PhospholipidsPhospholipids

Polar Head Groups

Three carbon glycerol

What is a liposome?What is a liposome?

Spherical vesicles with a phospholipid bilayer

Hydrophilic

Hydrophobic

Cell MembraneCell Membrane

Uses of LiposomesUses of Liposomes

Chelation therapy for treatment of heavy metal poisoning

Enzyme replacement

Diagnostic imaging of tumors

Study of membranes

Cosmetics

Drug Delivery

Why Use Liposomes in Drug Delivery?

Inactive: Unmodified liposomes gather in specific tissue reticuloendothelial system

Active: alter liposome surface with ligand (antibodies, enzymes, protein A, sugars)

Directly to site

Physical: temperature or pH sensitive liposomes

Drug Targeting

ProtectionDecrease harmful side effects

Pharmokinetics - efficacy and toxicityChanges the absorbance and biodistribution

Change where drug accumulates in the body

Protects drug

Deliver drug in desired formMultidrug resistance

Why Use Liposomes in Drug Delivery?

ReleaseAffect 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

Why Use Liposomes in Drug Delivery?

Modes of Liposome/Cell Interaction

Adsorption Endocytosis

Fusion Lipid transfer

Classes of Liposomes

Conventional Long circulating

Immuno Cationic

Liposomes Help ImproveLiposomes Help Improve

Therapeutic indexRapid metabolismUnfavorable pharmokineticsLow solubilityLack of stabilityIrritationCustom designLipid contentSize

Surface chargeMethod of preparation

Current liposomal drug preparations

Type of Agents ExamplesAnticancer Drugs

Anti bacterial

AntiviralDNA materialEnzymes

RadionuclideFungicidesVaccines

*Currently in Clinical Trials or Approved for Clinical Use

Malaria merozoite, Malaria sporozoiteHepatitis B antigen, Rabies virus glycoprotein

Amphotericin B*In-111*, Tc-99m

Hexosaminidase A Glucocerebrosidase, Peroxidase

Duanorubicin, Doxorubicin*, Epirubicin Methotrexate, Cisplatin*, CytarabinTriclosan, Clindamycin hydrochloride, Ampicillin, peperacillin, rifamicinAZTcDNA - CFTR*

CFTRGene Therapy

Deliver cDNA of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to epithelial tissue of respiratory system

Fuse to cell membrane and incorporate cDNA into cell

Clinical trials - no significant change in symptoms

Now trying adeno associated virus

Cationic liposome

DoxilChemotherapy drug doxorubin

Anemia, 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 minutes

concentrates at KS lesions and tumors

*Just approved by FDA*

Amphotericin BAmphotericin B

Side effects: nephrotoxicity, chills, and fevers

Systemic fungal infections in immune compromised patients

Fungizone - AmB with deoxycholate

AmB - kills ergosterol-containing fungal cells, also kills cholesterol-containing human cells

No decrease in effectiveness of drug against fungi

Liposomal Formulation of AmB

Decrease in toxicity

Exact Mechanism of liposomes not understood

Cholesterol - only few %moles

Phospholipid:AmB ratio

DiffusionLipid transfer

AmB

Lipid

Problems with Liposomal Problems with Liposomal Preparations of DrugsPreparations 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)

Freeze dry and pH adjustment

Low “Pay Load” - poor encapsulation

Physical and chemical instability

Polar drugs and drugs without opposite charge

Modifications

Possibility of new side effectsDoxil “hand and foot syndrome”

Problems continued

EfficacyCFTR

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

Future

JournalsAllen, 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, 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, 1994

WebsitesJames, 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#PHOSPHOLIPIDS

BooksJones, 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.