Liposomes

Introduction to liposomes and its types.

1. Liposomes Faculty Of Pharmacy ASU DFD Course

2. What’s the meaning of Liposomes??? * Liposomes are microscopic phospholipid bubbles with a bilayered membrane structure. *Many new developments have been seen in the area of liposomal drugs, from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest.

3. Some History… 50 years ago Alec Bangham noticed that phospholipids in aqueous systems can form closed bilayered structure. Since then they came from being an exotic object in research to common drug carrier with many clinical applications. Example: Doxorubicin in polyethylene glycol (PEG) liposomes for the treatment of solid tumors in patients with breast-carcinoma metastases which improved survival.

4. Types of Liposomal vesicles:

5. Attractive Biological Properties:

6. Goals of Liposomes Surface Modification:

7. Liposomes in Drug Delivery: Evolution One of drawbacks of use of liposomes is fast elimination from blood & capture of liposomal preparations by cells of RES mainly in liver. To reduce this problem: Immunoliposomes: To increase liposomal drug accumulation in desired tissues. Use of targeted liposomes with surface attached ligands able to recognize & bind to desired cells. IgG are most widely used targeting moieties for liposomes . 2) Long circulating liposomes: I nclude coating liposome surface with inert, biocompatible polymers as PEG , which slow down liposome recognition by opsonins and therefore clearance of liposomes.

8. Liposomes in Drug Delivery: Evolution Although, PEG remains the gold standard for the steric protection of liposomes, attempts continue to identify other polymers that could be used to prepare long-circulating liposomes. Earlier studies with various water-soluble flexible polymers have been summarized elsewhere. More recent papers describe long-circulating liposomes that were prepared using poly [N-(2-hydroxypropyl) methacrylamide )] ,poly-N- vinylpyrrolidone , L-amino-acid-based biodegradable polymer lipid conjugates and polyvinyl alcohol.

9. Liposomes in Drug Delivery: Evolution 3) Long-circulating Immunoliposomes: Involved the combination of the properties of long-circulating liposomes and immunoliposomes in one preparation. Performed by simple co-immobilization of an antibody and PEG on the surface of the liposome, although the protective polymer can create steric hindrances for target recognition with the targeting moiety. Solution : To achieve better selectivity of PEG-coated liposomes, it is advantageous to attach the targeting ligand via a PEG spacer arm , so that the ligand is extended outside of the dense PEG brush, which reduces steric hindrance.

10. Liposomes Surface Modification Chemistry The preparation of modified Liposomes with controlled properties requires the chemical conjugation of proteins, peptides , polymers and other molecules to the liposome surface. The conjugation methodology is based on 3 main Rxs : 1- reaction bet. Activated carboxyl gps and amino gps , which yields an amide bond. 2- reaction bet. pyridyldithiols and thiols , which yields disulfide bonds. 3- reaction bet. Maleimide derivatives and thiols , which yields thioether bonds. Many lipid derivatives used in these techniques are comercially available. Other approaches exist ,such as those that yield the carbamate bond via the reaction of p- nitrophenylcarbonyl and amino gp .

11. New Ligands for Targeting Liposomes Examples for Antibody-mediated liposome targeting : 1) using anti-HER2 liposomes to target HER2-overexpressing tumors. 2) NUCLEOSOME-specific antibodies have improved Doxil targeting to tumour cells. Folate -mediated liposome targeting: A popular approach, because folate receptors (FR) are frequently overexpressed in a range of tumour cells. Possibility of delivering macromolecules and then liposomes into living cells using FR endocytosis , which could bypass multidrug resistance.

12. New Ligands for Targeting Liposomes Transferrin -mediated liposomal targeting: TF-receptors over expressed on surface of many tumor cells so coupling of TF on pegylated liposome was successfully used for brain targeting. Vasoactive intestinal peptide (VIP): Has been used to target PEG liposomes with radionuclides to VIP receptors on surface of tumor cell and resulted in enhanced breast cancer inhibition in rats. Epidermal growth factor receptor (EGFR): EGFR-targeted liposomes delivered to tumor cells that over express EGFR. Galactosylated liposome: Research also continues on the use of galactosylated liposomes to target drug to Liver for the treatmentof liver tumors and metastases. Cisplatin -loaded liposomes: Bind to chondroitin sulphate which is over expressed in many tumor cells have been used for suppression of tumor growth.

13. PH Sensitive Liposomes Focus on development of new lipid composition that confer PH sensitivity to liposomes by using P H sensitive polymers. Combining PH sensitive liposomes with longevity and ligand mediate targeting. Pegylated PH sensitive liposomes have long duration. Antisense oligonucleotides can be delivered into cells by anionic pH-sensitive phosphatidyl ethanolamine . containing liposomes that are stable in the blood but which, however undergo phase transition at acidic endosomal pH. Ex. oleyl alcohol and a mono- stearoyl derivative of morpholine . liposome pH-sensitivity and specificity of ligand targeting (folate and targeted liposomes).

14. PH Sensitive Liposomes

15. References… This Presentation is based on: RECENT ADVANCES WITH LIPOSOMES AS PHARMACEUTICAL CARRIERS By~ Vladimir P. Torchilin