1 MOLECULAR BASIS OF TARGATED DRUG DELIVERY SYSTEM
May 17, 2015
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MOLECULAR BASIS OF TARGATED DRUG DELIVERY
SYSTEM
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IntroductionReasons for site specific drug deliveryAnatomy & Physiology Of CellTypes Of Blood CapillariesAnatomical & Physiological considerations For Targeting Ideal Characteristics Of DDTSComponents Of DDTSLevels Of Drug TargetingLigend driven receptor mediated drug deliveryFuture perspective ConclusionReferences
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Contents:
Concept Of Targeting
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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.
Targeting is signified if target compartment is distinguished from other compartment.
Rationale Of Drug Targeting
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Target siteNon 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
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Reasons For Site-Specific Drug Delivery
Properties Factors
Pharmaceutical SolubilityDrug stability
Biopharmaceutical Low absorption
Pharmacokinetic & pharmacodinemic
Short half-lifeLarge volume of distibutionLow specificity
Clinical Low therapeutic indexAnatomical & cellular barrier
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Anatomy & Physiology Of Cell
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Extravasation
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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.(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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Lymphatic System
Solid tumors lack lymphatic system,so the macromolecules drugs enters tumor interstitium by extravasation & remain there,known as EPR effect.
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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
1. Particle size :
2. Particle charge :
3. 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.
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• 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 TDDS
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Components Of TDDS
TDDS Component Purpose
The active moiety To achieve the therapeutic effect
The carrier system (which can be either soluble orparticulate)
To effect a favorable distribution of the drugTo protect the drug from metabolismTo protect the drug from early clearance
A “homing device” To specifically target the drug to the target cells or targettissue
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
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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-glycoprotein2)Mabs3)Polysaccharides
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.
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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
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
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
Drug targeting employs carrier molecules,which have their own effect thus synergies the active ingradient effect.
Targeting can be achieved via physical(pemeation enhancer),chemival(prodrug),or carrier encapsulation
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Dual Targeting
Double Targeting
Controlled release of drug Sustained release
Stimuli responsive releaseSelf-regulating release
Drug targetingActive/passive
targeting
Double targeting
Combination Targeting
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
Problems Associated With Targeted Drug Delivery System
Cell Surface Biochemistry & Molecular Targets
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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
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Ligand As Drug Delivery
Types of ligand internalized via receptor mediated endocytosis.
1. The endogenously produced ligands may compete with exogenously delivered ligand.
2. Ligands may elicit immunological response.
3. 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
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
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Endocytosis Processes
Three internalization mechnisms have been proposed:
1. Fluid phase pinocytosis
2. Adsorptive,receptor mediated pinocytosis
3. 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.
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Receptor Madiated Endocytosis
Clathrin Coated Endocytosis
Functions
Clathrine Independent Endocytosis
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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
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.
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INTRACELLULAR DISPOSITION OF DRUG-CARRIER COMPLEX
Receptor Recognition & Ligand-Receptor Interaction
Cell Specific Recognition of Carrier
Binding Of Drug Conjugate
Intracellular release
Cellular Retention
Endocytosis
Influence By Proteine Kinase C
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Intracellular Complex Of Ligand-Receptor complex
Ligand-Receptor Complex
Transported In Endosome Vesicles
Receptor Ligand
Transported To Cell Surface
Lysosome
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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 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.
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.
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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
1. 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
2. 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:56-71
3. Banker s. g.,Rhodes t. c.,2002, ‘Target Oriented Drug Delivery System’Modern Pharmaceutics,4th Edition,United States Of America,Page no:531-580
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REFERENCES
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