MOLECULAR BASIS OFTARGATED DRUG DELIVERY       SYSTEM                         1
 Introduction Reasons for site specific drug delivery Anatomy & Physiology Of Cell Types Of Blood Capillaries Anatomi...
 The concept of targeted drug delivery system  given by “Paul Ehrlich”, proposed drug delivery  as a “magic bullet”. Tar...
 Targetingis signified if target compartment is distinguished from other compartment.                 Drug               ...
Reasons For Site-Specific Drug DeliveryProperties                       FactorsPharmaceutical                   Solubility...
Anatomy & Physiology Of Cell                               6
Extravasation                7
Types Of Blood Capillaries(1) Continuous capillary (as found in the general circulation). The endothelium is continuouswit...
9
Lymphatic SystemSolid tumors lack lymphatic system,so the macromolecules drugsenters tumor interstitium by extravasation &...
Anatomical & Physiological considerations For Targeting Phagocytic uptake by the cells of the mononuclear phagocyte system...
Ideal Characteristics Of TDDS• specifically target the drug to target cells or target tissue;• keep the drug out of non-ta...
Components Of TDDSTDDS Component                 PurposeThe active moiety              To achieve the therapeutic         ...
CarriersCarriers  are the drug vectors which protect,transport  and retain drug “an route” and deliver it to target  site...
Carrier System Used For Targeted Drug DeliveryColloidal Carriers   1)Vesicular system:                     liposomes,nioso...
Levels Of Drug Targeting               Targeting occurs because of the body‟sPassive Targeting   natural response to the p...
Inverse TargetingIt is based on successful attempts to avoid passive  uptake of colloidal carrier by reticuloendothelial  ...
Active TargetingThe natural distribution pattern of the drug carrier  composites is enhanced using chemical,biological  & ...
Dual TargetingDrug targeting employs carrier molecules,which have their   own effect thus synergies the active ingradient ...
Problems Associated With Targeted Drug Delivery System   Rapid clearance of targeted systems specially    antibody target...
Cell Surface Biochemistry & Molecular TargetsDistinctive cellular elements present on the surface of thetarget cells are i...
Ligand As Drug Delivery    Types of ligand internalized via receptor mediated     endocytosis.Endogenous      Immunologic...
LIGAND DRIVEN RECEPTOR MEDIATED          DRUG DELIVERY Cellular ProcessesEndocytosis:(1) Recognition: Coating mediated by ...
Endocytosis Processes                        24
Receptor Madiated EndocytosisThree internalization mechnisms have been proposed:1. Fluid phase pinocytosis2. Adsorptive,re...
Clathrine Independent Endocytosis It involve the component of cytoskeleton. Caveolae are coated investigations of plasma...
Ligand Mediated Transcytosis   receptor-mediated pinocytosis,    the endosomes carrying the    drug actually bypass the  ...
INTRACELLULAR DISPOSITION OF DRUG-CARRIER COMPLEXReceptor Recognition & Ligand-Receptor Interaction                  Cell ...
Intracellular Complex Of Ligand-Receptor complex                           Ligand-Receptor Complex                        ...
Delivery Of Drug-Carrier complex To Acidic Endosomal & Lysosomal                                Compartment “Lysomotropic ...
Future Perspective    The innovation in this field of research on the targeted drug     delivery in the coming years woul...
REFERENCES1. Vyas s. p.,Khar r. k., 2010, „Molecular Basis Of   Targeted Drug Delivery‟ Targeted & Controlled   Drug Deliv...
33
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Molecular basis of targated drug delivery system

  1. 1. MOLECULAR BASIS OFTARGATED DRUG DELIVERY SYSTEM 1
  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
  3. 3.  The concept of targeted drug delivery system given by “Paul Ehrlich”, 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. 3
  4. 4.  Targetingis signified if target compartment is distinguished from other compartment. Drug Drug in carrier Non target Target site Non target site Target site site No affinity- Targeted No affinity- Affinity - low effect effect low effect toxicity Inactivation/ Less More therapeutic therapeutic effect effect Bio-environmental factors 4
  5. 5. Reasons For Site-Specific Drug DeliveryProperties FactorsPharmaceutical Solubility Drug stabilityBiopharmaceutical Low absorptionPharmacokinetic & Short half-lifepharmacodinemic Large volume of distibution Low specificityClinical Low therapeutic index Anatomical & cellular barrier 5
  6. 6. Anatomy & Physiology Of Cell 6
  7. 7. Extravasation 7
  8. 8. Types Of Blood Capillaries(1) Continuous capillary (as found in the general circulation). The endothelium is continuouswith tight junctions between adjacent endothelial cells. The subendothelial basementmembrane is also continuous.(2) Fenestrated capillary (as found in exocrine glands and the pancreas). The endotheliumexhibits a series of fenestrae which are sealed by a membranous diaphragm. Thesubendothelial basement membrane is continuous.(3) Discontinuous (sinusoidal) capillary (as found in the liver, spleen and bone marrow). Theoverlying endothelium contains numerous gaps of varying size. The subendothelial basement iseither absent (liver) or present as a fragmented interrupted structure (spleen, bone marrow) 8
  9. 9. 9
  10. 10. Lymphatic SystemSolid tumors lack lymphatic system,so the macromolecules drugsenters tumor interstitium by extravasation & remain there,known asEPR effect. 10
  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) MPS System • fixed cells: macrophages in liver (also known as Kuppfer cells), spleen, lung, bone marrow and lymph nodes • mobile cells: blood monocytes and tissue macrophages Factors Affecting MPS Clearance1. Particle size : 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 relatively2. Particle charge : rapidly from the circulation whereas neutral vesicles tend to remain in the circulation for longer periods.3. Surface hydrophobicity : Hydrophobic particles rapidly taken up by MPS system. 11
  12. 12. Ideal Characteristics Of TDDS• 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. 12
  13. 13. Components Of TDDSTDDS Component PurposeThe active moiety To achieve the therapeutic effectThe carrier system (which can To effect a favorablebe either soluble or distribution of the drugparticulate) To protect the drug from metabolism To protect the drug from early clearanceA “homing device” To specifically target the drug to the target cells or target tissue 13
  14. 14. CarriersCarriers are the drug vectors which protect,transport and retain drug “an route” and deliver it to target site. Ideal characteristics of carrier 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
  15. 15. Carrier System Used For Targeted Drug DeliveryColloidal Carriers 1)Vesicular system: liposomes,niosomes,virosomes,immunoliposomes 2)Microparticulate system: microspheres,nanoparticlesCellular carriers Resealed erythrocytes,serum albumin,antibodies,platlets,leukocytesSupramolecular Micelles,reverse micelle,liquid crystals,lipoprotein (VLDL,LDL)deliveryPolymer based Muco-adhesive,biodegradable,bioerodible,soluble synthetic carriersdeliveryMacromolecular 1)proteins,glycoprotein,neo-glycoprotein 2)Mabscarriers 3)Polysaccharides 15
  16. 16. Levels Of Drug Targeting Targeting occurs because of the body‟sPassive Targeting natural response to the physiological characteristics of the drug-carrier system. colloidal carriers are taken up by RES in liver & spleen. Disadvantage :extravasation is poor with microparticulate system. Macrophage related infected cell lines Drug proposed for encapsulation INTRACELLULAR PARASITES: Antimalarial & Leismaniasis,Brucellosis, Candidiasis Antiinfective NEOPLASM: lukemia,hodgkin’s disease,viral Cytotoxic & antiviral infected disease drugs 16
  17. 17. Inverse TargetingIt is based on successful attempts to avoid passive uptake of colloidal carrier by reticuloendothelial system. Methods For Inverse Targeting Inverse Targeting Pre injection of blank Change in size, surface charge, colloidal carrier hydrophilicity of carrier Blockade of RESPhospholipid microsphere emulsified with poloxamer 338 showed the lowest RES uptake in mouse. 17
  18. 18. Active TargetingThe natural distribution pattern of the drug carrier composites is enhanced using chemical,biological & physical method. Active Targeting First order targeting Second order targeting Third order targeting Organ targeting Cellular targeting Intracellular targetingActive targeting devided in two types:1)Ligand mediated targeting pH sensitive2)Physical targeting Temperature sensitive 18
  19. 19. Dual TargetingDrug targeting employs carrier molecules,which have their own effect thus synergies the active ingradient effect. Double Targeting Controlled release of drug Drug targeting Sustained release Active/passive Double Stimuli responsive release targeting targeting Self-regulating release Combination TargetingTargeting can be achieved via physical(pemeation enhancer),chemival(prodrug),or carrier encapsulation 19
  20. 20. Problems Associated With Targeted Drug Delivery System 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 Redistribution of released drug leading to non-specific accumulation. 20
  21. 21. Cell Surface Biochemistry & Molecular TargetsDistinctive cellular elements present on the surface of thetarget cells are important for targeting.• Cell surface antigen• Cell specific antibodies• Cell surface receptors Receptor as drug deliveryTypes of receptors present on biocell,• lectin like receptors• Monoclonal antibody• Hormone• MHC-1 21
  22. 22. Ligand As Drug Delivery Types of ligand internalized via receptor mediated endocytosis.Endogenous Immunological Glycoconjugate Antibodiesligand ligandTransferin Interferons Glycolipid HaptensFolate MHC-peptides Glycosides MabsLipoprotein Interlukins Polysaccharides ImmunotoxinsLimitations of natural ligands1. The endogenously produced ligands may compete with exogenously delivered ligand.2. Ligands may elicit immunological response.3. Bind to multi receptor types. 22
  23. 23. LIGAND DRIVEN RECEPTOR MEDIATED DRUG DELIVERY Cellular ProcessesEndocytosis:(1) Recognition: Coating mediated by blood components(2) Adhesion: Attachment of ligand to macrophage cells ofRES(3) Digestion: Particle transfer to phagosome,phago-lysosome,digestive vacuoles. 23
  24. 24. Endocytosis Processes 24
  25. 25. Receptor Madiated EndocytosisThree internalization mechnisms have been proposed:1. Fluid phase pinocytosis2. Adsorptive,receptor mediated pinocytosis3. Adsorptive,non-receptor (diffusive)mediated pinocytosis Clathrin Coated Endocytosis Clathrin is vesicular coat proteins mediate internalization of receptor-ligand complex Functions They concentrate carriers & receptors in the vesicles. They serve to transport & target vesicles from the donor compartment to appropriate destinations. 25
  26. 26. Clathrine Independent Endocytosis 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. Non clathrine micropinosomes Clathrine coated pinocytosis coated phagosome 26
  27. 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 COMPLEXReceptor Recognition & Ligand-Receptor Interaction Cell Specific Recognition of Carrier Binding Of Drug Conjugate Influence By Proteine Kinase C Endocytosis Intracellular release Cellular Retention 28
  29. 29. Intracellular Complex Of Ligand-Receptor complex Ligand-Receptor Complex Transported In Endosome Vesicles Lysosome Receptor Ligand Transported To Cell Surface 29
  30. 30. Delivery Of Drug-Carrier complex To Acidic Endosomal & Lysosomal 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 endosomesLigand degradation by lysosomal pH decrease by Ammonium Chloride whichneutralise acidic pH of lysosome Delivery Of Drug-Carrier complex To Cytosolic CompartmentVarious methods available to target cytosole by exposing the vesicle to adenovirus& immunotoxins which degrade endosomal vesicles & deliver the content tocytosol. 30
  31. 31. Future Perspective 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. Conclusion•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. 31
  32. 32. REFERENCES1. 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:38-802. Hillery m.,Lloyd w.,2005, „Advanced Drug Delivery and Targeting: An Introduction‟Drug Delivery & Targeting, 3rd Edition, Taylor & Francis Inc,29 West 35th Street, New York,Page no:56-713. Banker s. g.,Rhodes t. c.,2002, „Target Oriented Drug Delivery System‟Modern Pharmaceutics,4th Edition,United States Of America,Page no:531-580 32
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