liposome PPT2 HCU

8/3/2019 liposome PPT2 HCU

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Dr. M. A. HalablabDr. M. A. Halablab


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PhospholipidsPhospholipidsPolar Head Groups

Three carbon glycerol


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What is a liposome?What is a liposome? Spherical vesicles with a phospholipid bilayerSpherical vesicles with a phospholipid bilayer

Hydrophilic

Hydrophobic


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Cell MembraneCell Membrane


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UsesofLiposomesUsesofLiposomesChelation therapy for treatment of heavy metal

poisoning

Enzyme replacement

Diagnostic imaging of tumors

Study of membranes

Cosmetics

Drug Delivery


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Why Use Liposomes in DrugWhy Use Liposomes in Drug

Delivery?Delivery?

Inactive: Unmodified liposomes gather in specific tissue

reticuloendothelial systemActive: alter liposome surface with ligand (antibodies,

enzymes, protein A, sugars)

Directly to sitePhysical: temperature or pH sensitive liposomes

Drug Targeting


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ReleaseAffect the time in which the drug is released

Prolong time -increase duration of action and

decrease administration

Dependent on drug and liposome propertiesLiposome composition, pH and osmotic gradient, and

environment

Why Use Liposomes in

Drug Delivery?


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ModesofLiposome/CellModesofLiposome/Cell

InteractionInteractionAdsorption Endocytosis

Fusion Lipid transfer


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ClassesofLiposomesClassesofLiposomesConventional Long circulating

ImmunoCationic


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Liposomes Help ImproveLiposomes Help ImproveTherapeutic indexRapid metabolism

Unfavorable pharmokineticsLow solubilityLack of stabilityIrritation

Custom designLipid contentSizeSurface charge

Method of preparation


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Current liposomal drugCurrent liposomal drug

preparationspreparationsType of Agents ExamplesAnticancer Drugs

Anti bacterial

Antiviral

DNA material

Enzymes

Radionuclide

Fungicides

Vaccines

*Currently in Clinical Trials or Approved forClinical 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

AZTcDNA - CFTR*


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CFTRCFTRGene Therapy

Deliver cDNA ofCystic Fibrosis Transmembrane Conductance

Regulator (CFTR) to epithelial tissue of respiratory system

Fuse to cell membrane and

incorporate cDNA into cellClinical trials - no significant

change in symptoms

Now trying adeno associated

virus

Cationic liposome


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DoxilDoxilChemotherapy drug doxorubin

Anemia, damage to veins and tissue at injection, decrease

platelet and WBC count, toxic to

Treats Kaposis sarcoma lesions or cancer tumorsModifications of liposome stealth

keeps doxorubin in blood for 50 hours instead of20 minutes

concentrates at KS lesions and tumors

*Just approved by FDA*


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Amphotericin BAmphotericin B

Side effects: nephrotoxicity, chills, and fevers

Systemic fungalinfections in immune compromised patients

Fungizone - AmB with deoxycholate

AmB - kills ergosterol-containing fungal cells, also

kills cholesterol-containing human cells


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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


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Problems with LiposomalProblems with Liposomal

PreparationsofDrugsPreparationsofDrugs$$$$

Fungizone $40.58 Amphotec $2334

Doxil $1200 per treatment, twice the cost of normal protocolof 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


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Possibility of new side effectsDoxil hand and foot syndrome

Problems continued

EfficacyCFTR


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Studies with insulin show that liposomes may

be an effective way to package proteins

and peptides for useClinical Trials for several liposomal formulations

More studies on the manipulation of liposomes

Future


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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, 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?" PSTT1: 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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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.html

www.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.

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