Liposomes

1. Naval Chaudhary
70700029

2. PhospholipidsPhospholipids
Polar Head Groups
Three carbon glycerol

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

4. A liposome encapsulates a region on aqueous
solution inside a hydrophobic membrane;
dissolved hydrophilic solutes cannot readily pass
through the lipids. Hydrophobic chemicals can be
dissolved into the membrane, and in this way
liposome can carry both hydrophobic molecules
and hydrophilic molecules. To deliver the
molecules to sites of action, the lipid bilayer can
fuse with other bilayers such as the
cell membrane, thus delivering the liposome
contents
About the Liposomes :

5. Liposome Preparation
Lipid in organic solvent solution
Evaporation
Extrusion (or sonication)
Liposomes and unencapsulated SRB
Lipid film
Freeze/thaw cycles
Gel filtration
Purified liposomes
Hydrate with sulforhodamine B (SRB) solution

6. Liposome Preparation

7. Liposome Preparation

8. Liposome Preparation

9. Liposome Preparation
http://www.avantilipids.com

10. Liposome Preparation

11. Liposome Ingredients
45% DPPC dipalmitoylphosphatidylcholine
45% Cholesterol
5% DPPG dipalmitoylphosphatidylglycerol
5% DPPE dipalmitolyphosphatidylanolamine

13. 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

14. 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

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

16. 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
Why Use Liposomes in
Drug Delivery?

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

18. Classes of Liposomes
Conventional Long circulating
Immuno
Cationic

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

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

21. CFTR
Gene 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
changein symptoms
Now trying adeno associated
virus
Cationic liposome

22. 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*

23. 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

24. 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
Diffusion
Lipid transfer
AmB
Lipid

25. Name Trade name Company Indication
Liposomal amphotericin BAbelcet Enzon Fungal infections
Liposomal amphotericin BAmbisome Gilead Sciences
Fungal and protozoal
infections
Liposomal cytarabineDepocyt
Pacira (formerly
SkyePharma)
Malignant lymphomatous
meningitis
Liposomal daunorubicinDaunoXome Gilead Sciences
HIV-related Kaposi’s
sarcoma
Liposomal doxorubicinMyocet Zeneus
Combination therapy with
cyclophosphamide in
metastatic breast cancer
Liposomal IRIV vaccineEpaxal Berna Biotech Hepatitis A
Liposomal IRIV vaccineInflexal V Berna Biotech Influenza
Liposomal morphine DepoDur SkyePharma, Endo Postsurgical analgesia
Liposomal verteporfinVisudyne QLT, Novartis
Age-related macular
degeneration, pathologic
myopia, ocular
histoplasmosis
Liposome-PEG doxorubicinDoxil/Caelyx
Ortho Biotech,
Schering-Plough
HIV-related Kaposi’s
sarcoma, metastatic breast
cancer, metastatic ovarian
cancer
Micellular estradiolEstrasorb Novavax Menopausal therapy

26. 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

27. Possibility of new side effects
Doxil “hand and foot syndrome”
Problems continued
Efficacy
CFTR

28. 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

29. 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

30. 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, 2
nd
ed. Saunders Colleges Publishing. New York (1999). 264.