liposomes
TRANSCRIPT
Naval Chaudhary70700029
PhospholipidsPhospholipids
Polar Head Groups
Three carbon glycerol
What is a liposome?What is a liposome?
• Spherical vesicles with a phospholipid bilayer
Hydrophilic
Hydrophobic
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 :
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
Liposome Preparation
Liposome Preparation
Liposome Preparation
Liposome Preparation
http://www.avantilipids.com
Liposome Preparation
Liposome Ingredients
45% DPPC dipalmitoylphosphatidylcholine
45% Cholesterol
5% DPPG dipalmitoylphosphatidylglycerol
5% DPPE dipalmitolyphosphatidylanolamine
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 LiposomesConventional Long circulating
Immuno Cationic
Liposomes Help ImproveLiposomes Help ImproveTherapeutic indexRapid metabolismUnfavorable pharmokineticsLow solubilityLack of stabilityIrritation
Custom 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
Name Trade name Company Indication
Liposomal amphotericin B Abelcet Enzon Fungal infections
Liposomal amphotericin B Ambisome Gilead Sciences Fungal and protozoal infections
Liposomal cytarabine Depocyt Pacira (formerly SkyePharma)
Malignant lymphomatous meningitis
Liposomal daunorubicin DaunoXome Gilead Sciences HIV-related Kaposi’s sarcoma
Liposomal doxorubicin Myocet ZeneusCombination therapy with cyclophosphamide in metastatic breast cancer
Liposomal IRIV vaccine Epaxal Berna Biotech Hepatitis ALiposomal IRIV vaccine Inflexal V Berna Biotech InfluenzaLiposomal morphine DepoDur SkyePharma, Endo Postsurgical analgesia
Liposomal verteporfin Visudyne QLT, Novartis
Age-related macular degeneration, pathologic myopia, ocular histoplasmosis
Liposome-PEG doxorubicin Doxil/Caelyx Ortho Biotech, Schering-Plough
HIV-related Kaposi’s sarcoma, metastatic breast cancer, metastatic ovarian cancer
Micellular estradiol Estrasorb Novavax Menopausal therapy
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.