Presented by: Anvita

M. Pharm (IP)

What is drug targeting

The therapeutic response of a drug depends upon the interaction of drugmolecules with cell on cell membrane related biological events at receptorsites in concentration dependent manner.

Selective and effective localization of the pharmacologically-activemoiety at preidentified target(s) in therapeutic concentration, whilerestricting its access to non-target(s) normal cellular linings, thusminimizing toxic effects and maximizing the therapeutic index.

Target cell

Normal Cell

Normal Cell

Reasons for Drug Targeting

Drug instability

Low absorption

Short half-life

Large volume of distribution

Low specificity

Low therapeutic index

Common Approaches of Targeted Drug

Delivery

Controlling the distribution of drug by incorporating it in a carrier system

Altering the structure of the drug at molecular level

Controlling the input of the drug into bioenvironment to ensure a programmed and desirable biodistribution

Properties of Ideal Targeted Drug Delivery

Nontoxic, biocompatible and physicochemical stable in vivo and invitro.

Restrict drug distribution to target cells or tissue or organ or should have

uniform capillary distribution.

Controllable and predictable rate of drug release.

Minimal drug leakage during transit.

Carrier used must be biodegradable or readily eliminated from the body

without any problem.

Its preparation should be easy or reasonably simple, reproductive and

cost effective.

Important Properties Influencing

Drug Targeting

Drug Concentration, Particulate location and DistributionMolecular Weight, Physiochemical propertiesDrug Carrier Interaction

Carrier Type, Amount of Excipients, Surface Characteristics, size, Density

In Vivo Environment

PH, Polarity, Ionic Strength, Surface Tension, Viscosity, Temperature, Enzyme, Electric Field

Drug Targeting strategies

Passive Targeting

Inverse Targeting

ActiveTargeting

Ligand-mediatedTargetingPhysical

Targeting

DualTargeting

DoubleTargeting

CombinationTargeting

Passive Targeting

It utilizes the natural course of biodistribution of the carrier.

The colloids which are taken up by the reticulo-endothelial system(RES) can be ideal vectors for passive targeting of drugs to RESpredominant compartments.

Passive capture of colloidal carriers by macrophages offerstherapeutic opportunities for the delivery of anti-infective agents.

Inverse Targeting

It is a result of the avoidance of passive uptake of colloidal carriersby the RES.

It can be achieved by suppressing the function of RES by pre-junction of a large amount of blank colloidal carriers ormacromolecules like dextran sulphate.

Other strategies include modification and defined manipulation ofthe size, surface charge, composition, surface rigidity &hydrophilicity characteristics of carriers for desirable biofate.

Active Targeting

It involves the modification or functionalization of the drug carriers so that the contents are delivered exclusively to the site corresponding to which the carrier is architected.

Active targeting can be affected at different levels –1. First order targeting (organ compartmentalization)

2. Second order targeting (cellular targeting)

3. Third order targeting (intercellular organelles targeting)

Active Targeting

First Order Targeting

Second Order

Targeting

Third Order Targeting

Restricted distribution of the drug

carrier system to the capillary bed

of a pre-determined target site,

organ or tissue.

The selective drug delivery to a

specific cell type such as tumor

cells (& not to the normal cells)

Drug delivery specifically to the

intracellular organelles of the target

cells

Strategies for Drug Targeting

Ligand-mediated Targeting

Ligands are carrier surface group(s), which can selectively direct thecarrier to the pre-specified site(s) housing the appropriate receptorunits to serve as ‘homimg device’ to the carrier/drug.

Most of the carrier systems are colloidal in nature & can be specificallyfunctionalized using various biologically-relevant molecular ligandsincluding antibodies, polypeptides, oligosaccharides, viral proteins &fusogenic residues.

The ligands confer recognition & specificity upon drug carrier & endowthem with an ability to approach the respective target selectivity &deliver the drug

Examples of Ligands

Ligands Target Tumor targetFolate Folate receptor Overexpression of folate

receptorTransferrin Transferrin receptor Overexpression of transferrin

receptorGalactosamine Galactosamine receptors

on hepatocytesHepatoma

Physical Targeting

Characteristics of environment changes like pH, temperature, light intensity, electric field, and ionic strength.

This approach was found exceptional for tumor targeting as well as cytosolic delivery of entrapped drug or genetic material.

Physical Targeting

Physical Targeting Formulation System Mechanism for DrugDelivery

Heat Liposome Change in Permeability

MagneticModulation

Magnetically Responsive Microspheres Containing Iron oxide

Magnetic Field can retard fluid Flow of particles.

Ultrasound Polymers Change in Permeability

Electrical Pulse Gels Change in Permeability

Light Photo responsive Hydro gels Containing Azo-Derivatives

Change in Diffusion Channels, Activated by Specific Wavelength

Dual Targeting

In this targeting approach, carrier molecule,itself have their own therapeutic activity andthus increase the therapeutic effect of drug.

A carrier molecule having its own antiviral

activity can be loaded with antiviral drug

and for the synergistic effect of drug

conjugate.

Double Targeting

Spatial Control

Temporal

Control

Double Targeting

Targeting drugs to specific organs, tissues, cells or even sub cellular compartment

Controlling the rate of drug delivery to target site

Combination Targeting

These targeting systems are equipped with carriers, polymers and homing devices of molecular specificity that could provide a direct approach to target site.

Components for Drug

Targeting

Target

• Specific organ or a cell or group of cells, which in chronic or acute condition need treatment.

Carrier

• Special molecules or system essentially required for effective transportation of loaded drug up to the pre selected sites

Carriers

Liposomes

Microspheres

NanoparticlesQuantum Dots

Dendrimers

Nanoerythrocytes

Resealed Erythrocytes

Targeted NanoparticlesPlatform Targeting ligand Drug Stage

PEGylated liposome F(ab ¢ ) 2 fragment of humanantibody GAH

Doxorubicin Phase I

NGPE liposome Transferrin Oxaliplatin Phase I/II

Liposome Single-chain antibody fragment p53 gene Phase I

PEGylated PLGA NP Peptide Docetaxel Phase I

Applications of Resealed Erythrocytes

Diseases Name of Drug(s) Purpose

Liver tumors Bleomycin, Adriamycin, Carboplatin,Gentamycin

Targeting to hepatic carcinoma

Parasitic diseases Pentamidine loaded, IgGcoated erythrocytes, Glutaraldehyde treated erythrocytes

Macrophage containing leshmania, liver targeting of primaquinephosphate, metronidazole

Other Approaches of Drug

Targeting

1. Magnetically modulated drug targeting

2. Monoclonal antibody based targeted drug delivery

3. Prodrug

Magnetically modulated drug targeting

An interesting approach of targeting carrier system has been tomagnetize the carrier so that these particles can be retained at orguided to the target site by the application of an external magneticfield of appropriate strength.

Retention of magnetic carrier at the target site will delayreticuloendothelial clearance, facilitate extravasation & thus prolongthe systemic action of drug.

Magnetic Drug /Carrier Circulation

Major Pathway

Minor Pathway

RES Organs( liver/spleen/ bone

marrow)

N

S

Target Tissues

Principle of Magnetic Drug Targering

ADVANTAGES

Therapeutic responses in target organs at only 1/10th of the free drug dose.

Controlled drug release within target tissues for intervals of 30 min to 30 h, as desired.

Avoidance of acute drug toxicity directed against endothelium & normal parenchymal cells.

Adaptable to any part of the body.

DISADVANTAGES

It is expensive

It needs miniaturized specialized magnet for targeting, advanced techniques for monitoring, & trained personnel to perform procedures.

Magnet must have relatively constant gradients, in order to avoid focal overdosing with toxic drugs.

A large fraction (40 – 60 %) of the magnetite, which is entrapped in the carriers, may be deposited permanently in target tissues.

Magnetic Drug Targeting

Magnetic microspheres

Magnetic nanoparticles

Magnetic liposomes

Magnetic emulsion

Magnetic resealed erythrocytes

Magnetic delivery systems

Monoclonal antibody based targeted

drug delivery

The recognition site for the monoclonal antibody should be located on thesurface of the cell.

The antibodies should have sufficient tumor tissue specificity.

The extent of localization of the antibody at the target site. Biodistribution ofthe drug–antibody conjugate in the body relative to that of the parentantibody.

Stability of the drug–antibody conjugates in blood.

The host toxicity of the conjugate. The conjugate must be biodegradable andnon-immunogenic. Drugs should be released upon interaction between thecarrier molecule and the cell.

Approved Monoclonal Antibodies

Antibody Target Indication

Trastuzumab HER2 Breast Cancer

Bevacizumab VEGF Lung Cancer

Cetuximab EGFR Colorectal carcinoma

Panitumumab EGFR Colorectal carcinoma

Immunoconjugates

The possibility of raising monoclonal antibodies against cell surface markers allowtumor site targeting discretely.

Many cytotoxic drugs have been conjugated with monoclonal antibodies. Theseconjugates have been used to study drug localization in tumors and modulation ofdrug toxicity. They have been found to be useful in the management of varioustypes of carcinomas.

The conjugation of antibodies developed against a specific tumor determinant withanother recognition component provides them dual specificity to target the drug ortoxin intracellularly.

Bispecific antibodies

The approach has been mainly suggested for immunotherapy ofimmunological disorders especially those related to lack of MHC restrictedrecognition by immune effectors cells.

Bispecific antibodies against tumor endothelium & tissue factors (theinitiator of the intrinsic pathway of blood conjugation) have also beenproposed for synergistic effects.

Immunotoxins

These are conjugates of antibody (Mab & Fab) fragments & toxins, in which cell binding moieties of the toxins are replaced with specific binding chain of the antibodies.

Advantages The naturally occurring toxins used have very specific biological pathways in

producing their cytocidal effects.

The cytotoxic activity of the toxin that is conjugated to the antibody does not involve any other secondary agent(s).

Theoretically, immunotoxins should not bind to non-malignant cells, and even if they do bind, the internalization of the agent should not be sufficient to neutralize the therapeutic effect.

Immunotoxins under clinical trials

Immunotoxin Target antigen Target malignancy Stage

LMB-2 CD25 Leukemia Phase II

SSIP Mesothelin Pancreatic cancers Phase I

UCHT1 CD3ε Leukemia Phase II

RFT5-dgA CD25 Melanoma Phase I/II

Prodrugs

Prodrug is an inactive pharmacological moiety developed to optimizepharmacokinetics or site selectivity of a drug.

Since the prodrug has low cytotoxicity prior to its activation, it has very fewchances of its encounter with healthy cells.

In general, selective enzyme expression, hypoxia, & low extracellular pH at tumorsite is utilized for prodrug activation.

ADEPT has been investigated in the treatment of tumors, where an antibody-enzyme conjugate is administered systemically, where it clears from the circulation& localizes to its target by virtue of the antibody binding to its specific biomarkeron the tumor.

Enzymes & prodrugs used for ADEPT

Enzymes Prodrug ReactivityAlkaline Phosphatase Doxorubicin Hydrolysis of Phosphate Group

Etoposideβ lactamase Mitomycin Cleavage of Lactam Ring

Paclitaxel

Schematic representation of ADEPT

Conclusion

Targeted drug delivery essentially implies for selective and effective localization of the pharmacologically-active moiety at preidentified

target(s) in therapeutic concentration,

Various strategies such as active targeting, passive targeting etc. can be applied to achieve efficient drug targeting.

The targeted delivery is of great importance in cancer chemotherapy which always demands for reduction in adverse effect.

.

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