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
 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
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
Custom design
Lipid content
Size
Surface charge
Method of preparation
 Current liposomal drug
preparations
Type of Agents Examples
Anticancer Drugs Duanorubicin, Doxorubicin*, Epirubicin
Methotrexate, Cisplatin*, Cytarabin
Anti bacterial Triclosan, Clindamycin hydrochloride,
Ampicillin, peperacillin, rifamicin
Antiviral AZT
DNA material cDNA - CFTR*
Enzymes Hexosaminidase A
Glucocerebrosidase, Peroxidase
Radionuclide In-111*, Tc-99m
Fungicides Amphotericin B*
Vaccines 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
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

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 $40.58 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

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
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.