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Slide 1PhospholipidsWhat is a liposome?Cell MembraneUses of LiposomesWhy Use Liposomes in Drug Delivery?Slide 7Slide 8Modes of Liposome/Cell InteractionClasses of LiposomesLiposomes Help ImproveCurrent liposomal drug preparationsCFTRDoxilAmphotericin BSlide 16Problems with Liposomal Preparations of DrugsSlide 18Slide 19Slide 20Slide 21Jessica ScottJessica ScottMay 17, 1999May 17, 1999PhospholipidsPhospholipidsPolar Head GroupsThree carbon glycerolWhat is a liposome?What is a liposome?–Spherical vesicles with a phospholipid bilayerSpherical vesicles with a phospholipid bilayerHydrophilicHydrophobicCell MembraneCell MembraneUses of LiposomesUses of LiposomesChelation therapy for treatment of heavy metal poisoningEnzyme replacementDiagnostic imaging of tumorsStudy of membranesCosmeticsDrug DeliveryWhy Use Liposomes in Drug Why Use Liposomes in Drug Delivery?Delivery?Inactive: Unmodified liposomes gather in specific tissue reticuloendothelial system Active: alter liposome surface with ligand (antibodies, enzymes, protein A, sugars)Directly to sitePhysical: temperature or pH sensitive liposomes Drug TargetingProtectionDecrease harmful side effectsPharmokinetics - efficacy and toxicityChanges the absorbance and biodistributionChange where drug accumulates in the bodyProtects drug Deliver drug in desired formMultidrug resistanceWhy Use Liposomes in Drug Delivery?ReleaseAffect the time in which the drug is released Prolong time -increase duration of action and decrease administrationDependent on drug and liposome properties Liposome composition, pH and osmotic gradient, and environmentWhy Use Liposomes in Drug Delivery?Modes of Liposome/Cell Modes of Liposome/Cell Interaction Interaction Adsorption EndocytosisFusionLipid transferClasses of LiposomesClasses of LiposomesConventional Long circulating ImmunoCationicLiposomes Help ImproveLiposomes Help ImproveTherapeutic indexRapid metabolismUnfavorable pharmokineticsLow solubilityLack of stabilityIrritationCustom designLipid contentSize Surface chargeMethod of preparationCurrent liposomal drug Current liposomal drug preparationspreparationsType of Agents ExamplesAnticancer DrugsAnti bacterialAntiviralDNA materialEnzymesRadionuclideFungicidesVaccines *Currently in Clinical Trials or Approved for Clinical UseMalaria merozoite, Malaria sporozoiteHepatitis B antigen, Rabies virus glycoproteinAmphotericin B*In-111*, Tc-99mHexosaminidase A Glucocerebrosidase, PeroxidaseDuanorubicin, Doxorubicin*, Epirubicin Methotrexate, Cisplatin*, CytarabinTriclosan, Clindamycin hydrochloride, Ampicillin, peperacillin, rifamicinAZTcDNA - CFTR*CFTRCFTRGene TherapyDeliver cDNA of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to epithelial tissue of respiratory systemFuse to cell membrane and incorporate cDNA into cellClinical trials - no significant change in symptomsNow trying adeno associated virusCationic liposomeDoxilDoxilChemotherapy drug doxorubinAnemia, damage to veins and tissue at injection, decrease platelet and WBC count, toxic to Treats Kaposi’s sarcoma lesions or cancer tumorsModifications of liposome “stealth”keeps doxorubin in blood for 50 hours instead of 20 minutesconcentrates at KS lesions and tumors*Just approved by FDA*Amphotericin BAmphotericin BSide effects: nephrotoxicity, chills, and feversSystemic fungal infections in immune compromised patientsFungizone - AmB with deoxycholateAmB - kills ergosterol-containing fungal cells, also kills cholesterol-containing human cellsNo decrease in effectiveness of drug against fungiLiposomal Formulation of AmBDecrease in toxicity Exact Mechanism of liposomes not understood Cholesterol - only few %molesPhospholipid:AmB ratioDiffusionLipid transferAmBLipidProblems with Liposomal Problems with Liposomal Preparations of DrugsPreparations of Drugs $$$$ Fungizone $40.58 Amphotec $2334Doxil $1200 per treatment, twice the cost of normal protocol of chemotherapy and drugs Lack long term stability (short shelf life)Freeze dry and pH adjustment Low “Pay Load” - poor encapsulationPhysical and chemical instability Polar drugs and drugs without opposite chargeModificationsPossibility of new side effectsDoxil “hand and foot syndrome”Problems continuedEfficacyCFTRStudies with insulin show that liposomes may be an effective way to package proteins and peptides for use Clinical Trials for several liposomal formulations More studies on the manipulation of liposomesFutureJournalsAllen, Theresa M. "Liposomal Drug Formulations: Rationale for Development and What We CanExpect for the Future." Drugs 56: 747-756, 1998.Allen, Theresa M. "Long-circulating (sterically stabilized) liposomes for targeted drug delivery." TiPs 15: 214-219, 1994.Allen, Theresa M. "Opportunities in Drug Delivery." Drugs 54 Suppl. 4: 8-14, 1997Janknegt, Robert. "Liposomal and Lipid Formulations of Amphotericin B." Clinical Pharmacokinetics. 23(4): 279-291, 1992. Kim, Anna et al. "Pharmacodynamics of insulin in polyethylene glycol-coated liposomes." International Journal of Pharmaceutics. 180: 75-81, 1999.Quilitz, Rod. "Oncology Pharmacotherapy: The Use of Lipid Formulations of Amphotericin B in Cancer Patients." Cancer Control.5:439-449, 1998. Ranade, Vasant V. "Drug Delivery Systems: Site-Specific Drug Delivery Using Liposomes as Carriers." Pharmacology. 29: 685-694, 1989. Storm, Gert and Daan J.A. Crommelin. "Liposomes:quo vadi?" PSTT 1: 19-31, 1998. Taylor, KMG and JM Newton. "Liposomes as a vecicle for drug delivery." British Journal of Hospital Medicine. 51: 55-59, 1994WebsitesJames, John S. "Doxil Approved for KS." www.immunet. org.imminet/atn.nsf/page/a-235-03.Wasan, Ellen. "Targeted Gene Transfer." Member.tripod.com/~rrishna/lipos1.html"Introduction to Controlled Drug Delivery Systems." www5.bae.ncsu.edu/bae/reearch/blak…k/otherprojects/drugDeliver_97/http://www. Mssm.edu/medicine/thrombosis/phosphol.html"Doxorubicin." http://tirgan.com/adria.htm"Clinical Pharmacology Online." http://www.cponline.gsm.com/scripts/fullmono/showmono. "Drugstore.com" http://www.drugstore.com/pharmacy/prices/Amphotec."Sequus' Doxil Becomes First Liposome Product Approved In U.S." www.slip.net/~mcdavis/database/doxor_1"Liposomes." www.collabo.com/liposom0.htmPaustin, Timothy. “Cellular Membranes.”www.bact.wisc.edu/microtextbook/bacterialstructure/Membranegen.htmlwww.cbc.umn.edu/~mwd/cell_www/chapter2/membrane.html#PHOSPHOLIPIDSBooksJones, Macolm N. and Chapman, David.


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UWEC CHEM 412 - Liposomes

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