Jessica Scott May 17, 1999

Phospholipids
Polar Head Groups

Three carbon glycerol

What is a liposome? ± Spherical vesicles with a phospholipid bilayer Hydrophilic Hydrophobic .

Cell Membrane .

Uses of Liposomes Chelation therapy for treatment of heavy metal poisoning Enzyme replacement Diagnostic imaging of tumors Cosmetics Study of membranes Drug Delivery .

sugars) Physical: temperature or pH sensitive liposomes Directly to site . protein A.Why Use Liposomes in Drug Delivery? Drug Targeting Inactive: Unmodified liposomes gather in specific tissue reticuloendothelial system Active: alter liposome surface with ligand (antibodies. enzymes.

Why Use Liposomes in Drug Delivery? Pharmokinetics .efficacy and toxicity Changes the absorbance and biodistribution Deliver drug in desired form Multidrug resistance Protection Decrease harmful side effects Change where drug accumulates in the body Protects drug .

pH and osmotic gradient. and environment .Why Use Liposomes in Drug Delivery? Release Affect the time in which the drug is released Prolong time -increase duration of action and decrease administration Dependent on drug and liposome properties Liposome composition.

Modes of Liposome/Cell Interaction Adsorption Endocytosis Fusion Lipid transfer .

Classes of Liposomes Conventional Long circulating Immuno Cationic .

Liposomes Help Improve Therapeutic index Rapid metabolism Unfavorable pharmokinetics Low solubility Lack of stability Irritation Lipid content Size Surface charge Method of preparation Custom design .

Current liposomal drug preparations Type of Agents Anticancer Drugs Anti bacterial Antiviral DNA material Enzymes Radionuclide Fungicides Vaccines Examples Duanorubicin. Cytarabin Triclosan. Clindamycin hydrochloride. Cisplatin*. peperacillin. Doxorubicin*. Tc-99m Amphotericin B* Malaria merozoite. Malaria sporozoite Hepatitis B antigen. Rabies virus glycoprotein *Currently in Clinical Trials or Approved for Clinical Use . rifamicin AZT cDNA . Peroxidase In-111*.CFTR* Hexosaminidase A Glucocerebrosidase. Ampicillin. Epirubicin Methotrexate.

no significant change in symptoms Now trying adeno associated virus .CFTR Gene Therapy Deliver cDNA of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to epithelial tissue of respiratory system Cationic liposome Fuse to cell membrane and incorporate cDNA into cell Clinical trials .

toxic to Treats Kaposi¶s sarcoma lesions or cancer tumors Modifications of liposome ³stealth´ keeps doxorubin in blood for 50 hours instead of 20 minutes concentrates at KS lesions and tumors *Just approved by FDA* . decrease platelet and WBC count. damage to veins and tissue at injection.Doxil Chemotherapy drug doxorubin Anemia.

kills ergosterol-containing fungal cells.Amphotericin B Systemic fungal infections in immune compromised patients AmB . chills. also kills cholesterol-containing human cells Side effects: nephrotoxicity.AmB with deoxycholate . and fevers Fungizone .

Liposomal Formulation of AmB Phospholipid:AmB ratio AmB Cholesterol .only few %moles Lipid Exact Mechanism of liposomes not understood Diffusion Lipid transfer Decrease in toxicity No decrease in effectiveness of drug against fungi .

Problems with Liposomal Preparations of Drugs $$$$ Fungizone $40.poor encapsulation Polar drugs and drugs without opposite charge Modifications . twice the cost of normal protocol of chemotherapy and drugs Lack long term stability (short shelf life) Physical and chemical instability Freeze dry and pH adjustment Low ³Pay Load´ .58 Amphotec $2334 Doxil $1200 per treatment.

Problems continued Possibility of new side effects Doxil ³hand and foot syndrome´ Efficacy CFTR .

Future Studies 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 liposomes .

1999. 29: 685-694. 1997 Janknegt. Taylor. "Liposomal and Lipid Formulations of Amphotericin B. 1998. 1994. Ranade." Drugs 54 Suppl. "Pharmacodynamics of insulin in polyethylene glycol-coated liposomes." Drugs 56: 747-756. 51: 55-59. 1998." Cancer Control. Quilitz.5:439-449." TiPs 15: 214-219. Theresa M. Vasant V. "Oncology Pharmacotherapy: The Use of Lipid Formulations of Amphotericin B in Cancer Patients." British Journal of Hospital Medicine. 1989. Allen. Theresa M. "Liposomal Drug Formulations: Rationale for Development and What We Can Expect for the Future. Robert. "Long-circulating (sterically stabilized) liposomes for targeted drug delivery. 1998. Theresa M. 180: 75-81. 1992. Kim. Storm." Pharmacology. Allen. "Liposomes:quo vadi?" PSTT 1: 19-31. 4: 8-14. Gert and Daan J. Crommelin." International Journal of Pharmaceutics. KMG and JM Newton. "Opportunities in Drug Delivery.Journals Allen. Rod. "Liposomes as a vecicle for drug delivery." Clinical Pharmacokinetics. "Drug Delivery Systems: Site-Specific Drug Delivery Using Liposomes as Carriers. 1994 . Anna et al. 23(4): 279-291.A.

html "Doxorubicin.com" http://www.Websites James. Wiley-Liss.immunet.com/liposom0.htm Paustin.edu/medicine/thrombosis/phosphol." www5. "Targeted Gene Transfer. John S.nsf/page/a-235-03. Mssm.´www.htm "Clinical Pharmacology Online." www." www. Biochemistry. "Doxil Approved for KS. 2nd ed.imminet/atn.wisc.com/scripts/fullmono/showmono.S. Garrett.html "Introduction to Controlled Drug Delivery Systems.ncsu.gsm. Ellen. R.slip.html#PHOSPHOLIPIDS Books Jones. New York (1995). Micelles." Member. Timothy. Saunders Colleges Publishing.edu/bae/reearch/blak« k/otherprojects/drugDeliver_97/ http://www." http://tirgan. ." http://www." www.com/~rrishna/lipos1.cponline.com/adria. Macolm N.bae. "Sequus' Doxil Becomes First Liposome Product Approved In U. Monolayers and Biomembranes. org. Wasan.tripod. "Drugstore. New York (1999). ³Cellular Membranes.com/pharmacy/prices/Amphotec.net/~mcdavis/ database/doxor_1 "Liposomes.drugstore.umn.edu/~mwd/cell_www/chapter2/membrane.cbc. David.html www.bact. 264. and Chapman.edu/microtextbook/bacterialstructure/Membranegen.collabo. and Grisham C.

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