Liposom

1. LIPOSOMAL DRUG DELIVERY SYSTEM FOR CANCER Prepared by: Potdar Santosh PE/2014/312 11/30/2014 1

2. Content: 1. Introduction 2. Structure Of Liposome 3. Reasons for using liposome as carriers 4. Current trends in liposome 5. Therapeutic application of Liposomes 6. Marketed liposomal products 7.Conclusion 8.References 11/30/2014 2

3. Introduction : 11/30/2014 3 Liposomes are artificially prepared spheres, consisting of concentric phospholipids bilayers separated by aqueous compartments . Liposomes were first produced in England in1961 by Alec D. Bangham .

4. 11/30/2014 4 Structure Of Liposome Liposome =Phospholipid+ cholesterol Hydrophillic head Hydrophobic tail

5. Components of liposomes: The structural components of liposomes include: A. Phospholipids B. Cholesterol A. Phospholipids: 11/30/2014 5

6. Phospholipids : 1.Naturally occurring phospholipids used are : PC : Phosphatidylcholine. PE : Phosphatidylethanolamine. PS : Phosphatidylserine The most commonly used is phospatidylcholine (PC ). 2.Synthetic phospholipids used are: DOPC: Dioleoyl phosphatidylcholine DSPC: Disteroyl phosphatidylcholine DOPE: Dioleoyl phosphatidylethanolamine DSPE: Distearoyl phosphatidylethanolamine 11/30/2014 6

7. B. Cholesterol: 11/30/2014 7 1. Stabilizes the membrane. 2. Act as fluidity buffer. 3. Restricts the transformations of trans to cis or staggered to gauche Conformations .

8. 11/30/2014 8 Advantages of liposomes: Provides selective passive targeting to tumor tissues. (liposomal doxorubicin) . Site avoidance effect (avoids non-target tissues). Increased efficacy and therapeutic index. Reduces toxicity . Improved pharmacokinetic effects .   Couple with site-specific ligands to achieve  active targeting.

9. Production cost is high. Leakage and fusion of encapsulated molecules. Sometimes phospholipids undergoes oxidation and hydrolysis like reaction. Short half-life. Low solubility. 11/30/2014 9 Disadvantages of liposomes:

10. Basic reasons for using liposomes as drug carriers 11/30/2014 10

11. 11/30/2014 11

12. Evolution of liposomes. A Conventional Liposome B Antibody-targeted immunoliposome with antibody covalently coupled ( c ) to the reactive phospholipids in the membrane C Long-circulating liposome grafted with a protective polymer (such as PEG) D Long-circulating immunoliposome simultaneously bearing both protective polymer and antibody . 11/30/2014 12 Torchilin , Vladimir P. "Recent advances with liposomes as pharmaceutical carriers ." Nature reviews Drug discovery 4.2 (2005): 145-160.

13. 11/30/2014 13 As folate receptors (FR) are frequently overexpressed in a wide range of tumour cells. Delivering ofliposomes into living cells using FR endocytosis. Liposomal doxorubicin have been delivered into various tumour cells through FR and demonstrated increased cytotoxicity show inceased survival rate. 1. Folate-mediated liposome targeting : Pan, Xing Q., et al. "Strategy for the treatment of acute myelogenous leukemia based on folate receptor β– targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid."  Blood  100.2 (2002): 594-602.

14. Long residence of liposome in the body is achieved by coating the liposome surface with inert , biocompatible polymers, such as PEG, which form a protective layer over the liposome surface and slow down liposome recognition by opsonins and therefore subsequent clearance of liposomes. It show dose-independent , non- saturable kinetics. Increased bioavailability. Increased action. 11/30/2014 14 2 .Long-circulating liposomes Yang, Chuang, Hai- Zhong Liu, and Zhong-Xue Fu. "Effects of PEG-liposomal oxaliplatin on apoptosis, and expression of Cyclin A and Cyclin D1 in colorectal cancer cells."  Oncology reports  28.3 (2012): 1006-1012.

15. 3 .Antibody-mediated liposome targeting. Liposome with specific antibodies capable of recognizing various tumour cells through tumour-cell-surface-bound nucleosomes improved targeting to tumour cells and increased its cytotoxicity . Incresed target specific drug delivery and reduced toxicity of cytotoxic drug. Torchilin , Vladimir P. "Recent advances with liposomes as pharmaceutical carriers ." Nature reviews Drug discovery 4.2 (2005): 145-160. 11/30/2014 15

16. 4 .pH-sensitive liposome : 11/30/2014 16 As tumour has low pH than normal cells hence we can use pH sensitive release of liposome content, liposomes are constructed from pH-sensitive components to release their contents into the cytoplasm Of the tumour cell . Transferrin receptors ( TfR ) are overexpressed on the surface of many tumour cells, and so antibodies against TfR , as well as Transferrin itself, are popular ligands for liposome targeting to tumours and inside tumour cells. 5 .Transferrin-mediated liposome targeting:

17. 11/30/2014 17 European Patent, international publication No. WO2014159760A1

18. 11/30/2014 18 Woodle , Martin C., and Danilo D. Lasic. "Sterically stabilized liposomes." Biochimica et Biophysica Acta (BBA)-Reviews on Biomembranes  1113.2 (1992): 171-199.

19. Therapeutic application of Liposomes : 11/30/2014 19 1 .Liposome in enzyme replacement therapy 2 .Liposome in tumor therapy increase effectiveness and decrease toxicity carrier for small cytotoxic drug 3 .Liposome in gene delivery Gene and antisense delivery Genetic (DNA) vaccination 4 .Liposome in Immunology

20. 1.Liposomal doxorubicin( myocet ) Use: Combination therapy with cyclophosphamide in metastatic breast cancer. 2.Liposomal daunorubicin( Daunoxome ) Use : HIV-related Kaposi’s sarcoma 3.Liposomal cytarabine ( DepoCyt (e )) Use : treatment of lymphoma Marketed liposomal products 11/30/2014 20

21. Conclusion : 11/30/2014 21

22. Torchilin , Vladimir P. "Recent advances with liposomes as pharmaceutical carriers." Nature reviews Drug discovery 4.2 (2005 ): 145-160. Yang, Chuang, Hai- Zhong Liu, and Zhong-Xue Fu. "Effects of PEG-liposomal oxaliplatin on apoptosis, and expression of Cyclin A and Cyclin D1 in colorectal cancer cells."  Oncology reports  28.3 (2012): 1006-1012. Pan, Xing Q., et al. "Strategy for the treatment of acute myelogenous leukemia based on folate receptor β– targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid."  Blood  100.2 (2002): 594-602 . Woodle , Martin C., and Danilo D. Lasic . " Sterically stabilized liposomes." Biochimica et Biophysica Acta (BBA)-Reviews on Biomembranes  1113.2 (1992): 171-199. 11/30/2014 22 References :

23. 11/30/2014 23 THANK YOU