Molecular basis of targated drug delivery system chatap

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1. 1 MOLECULAR BASIS OF TARGATED DRUG DELIVERY SYSTEM Presented by: Chinchole Pravin Sonu (M.PHARM 2 nd SEM) DEPARTMENT OF PHARMACEUTICS & QUALITY ASSURANCE R. C. Patel Institute of Pharmaceutical Education and Research, shirpur .

2. 2 Introduction Reasons for site specific drug delivery Anatomy & Physiology Of Cell Types Of Blood Capillaries Anatomical & Physiological considerations For Targeting Ideal Characteristics Of DDTS Components Of DDTS Levels Of Drug Targeting Ligend driven receptor mediated drug delivery Future perspective Conclusion References 2 Contents:

3. Concept Of Targeting 3 The concept of targeted drug delivery system given by “Paul Ehrlich”.he proposed drug delivery as a “magic bullet”. Targeted drug delivery implies for selective and effective localization of pharmacologically active moiety at preselected target(s) in therapeutic concentration. It restrict the entry of drug in non-targeted cells,thus minimizing toxic effects.

4. Targeting is signified if target compartment is distinguished from other compartment. Rationale Of Drug Targetinng 4 Target site Non target site Affinity -toxicity No affinity-low effect Bio-environmental factors Target site Non target site Inactivation/Less therapeutic effect More therapeutic effect No affinity-low effect Targeted effect Drug Drug in carrier

5. 5 Reasons For Site-Specific Drug Delivery Properties Factors Pharmaceutical Solubility Drug stability Biopharmaceutical Low absorption Pharmacokinetic & pharmacodinemic Short half-life Large volume of distibution Low specificity Clinical Low therapeutic index Anatomical & cellular barrier

6. 6 Anatomy & Physiology Of Cell

7. 7 Extravasation

8. 8 Types Of Blood Capillaries (1) Continuous capillary (as found in the general circulation). The endothelium is continuous with tight junctions between adjacent endothelial cells. The subendothelial basement membrane is also continuous.(particle size should be <10nm) (2) Fenestrated capillary (as found in exocrine glands and the pancreas). The endothelium exhibits a series of fenestrae which are sealed by a membranous diaphragm. The subendothelial basement membrane is continuous. (3) Discontinuous (sinusoidal) capillary (as found in the liver, spleen and bone marrow). The overlying endothelium contains numerous gaps of varying size. The subendothelial basement is either absent (liver) or present as a fragmented interrupted structure (spleen, bone marrow)

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10. 10 Lymphatic System Solid tumors lack lymphatic system,so the macromolecules drugs enters tumor interstitium by extravasation & remain there,known as EPR effect.

11. 11 Anatomical & Physiological considerations For Targeting Phagocytic uptake by the cells of the mononuclear phagocyte systems (MPS; also sometimes known as the reticuloendothelial system, RES) • fixed cells: macrophages in liver (also known as Kuppfer cells), spleen, lung, bone marrow and lymph nodes • mobile cells: blood monocytes and tissue macrophages MPS System Factors Affecting MPS Clearance Particle size : Particle charge : Surface hydrophobicity : Hydrophobic particles rapidly taken up by MPS system. Particulates in the size range of 0.1−7 μm tend to be cleared by the MPS, localizing predominantly in the Kuppfer cells of the liver. Negatively charged vesicles tend to be removed relatively rapidly from the circulation whereas neutral vesicles tend to remain in the circulation for longer periods.

12. 12 • specifically target the drug to target cells or target tissue; • keep the drug out of non-target organs, cells or tissue; • ensure minimal drug leakage during transit to target; • protect the associated drug from metabolism; • protect the associated drug from premature clearance; • retain the drug at the target site for the desired period of time; • facilitate transport of the drug into the cell; • deliver the drug to the appropriate intracellular target site; • Should be biodegradable and non-antigenic. Ideal Characteristics Of DDTS

13. 13 Components Of DDTS DDTS Component Purpose The active moiety To achieve the therapeutic effect The carrier system, which can be either soluble or partaculate To effect a favorable distribution of the drug To protect the drug from metabolism To protect the drug from early clearance A “homing device” To specifically target the drug to the target cells or target tissue

14. Carriers are the drug vectors which protect,transport and retain drug “ an route” and deliver it to target site. It must be able to cross anatomical barriers. It must be recognized selectively by target cell. Carrier should be non- toxic,non -immunogenic, biodegradable particulate. After internalization carrier should release the drug moiety inside target organ. Extravasation and Passive delivery 14 Carriers Ideal characteristics of carrier

15. 15 Carrier System Used For Targeted Drug Delivery Colloidal Carriers 1)Vesicular system: liposomes,niosomes,virosomes,immunoliposomes 2) Microparticulate system: microspheres,nanoparticles Cellular carriers Resealed erythrocytes,serum albumin,antibodies,platlets,leukocytes Supramolecular delivery Micelles,reverse micelle,liquid crystals,lipoprotein (VLDL,LDL) Polymer based delivery Muco-adhesive,biodegradable,bioerodible,soluble synthetic carriers Macromolecular carriers 1) proteins,glycoprotein,neo -glycoprotein 2) Mabs 3)Polysaccharides

16. Targeting occurs because of the body’s natural response to the physiological characteristics of the drug-carrier system. colloidal carriers are taken up by RES in liver & spleen. :extravasation is poor with microparticulate system. 16 Levels Of Drug Targeting Macrophage related infected cell lines Drug proposed for encapsulation INTRACELLULAR PARASITES: Leismaniasis,Brucellosis , Candidiasis Antimalarial & Antiinfective NEOPLASM: lukemia,hodgkin’s disease,viral infected disease Cytotoxic & antiviral drugs Disadvantage Passive Targeting

17. It is based on successful attempts to avoid passive uptake of colloidal carrier by reticuloendothelial system. Phospholipid microsphere emulsified with poloxamer 338 showed the lowest RES uptake in mouse. 17 Inverse Targeting Inverse Targeting Pre injection of blank colloidal carrier Change in size,surface charge,hydrophilicity of carrier Blockade of RES Methods For Inverse Targeting

18. The natural distribution pattern of the drug carrier composites is enhanced using chemical,biological & physical method. Active targeting devided in two types: 1)Ligand mediated targeting 2)Physical targeting 18 Active Targeting Active Targeting First order targeting Second order targeting Third order targeting Organ targeting Cellular targeting Intracellular targeting pH sensitive Temperature sensitive

19. Drug targeting employs carrier molecules,which have their own effectthus synergies the active ingradient effect. Targeting can be achieved via physical( pemeation enhancer), chemival ( prodrug ),or carrier encapsulation 19 Dual Targeting Double Targeting Controlled release of drug Sustained release Stimuli responsive release Self-regulating release Drug targeting Active/passive targeting Double targeting Combination Targeting

20. Rapid clearance of targeted systems specially antibody targeted system. Immune reactions against intravenous administered carrier system. Problems of insufficient localization of targeted systems into tumour cells. Down regulation of surface epitopes . Diffusion and Redistibution of released drug leading to no-specific accumulation. 20 Problems Associated With Targeted Drug Delivery System

21. Cell Surface Biochemistry & Molecular Targets 21 Distinctive cellular elements present on the surface of the target cells are important for targeting. Cell surface antigen Cell specific antibodies Cell surface receptors Types of receptors present on biocell, lectin like receptors Monoclonal antibody Hormone MHC-1 Receptor as drug delivery

22. 22 Ligand As Drug Delivery Types of ligand internalized via receptor mediated endocytosis . The endogenously produced ligands may compete with exogenously delivered ligand . Ligands may elicit immunological response. Bind to multi receptor types. Endogenous ligand Immunological ligand Glycoconjugate Antibodies Transferin Interferons Glycolipid Haptens Folate MHC-peptides Glycosides Mabs Lipoprotein Interlukins Polysaccharides Immunotoxins Limitations of natural ligands

23. LIGAND DRIVEN RECEPTOR MEDIATED DRUG DELIVERY Endocytosis : (1) Recognition: Coating mediated by blood components (2) Adhesion: Attachment of ligand to macrophage cells of RES (3) Digestion: Particle transfer to phagosome,phago-lysosome,digestive vacuoles. Cellular Processes 23

24. 24 Endocytosis Processes

25. Three internalization mechnisms have been proposed: Fluid phase pinocytosis Adsorptive,receptor mediated pinocytosis Adsorptive,non -receptor (diffusive)mediated pinocytosis Clathrin is vesicular coat proteins mediate internalization of receptor- ligand complex They concentrate carriers & receptors in the vesicles. They serve to transport & target vesicles from the donor compartment to appropriate destinations. 25 Receptor Madiated Endocytosis Clathrin Coated Endocytosis Functions

26. Clathrine Independent Endocytosis 26 It involve the component of cytoskeleton. Caveolae are coated investigations of plasma membrane,they do not separate from the plasma membrane,known as “POTOCYTOSIS” Folate undergo potocytosis . Clathrine coated pinocytosis Non clathrine coated micropinosomes phagosome

27. Ligand Mediated Transcytosis receptor-mediated pinocytosis , the endosomes carrying the drug actually bypass the lysosomes and migrate toward the basolateral membrane, resulting in the release of the undegraded drug into the extracellular space bounded by the basolateral membrane. This process, known as transcytosis , represents a potentially useful and important pathway for the absorption of high molecular weight drugs such as peptides and proteins. 27

28. 28 INTRACELLULAR DISPOSITION OF DRUG-CARRIER COMPLEX Receptor Recognition & Ligand -Receptor Interaction Cell Specific Recognition of Carrier Binding Of Drug Conjugate Intracellilar release Cellular Retention Endocytosis Influence By Proteine Kinase C

29. 29 Intracellular Complex Of Ligand -Receptor complex Ligand -Receptor Complex Transported In Endosome Vesicles Receptor Ligand Transported To Cell Surface Lisosome

30. 30 Delivery Of Drug-Carrier complex To Acidic Endosomal & Lisosomal Compartment “ Lysomotropic Approach” Vesicle Shunt Model Assumes that early & late endosomes are pre-existing compartments that communicate through vesicle-mediate transport Maturation model Assumes that early endosomes mature gradually into late endosomes Delivery Of Drug-Carrier complex To Cytosolic Compartment Ligand degradation by lysosomal pH decrease by Ammonium Chloride which neutralise acidic pH of lysosome Various methods available to target cytosole by exposing the vesicle to adenovirus & immunotoxins which degrade endosomal vesicles & deliver the content to cytosol.

31. The innovation in this field of research on the targeted drug delivery in the coming years would be a shift from “receptor to nucleus”. This site-specific delivery rotate towards the gene delivery to nucleus. 31 Future Perspective In the early days of the 20th century, Paul Ehrlich developed his “magic bullet” concept: the idea that drugs reach the right site in the body, at the right time, at the right concentration. It should not exert side-effects, neither on its way to the therapeutic target, nor at the target site, nor during the clearance process. they are indicated for the treatment of life-threatening diseases like cancer, and severe infectious diseases. Conclusion

32. Vyas s. p.,Khar r. k., 2010, ‘Molecular Basis Of Targeted Drug Delivery’ Targeted & Controlled Drug Delivery System, 6th Edition, CBS Publishers & Distributors,New Delhi,Page no:38-80 Hillery m.,Lloyd w.,2005, ‘Advanced Drug Delivery and Targeting: An Introduction’ Drug Delivery & Targeting, 3 rd Edition, Taylor & Francis Inc,29 West 35th Street, New York,Page no:56-71 Banker s. g.,Rhodes t. c.,2002, ‘Target Oriented Drug Delivery System’ Modern Pharmaceutics ,4 th Edition,United States Of America,Page no:531-580 32 REFERENCES

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34. 34 Particulates in the size range of 100 nm to 7 μm are prone to be cleared by the MPS, especially by the fixed Kupffer cells in the liver. In the case of biomacromolecules such as oligonucleotides, proteins, RNA, and DNA,7 the delivery system often needs to transfer the payload across the plasma membrane either by fusion or by endocytosis.7,14 If taken up by the cells via endocytosis, the macromolecule later must be released from the endosome into the cytoplasm to avoid degradation in the lysosomes. In the case of gene delivery, DNA must further relocate from the cytoplasm into the nucleus to direct the expression of the gene products. the delivery of high-molecular-weight hydrophilic molecules across biomembranes is one of the most challenging problems facing the pharmaceutical community. If the target is the vascular endothelial cell layer, the delivery system can reach the target site readily via the blood circulation. To reach other tissues such as hepatocytes and cancer cells in solid tumors, the carrier needs to extravasate through the endothelial capillaries and diffuse to the target site. The endothelial cells that outline the capillaries enforce an upper size limit of about 100 nm if the delivery system is to reach the extravascular tissues.

35. 35 Clearance by the MPS involves two steps. First, plasma proteins called opsonins adsorb onto the “foreign surface” of a particulate; second, the macrophages recognize the opsonsincovered particles and initiate phagocytosis. Particles with hydrophobic surfaces are recognized immediately as “foreign,” covered by the opsonins, and taken up by macrophages. Surface hydrophobicity if a delivery system is to be targeted to other cell types, its interaction with the MPS must be minimized. The standard approach is to coat the surface of the system with hydrophilic materials to reduce opsonin adsorption. The natural tendency of macrophages to uptake the lipidic particulates was exploited in a number of MPS targeting liposome formulations.30 The potential therapeutic benefits of such liposomes include the treatment of macrophagerelated microbial, viral, or bacterial infections; the immunopresentation of vaccines; potentiation of the immune system using a macrophageactivating agent such as interferon- g ; and treatment of lysosomal enzyme deficiencies .

36. 36 The surface charge of a drug carrier also plays an important role in its pharmacokinetic behavior. For liposomes, it has been shown that a neutral surface charge is optimal for a long circulation time.33 Liposomes with a negative charge tend to be cleared more rapidly from the circulation by the Kupffer cells in the liver.34 Positively charged particulates rapidly absorb negatively charged plasma proteins in the blood circulation and are recognized as foreign objects by the immune system.35 Charge