APPROACHES TO TARGET BRAIN VIA LIPOSOMES

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APPROACHES TO TARGET BRAIN VIA LIPOSOMES:

APPROACHES TO TARGET BRAIN VIA LIPOSOMES M. ALAGUSUNDARAM DEPT. OF PHARMACEUTICS ANNAMACHARYA COLLEGE OF PHARMACY, RAJAMPET, ANDHRA PRADESH

CONTENTS:

CONTENTS APPROACHES TO DRUG TARGETING LIPOSOMES BLOOD BRAIN BARRIER ROLE OF BBB IN BRAIN DRUG DELIVERY ROLE OF LIPOSOMES IN BRAIN TUMOUR THERAPY CONCLUSION REFERENCES

APPROACHES TO DRUG TARGETING :

APPROACHES TO DRUG TARGETING The development of a drug that is biologically selective for the target region e.g. A BIOLOGICAL APPROACH Develop a form of the drug that is biologically inert and becomes activated at the intended site of action e.g. A CHEMICAL APPROACH The use of a carrier system ( or a device) that transport the drug to a specific target site e.g. A PHYSICAL APPROACH

LIPOSOMES:

LIPOSOMES Liposomes are nano size artificial vesicles of spherical shape. They can be produced from natural phospholipids and cholesterol. Phospholipids combine with water immediately forms a bi-layered sphere. They acts as a carriers for drug molecules. Liposomes are more target specific. Though slightly toxic can be inserted until level of toxicity reached.

COMPOSITION OF LIPOSOMES:

COMPOSITION OF LIPOSOMES Components of liposomes are: 1) Phospholipids: Major component of the biological membrane. Two types: a)Natural : Phospatidylcholine (PC)/ lecithin. It is originated from animal and vegetable. b)Synthetic 2)Cholesterol: Itself cannot form bilayer membrane structure. But can be incorporated into phospholipids membrane in very high concentration up to 1:1 or 2:1 molar ratios of cholesterol to phospatidylcholine. Cholesterol inserts into the membrane with its hydroxyl group of cholesterol oriented towards the aqueous surface.

MANUFACTURING OF LIPOSOMES:

MANUFACTURING OF LIPOSOMES Phospholipids combined with water immediately forms a bi-layered sphere liposomes. These are mainly manufactured in two methods- They are: 1)Simple hydration method: Lipids are mixed and dissolved in organic solvent like chloroform, ethylene chloride, methanol, tertiary butanol etc. These solvents can be removed either by evaporation, vacuum drying or lyophilisation then hydrated. Upon hydration of lipids, large multilamellar vesicles are formed 2)Emulsion method: Phospholipids is dissolved in an organic solvent . Then Added Under Control To An Aqueous Medium With Vigorous Agitation. The organic solvent then is removed under reduced pressure.

TYPES OF LIPOSOMES   :

TYPES OF LIPOSOMES Liposomes are broadly classified by their structure into two types- They are : 1) Multilamellar liposomes 2) Unilamellar liposomes 1) Multilamellar liposomes: Liposomes can be created by sonicating phospholipids in water. Low shear rates create multilamellar liposomes . These are spherically concentric multilamellar (many bilayers) structures. 2) Unilamellar liposomes: Continued high-shear sonication tends to form unilamellar liposomes . In this technique, the liposome contents are the same as the contents of the phase. These are Spherical concentric unilamellar (one bilayer) structures. Multilamellar liposome Unilamellar liposome

ADVANTAGES OF LIPOSOMES :

Liposomes are bio compatible, biodegradabable, non toxic, flexible and non immunogenic carriers. Suitable for hydrophilic, lipophillic and amphipathic drug delivery. Ability to protect the encapsulated drug from external environment. Act as sustained release depots. They can be formulated as a suspension, aerosol, gel, cream and lotion. Liposomes are reduced toxicity and increased stability of entrapped drug via encapsulation. They increasing the efficacy and therapeutic index of the drug. They help to reduce the exposure of sensitive tissue to toxic drugs. Alter the pharmacokinetic and pharmacodynamic property of drugs. Fixibility to couple with site-specific ligands to achieve targeting. ADVANTAGES OF LIPOSOMES

BLOOD BRAIN BARRIER :

BLOOD BRAIN BARRIER Blood brain barrier is a specialized vascular system of Central Nervous System. It is located at the blood capillaries in the brain. It protect the brain from changes in levels of ions, amino acids, peptides etc. in the blood . It strictly regulates the uptake of any compound Oxygen, glucose and W.B.C are able to pass through this barrier but R.B.C cannot. It cannot allows the hydrophilic compounds, but lipophilic compounds easily pass through this barrier.

COMPOSITION OF BLOOD BRAIN BARRIER:

COMPOSITION OF BLOOD BRAIN BARRIER Blood Brain Barrier is composed of endothelial cells, which are sealed together at their edges by tight junctions. These junctions prevent water-soluble substances in the blood from passing between the cells of capillaries These capillaries are enclosed by the flattened ‘end-feet’ of astrocytic cells (one type of glia). The cell membranes are made up of a lipid/protein bilayer, they also act as a major part of the BBB. It also consists of carrier and ion channels. The enzymatic barrier. The efflux pump.

Blood Brain Barrier:

Blood Brain Barrier

ROLE OF BBB IN BRAIN DRUG DELIVERY :

ROLE OF BBB IN BRAIN DRUG DELIVERY The blood-brain barrier is a very specialized barrier system that providing protection to brain cells and preserving brain homeostasis . The brain endothelium has a complex arrangement of tight junctions between the cells that restrict the passage of molecules. It is permeable to small and lipophilic (fat-loving) molecules (up to 800 atomic mass units), but larger molecules are not transported across unless there is an active transport system available. Thus this is one of the stumbling blocks for drug delivery. An additional problem is the very effective drug efflux systems, which pump the drug back out of cells. The drug efflux systems very rapidly and effectively clear a delivered drug from cells.

Delivery methods across the BBB : :

Delivery methods across the BBB : Permeabilisation of tight junctions using either osmotic disruption or biochemical opening . Enhance transcytosis across the endothelial cells – enhanced delivery achieved by increasing endocytosis by using liposomes . Receptors on the brain endothelium surface that are capable of receptor mediated endocytosis, so brain specific targeting technology is used. Development of receptor specific ligands, which can be attached directly to the drug of interest or the drug delivery system itself

ROLE OF LIPOSOMES IN BRAIN TUMOUR THERAPY:

ROLE OF LIPOSOMES IN BRAIN TUMOUR THERAPY A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Liposomes can be filled with drugs and used to deliver drugs for cancer and other diseases. Brain tumour is an abnormal growth of tissue in the brain. It can spread by local extension and rarely outside the brain. It is composed of cancerous or non cancerous cells. Brain tumour

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Liposomes are their natural ability to target cancer. The endothelial wall of all healthy human blood vessels are bound together by tight junctions. Where as tumour vessels do not contain the same level of seal between cells and are diagnostically leaky. Liposomes of can rapidly enter tumour sites from the blood, but are kept in the bloodstream by the endothelial wall in healthy tissue vasculature .

Tumour Targted Liposomal Drug Delivery:

Tumour Targted Liposomal Drug Delivery when the drug is hydrophilic will be trapped inside the cavity and lipophillic drugs are incorporated with in the phospholipids bi-layer. Achieve better selective targeting by using PEG-coated liposomes. Targeting ligands were attached to liposomes via the PEG spacer arm. So that, the ligands was extended out side of the dense PEG brush, and it is binding to the target receptor.

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Most of the anticancer drugs are cytotoxic in nature so they can kill normal cells along with cancer cells Cytotoxic drugs can be wrapped in special biological envelops called liposomes. These drugs to be delivered to tumour without adversely affecting other healthy tissues. e.g.:- Nonliposomal cisplatin and liposomal cisplatin are two xenograft tumor models. In which lipsomal cisplatin had significant antitumour activity and increased survival time compared to non liposomal cisplatin – by colbern et al Doxil -First PEGylated liposomal formulation for doxorubicin. It considerably reduced the cardio toxicity of drugs

CONCLUSION:

CONCLUSION Liposomes are best tool for targeting brain, hence it is made up of lipid bilayer. And also its having a site specific delivery and it produces long term therapy. BBB is made up of lipid bilayer so when compared to other dosage form liposomes are easily crosses the B.B.B. Hence we can achieve very good site specific action via liposomes “Liposomes- Get it into hard to reach places like Brain. Works well for tumours”

REFERENCES :

REFERENCES Patil S. G., Gattani S. G., Gaud R. S., Surana S. J., Dewani S. P., Mahajan H. S., The Pharma Review., preparation of liposomes , 2005; 18(3):53-58. B. Chaize, J. P. Colletier, M. Winterhalter and D. Fournier, Encapsulation of drugs in liposomes: high encapsulation efficiency and control of substrate permeability, Artif. Cells Blood Substit. Immobil. Biotechnol. 32 (2004) 67–75. D. D. Lasic, P. M. Frederic, M. C. A. Stuart, Y. Berenholz and I. T. McIntosh, Gelation of liposomes interior: novel method of drug encapsulation, FEBS Lett. 312 (1992) 255–258. Y. Barenholz and G. Haran, Loading and controlled-release of amphiphilic pharmaceuticals to and from liposomes, Eur. Pat. Appl. EP 361,894 (Cl. A61K9/127) 4 Apr. 1990, US Appl. 250, G. Gregoriadis, Fate of Injected Liposomes: Observations on Entrapped Solute Retention, Vesicle Clearance and Tissue Distribution in vivo, in Liposomes as Drug Carrier: Recent Trends and Progress (Ed. G. Gregoriadis), Wiley, Chichester 1988, pp. 3–8. Muggia F. M., Hainsworth J. D., Jeffers S., Miller P., Groshen S., Tan M., Roman L., Uziely B., Burnett A., Greco F. A., 1997. J. Clin. Oncol. 1997;15:987-989. N. van Rooijen and R. van Nieuwmegen, Liposomes in immunology: multilamellar phosphatidylcholine liposome as a simple biodegradable and harmless adjuvant without any immunogenic activity of its own, Immunol. Commun. 9 (1980) 243–256

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N. Joan Abbott, Lars Rönnbäck & Elisabeth Hansson Nature Reviews Neuroscience., composition of bbb . 7 , 41-53 (January 2006) Gulati M., Grover M., Singh S., Singh M., Int. J. Pharm.,delivery of drugs across bbb., 1998;165:129. 10.American Brain Tumor Association. 2770 River Road, Des Plaines, IL 60018. (847) 827-9918, (800) 886-2289. Hashizume, H; Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (April 2000). "Openings between defective endothelial cells explain tumor vessel leakiness". American Journal of Pathology 156 (4): 1363-1380. PMID 10751361. D. D. Lasic , P. M. Frederic, M. C. A. Stuart, Y. Berenholz and I. T. McIntosh, Gelation of liposomes interior: novel method of drug encapsulation, FEBS Lett . 312 (1992) 255–258. Torchilin VP.  Liposomes as targetable drug carriers. Crit Rev Ther Drug Carrier Syst . 1985;2:65-115. Colbern G. D. Goren, A. Horowitz, D. Tzemach and A. Gabizon , Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models, Anticancer Drugs 10 (1999) 911–920. Q. G. C. M. Van Hoesel , P. A. Steerenberg, D. J. A. Crommelin , A. Van Dijk , W. Van Oost , S.Klein , J. M. C. Douze , D. J. Wildt and F. C. Hillen, Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes in theLOU/M Wsl rat, Cancer Res. 44 (1984) 3698–3705.

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