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Targeted Drug Delivery systems

General principles
controlling drug distribution within the body so that most of the dose
selectively interacts with the target tissue at a cellular or subcellular level.
Directing the drug specifically to where its activity is required, at the
optimum concentration, for the desired time.
1.Enhance the activity of drug
2.Enhance specificity
3.Reduce toxicity
4.Improve therapeutic profile
Requirements for effective drug targeting
No non specific interactions with biological components/tissues/organs
Non toxic/therapeutically acceptable
Specifically target the drug to the physiological target
Retain the drug during transit to the site
Able toacccessthe target site
Retained at the site
Released from its delivery system
Schematic representation

Targeting molecule

Drug carrier-targeting device

Consideration of the drug being delivered
Drugs with high total clearance
Not drugs that have the same site of efficacy and toxicity
Various sites and levels of the drug target
Specific organs: brain, lung
Tissues: tumours, sites of inflammation
Invading organisms: bacteria, viruses, parasites
Specific cells:trastuzumabto HER2+cancer cells
Cytosolic targets: proteins or receptors within the cytoplasm
Subcellular compartments: nucleus, mitochondria, DNA
How to reach a desired target? DDS
1. Chemically modify the drug using theprodrugapproach
2. Use a carrier system
Classes of carrier systems

Soluble Particulate

• Natural & synthetic water • Liposomes,

soluble polymers and microspheres,
antibodies nanoparticles
• The drug is conjugated to • The drug is surface
the carrier bound or entrapped
Physiological and biological barriers to drug
1. Elimination of the drug carrier

2. Escape from the systemic circulation

1. Eliminationof the drugcarrier
a. removal of particulates by mononuclear phagocyte system (MPS)

b. Recognition of the carriers: opsonisation (ex:fibronectin, antibodies,

complement proteins)

Important factors in opsonisation and clearance:

 Particle size (< 100 nm are preferred, MPS: 1-2m)

 Surface charge: neutral

 Surfacehydrophilicity: PEG-coated
2. Escapefrom the systemiccirculation
A long circulation profile does not ensure effective
The DDS needs to leave the vasculature before it
reach its target.
3 types of capillaries:
Continues: in the brain, lung and muscle
Fenestrated: in the kidney and GIT
Sinusoidal: in the spleen, liver
Most parts of body: continuous passive
processes, decrease with increasing molecular
Escaping  to fenestrated or sinusoidal: liver,
spleen, bone marrow, tumour or inflammation
Types of drug targeting

Passive Active
Actively targeted to the site using
Naturally accumulate at the target
a target-specific recognizing

1. By MPS (mononuclear phagocytes

1.Folatereceptors: overexpressed
system): treatment of macrophage
in tumour tissue
intracellular microbial, viral or
2. Antibodies-antigen targeting.
bacterial disease,lysosomalenzyme
Antigen: tumour tissue, bacteria,
2. Local physiological
3.Lectin-glycoprotein targeting.
condition:inceasingpH, enzymes
Glycoprotein on the surface of
(alkaline phosphatase and plasmin at
tumour cells
tumour sites)
4. Physical targeting:
3. EPR effect: in tumour
Cellular uptake and intracellular routing of the
1. Diffusion across membranes
2. Endocytosis
Receptor-mediated endocytosis
Cytoplasmic delivery
Most drugs exert their action in cytoplasm where their target enzymes are
located drug must escape theendosomalvesicles.

Target in the cytosol:

1. Nuclear targeting: gene therapy (target: DNA)

2. Mitochondrial targeting synthesise ATP and help control cell

metabolism, intracellularCalevels and apoptosis. Damage of

mitochondria:svhizophrenia,Alzheimers, Parkinson disease,epilepsi,

Drug release at the target site
The release mechanism depends on the carrier system and needs to be at
a rate that ensures drug accumulation at the target sites.
Drugs must be remained associated with the carriers during transit in the
Early release:
Low concentration at the target sites
Non specific distribution
Rate of elimination of free drug released in the circulation should be rapid:
To maintain a hightarget:nontarget drug concentration ratio
Perrie, Y. andRades, T., 2010, Pharmaceutics-Drug Delivery and Targeting,

Relevant papers