Improving drug delivery Liposomes: Improving drug delivery 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 Drug Delivery Chelation therapy for treatment of heavy metal poisoning Enzyme replacement Diagnostic imaging of tumors Cosmetics Study of membranes Drug Delivery

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, protein A, sugars) Physical: temperature or pH sensitive liposomes Directly to site

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

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, pH and osmotic gradient, and environment

Modes of Liposome/Cell Interaction Endocytosis Adsorption Lipid transfer Fusion

Classes of Liposomes Conventional Long circulating Immuno Cationic

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

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

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 - no significant change in symptoms Now trying adeno associated virus

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

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

Liposomal Formulation of AmB Phospholipid:AmB ratio Cholesterol - only few %moles AmB 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 $40.58 Amphotec $2334 Doxil $1200 per treatment, 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 “Pay Load” - poor encapsulation Polar drugs and drugs without opposite charge Modifications

Problems continued Possibility of new side effects Efficacy Doxil “hand 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

References Journals Allen, Theresa M. "Liposomal Drug Formulations: Rationale for Development and What We Can Expect 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, 1997 Janknegt, 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, 1994

Websites James, 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.htm Paustin, Timothy. “Cellular Membranes.”www.bact.wisc.edu/microtextbook/bacterialstructure/Membranegen.html www.cbc.umn.edu/~mwd/cell_www/chapter2/membrane.html#PHOSPHOLIPIDS Books Jones, Macolm N. and Chapman, David. Micelles, Monolayers and Biomembranes. Wiley-Liss. New York (1995). Garrett, R. and Grisham C. Biochemistry, 2nd ed. Saunders Colleges Publishing. New York (1999). 264.