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MOLECULAR BASIS OF TARGATED DRUG DELIVERY SYSTEM

Presented by: Chinchole Pravin Sonu

(M.PHARM 2nd SEM)DEPARTMENT OF PHARMACEUTICS & QUALITY ASSURANCE

R. C. Patel Institute of Pharmaceutical Education and Research, shirpur.

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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”.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.

Targeting is signified if target compartment is distinguished from other compartment.

Rationale Of Drug Targetinng

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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.(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 membranousdiaphragm. 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 SystemSolid 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 Clearance1. 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 DDTS

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Components Of DDTS

DDTS Component Purpose

The active moiety To achieve the therapeutic effect

The carrier system, which can be either soluble orpartaculate

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 DeliveryColloidal Carriers

1)Vesicular system: liposomes,niosomes,virosomes,immunoliposomes2)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 targeting2)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 effectthus 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 Redistibution of released drug leading to no-specific accumulation.

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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 HaptensFolate MHC-peptides Glycosides MabsLipoprotein 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 pinocytosis2. Adsorptive,receptor mediated pinocytosis3. 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

Intracellilar 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

Lisosome

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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.

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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Particulates in the size range of 100 nm to 7 μmare prone to be cleared by the MPS, especially by the fixed Kupffer cellsin the liver.In the case of biomacromolecules such as oligonucleotides, proteins,RNA, and DNA,7 the delivery system often needs to transfer the payloadacross the plasma membrane either by fusion or by endocytosis.7,14If taken up by the cells via endocytosis, the macromolecule later mustbe released from the endosome into the cytoplasm to avoid degradationin the lysosomes. In the case of gene delivery, DNA must further relocatefrom the cytoplasm into the nucleus to direct the expression of thegene products.

the delivery of high-molecular-weight hydrophilic moleculesacross biomembranes is one of the most challenging problemsfacing the pharmaceutical community.

If the target is the vascular endothelial cell layer, the delivery system canreach the target site readily via the blood circulation. To reach other tissuessuch as hepatocytes and cancer cells in solid tumors, the carrierneeds to extravasate through the endothelial capillaries and diffuse tothe target site. The endothelial cells that outline the capillaries enforcean upper size limit of about 100 nm if the delivery system is to reachthe extravascular tissues.

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Clearance by the MPS involves twosteps. First, plasma proteins called opsonins adsorb onto the “foreign surface”of a particulate; second, the macrophages recognize the opsonsincoveredparticles and initiate phagocytosis. Particles with hydrophobicsurfaces are recognized immediately as “foreign,” covered by theopsonins, and taken up by macrophages.

Surface hydrophobicity

if a delivery system is to be targeted to other cell types, itsinteraction with the MPS must be minimized. The standard approachis to coat the surface of the system with hydrophilic materials to reduceopsonin 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.

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The surface charge of a drug carrier also plays an important role in itspharmacokinetic behavior. For liposomes, it has been shown that a neutralsurface charge is optimal for a long circulation time.33 Liposomeswith a negative charge tend to be cleared more rapidly from the circulationby the Kupffer cells in the liver.34 Positively charged particulatesrapidly absorb negatively charged plasma proteins in the blood circulationand are recognized as foreign objects by the immune system.35

Charge