Jessica Scott

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Liposomes Improving drug delivery

• Jessica Scott
• May 17, 1999

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Phospholipids
Polar Head Groups
Three carbon glycerol
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What is a liposome?

• Spherical vesicles with a phospholipid bilayer

Hydrophilic
Hydrophobic
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Cell Membrane
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Uses of Liposomes
Chelation therapy for treatment of heavy metal
poisoning
Enzyme replacement
Diagnostic imaging of tumors
Cosmetics
Study of membranes
Drug Delivery
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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
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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
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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
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Modes of Liposome/Cell Interaction
Endocytosis
Adsorption
Lipid transfer
Fusion
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Classes of Liposomes
Conventional
Long circulating
Immuno
Cationic
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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
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Current liposomal drug preparations
Type of Agents Examples
Duanorubicin, Doxorubicin, Epirubicin
Methotrexate, Cisplatin, Cytarabin
Anticancer Drugs Anti bacterial Antiviral DNA
material Enzymes Radionuclide Fungicides Vaccine
s
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
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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
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Doxil
Chemotherapy drug doxorubin Anemia, damage to
veins and tissue at injection, decrease platelet
and WBC count, toxic to
Treats Kaposis 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
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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
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Liposomal Formulation of AmB
PhospholipidAmB ratio
Cholesterol - only few moles
Exact Mechanism of liposomes not understood
Diffusion Lipid transfer
Decrease in toxicity
No decrease in effectiveness of drug against
fungi
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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
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Problems continued
Possibility of new side effects
Doxil hand and foot syndrome
Efficacy
CFTR
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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
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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.5439-449,
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. "Liposomesquo 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
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Websites James, John S. "Doxil Approved for KS."
www.immunet. org.imminet/atn.nsf/page/a-235-03. Wa
san, Ellen. "Targeted Gene Transfer."
Member.tripod.com/rrishna/lipos1.html "Introducti
on to Controlled Drug Delivery Systems."
www5.bae.ncsu.edu/bae/reearch/blak k/otherprojec
ts/drugDeliver_97/ http//www. Mssm.edu/medicine/t
hrombosis/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/ databas
e/doxor_1 "Liposomes." www.collabo.com/liposom0.h
tm Paustin, Timothy. Cellular
Membranes.www.bact.wisc.edu/microtextbook/bacteri
alstructure/Membranegen.html www.cbc.umn.edu/mwd/
cell_www/chapter2/membrane.htmlPHOSPHOLIPIDS Book
s 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.