6.jpg

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