Basics To Targeted Drug Delivery

Prepared By : Mayur Pandya 14mph114 3rd Sem

Guided by : Dr. Tejal Mehta HOD Pharmaceutics

Introduction

A special form of drug delivery system where the pharmacologically active agent or medicament is selectively targeted or delivered only to its site of action or absorption and not to the non-target organs or tissues or cells.

Targeted drug delivery implies for selective and effective

localization of pharmacologically active moiety at pre identified (preselected) target in therapeutic concentration, while restricting its access to non-target normal cellular linings, thus minimizing toxic effects and maximizing therapeutic index.

ADVANTAGES OF DRUG TARGETING

Drug administration protocols may be simplified

Drug quantity may be greatly reduced as well as the cost of therapy

Drug concentration in the required sites can be sharply increased without negative effects on non-target compartments.

DISADVANTAGES

Rapid clearance of targeted systems.

Immune reactions against intravenous administered carrier systems.

Problems of Insufficient localization of targeted systems into tumour cells.

Diffusion and redistribution of released drugs.

Target tissue heterogeneity.

Down Regulation and Sloughing Of Surface Epitodes.

IDEAL CHARACTERISTICS

Targeted drug delivery system should be- biochemically inert (non-toxic), non-immunogenic.

Both physically and chemically stable in vivo and in vitro.

Restrict drug distribution to target cells or tissues or organs and should have uniform capillary distribution.

Controllable and predictable rate of drug release.

Drug release should not affect the drug action

Therapeutic amount of drug release Minimal drug leakage during transit.

Carriers used must be bio-degradable or readily eliminated from the body without any problem.

The preparation of the delivery system should be easy or reasonably simple,reproductive and cost effective.

CARRIERS

Most important entity required for successful transportation of the loaded drug.

Drug vectors which, retain and transport drug; deliver it within or in the vicinity of target.

Do so through an inherent characteristic or acquired through structural modification.

PROPERTIES OF AN IDEAL DRUG CARRIER

It must be able to cross anatomical barriers and in case of tumour chemotherapy tumour vasculature.

It must be recognized specifically and selectively by the target cells and must maintain the specificity of the surface ligands.

The linkage of the drug and the directing unit (ligand) should be stable in plasma, interstitial and other biofluids.

Carrier should be non-toxic, non-immunogenic and biodegradable particulate or macromolecule

After recognition and internalization, the carrier system

should release the drug moiety inside the target organs, tissues or cells.

TYPES OF CARRIERS

Based on the nature of their origin

Endogenous - LDL , HDL Chylomicrons, Serum albumin, Erythrocytes.

Exogenous - Microparticulates, Soluble polymeric and Biodegradable polymeric drug carriers.

Pharmaceutical Carriers Polymers

Microcapsules

Microparticles

Lipoproteins

Liposomes

Micelles

Targeting Moieties

Antibodies

Lectins and other proteins

Lipoproteins

Hormones

Charged molecules

Polysaccharides

Low-molecular-weight ligands

CARRIER SYSTEMS USED FOR TARGETED DRUG DELIVERY

Colloidal carriers

Cellular carriers

Supramolecular delivery systems

Polymer based systems

Macromolecular carriers

Colloidal carriers

Vesicular systems- Liposomes, Niosomes, Pharmacosomes, Virosomes, Immunoliposomes

Microparticulate systems- Microparticles, Nanoparticles, Magnetic microspheres, Albumin microspheres, Nanocapsules.

Cellular carriers

Erythrocytes, Serum albumin, Antibodies, Platelets, Leucocytes.

Supramolecular delivery systems

Micelles ( Reverse, mixed, polymeric) liquid crystals, lipoproteins (chylomicrons, VLDL,LDL )

Polymer based systems

Signal sensitive, Muco-adhesive, Biodegradable, Bioerodible, Soluble synthetic polymeric carriers.

Macromolecular carriers

Proteins, glycoproteins, Neo glycoproteins and artificial viral envelopes (AVE).

Glycosylated water soluble polymers (poly-L-lysine).

Mabs, Immunological fragments, antibody enzyme complex and bispecific Abs.

Toxins, immunotoxin .

Lectins and polysaccharides.

LEVELS OF DRUG TARGETING

1. Passive targeting

2. Inverse targeting

3. Active targeting

(a) Ligand mediated targeting

(b) Physical targeting

4. Dual targeting

5. Double targeting

6. Combination targeting

1. Passive targeting Systems that target the systemic circulation.

Devices include- drug bearing bilayer vesicular systems as well as cellular carriers of micron or submicron size range.

2 . Inverse targeting

Based on attempts to circumvent and avoid passive uptake of colloidal carriers by RES, leading to reversion of bio distribution trend of the carrier.

Strategy The function of RES is suppressed by a pre-injection of colloidal carriers or macromolecules like dextran sulphate leading to RES blockade and resulting in impairment of host defense system.

Alternative strategies include: modification of the size, surface charge,composition, surface rigidity & hydrophilicity of carriers for desirable biofate.

3. Active targeting

The facilitation of the binding of the drug carrier to target cells by the use of ligands to increase receptor mediated localization of the drug and target specific delivery of drug is referred to as active targeting.

Subtypes Of Active Targeting

First order targeting(organ compartmentalization).

Second order targeting (cellular targeting).

Third order targeting (intracellular targeting).

First order targeting

Restricted distribution of the drug carrier system to the capillary bed of the predetermined target site, organ or tissue.

Compartmental targeting in lymphatics, peritoneal cavity, plural cavity, cerebral ventricles, lungs, joints, eyes, etc.

Second order targeting

The selective delivery of drugs to a specific cell type such as tumour cells (and not to the normal cells) is referred to as second order targeting.

Third order targeting Drug delivery specifically to the intracellular site of

target cells.

e.g., receptor based ligand-mediated entry of a drug complex into a cell by endocytosis,lysosomal degradation of carrier followed by release of drug intracellularly or gene delivery to nucleolus.

Ligand mediated targeting

Achieved using specific mechanisms such as receptor dependent uptake of natural LDL particles and synthetic lipid microemulsions of partially reconstituted LDL particles coated with the apoproteins.

Physical targeting (Triggered Release)

The drug delivery programmed and monitored at the external level (ex vivo) with the help of physical means.

Temperature sensitive liposomes.

4 . Dual targeting

Drug targeting using carrier molecules, having intrinsic antiviral effect thus synergies the antiviral effect of the loaded active drug.

Based on this approach, drug conjugates can be prepared with fortified activity profile against the viral replication.

Advantage

The virus replication process can be attacked at multiple points, excluding the possibilities of resistant viral strain development.

5 . Double targeting

In order to achieve a double targeting effect, site specificity of the drug, by virtue of targeting moiety, a high specificity module (mainly a photosensitizer) is linked to antibodies.

6 . Combination targeting

Combination Targeting for site specific delivery of Proteins and

Peptides.

These targeting systems are equipped with Carriers, Polymers,

and Homing Devices of molecular specificity that could provide a

direct approach to target site.

Approaches to Drug Targeting1. Physical or Mechanical Approach.

2. Biological Approach.

3. Chemical Approach.

PHYSICAL OR MECHANICAL APPROACH

Involves formulation of drug using particulate delivery device physical localization differential release of drug.

Site specificity is due to higher drug concentrations at the site.

E.g. microspheres, nanoparticles or liposomes.

Targeting to the mononuclear phagocytic system (MPS)

IV administered liposomes—localize within MPS. MPS consists of connective tissues of mesenchymal

origin.

Functions of MPS› Clearance of large variety of harmful substances from

plasma.› Catabolism of macromolecules.› Participation in immune response.› Synthesis and secretion of various effector molecules.

EXAMPLES:

Targeting of azidothymidine (AZT) to macrophages as nanoparticle carriers by iv & oral routes.

Liposomal delivery of certain compounds may provide extended retention.

Liposomal delivery of drugs systemically enhances drug concentration of antimicrobials.

Targeting to the Pulmonary Region

• Liposomes 50 nm in size—retained for many hrs.• iv administered microspheres of certain drugs tend to localize in lungs—diagnostic purposes.

Extravascular Delivery

• Solid lipid nanoparticles on iv administration accumulate in the brain.• E.g.: anticancer drug camptothecin loaded in nanoparticles increase avg residence time.

Mucosal Delivery of Antigens

Mucosal surface—main site for pathogenic entry. Production of IgA provide immunity for mucosal

surface against many pathogens. Microspheres protect vaccine from acid pH of stomach. Cause induction of IgA Ab in gut mucosa as well as

other mucosal surfaces like respiratory & genitourinary tracts.

E.g. microspheres of Staphylococcal enterotoxin B toxoid

BIOLOGICAL APPROACH

Involves delivery of the drug using carrier system with targeting moiety either in-built (by virtue of the structure of the carrier) or is chemically coupled.

4 approaches

1. Antibodies directed against specific cell surface antigens,

2. Endogenous carbohydrate-binding proteins (lectins),

3. Glycoconjugates functioning as specific ligands for receptors on specific cells that recognize particular sugar residues, and

4. Hormones functioning as specific ligands for receptors on specific targets.

Antibodies for Antigen Targeting Higher immune response—when antigens are directed to antigen presenting cells (APCs) & lymphocytes.

Done by coupling antigen with a ligand of strong binding affinity for molecules of MHC.

E.g. coupling of viral antigens to monoclonal antibodies against a mouse Class II MHC.

Advantage› Preparation of safer vaccines.› Targeting without use of carriers.› Targeted antigen required only in 1st injection.› Upto 1,000 fold increase in efficiency achieved.

Lectins as Targeting Agents

Endogenous carbohydrate-binding proteins of tumours are known as lectins.

Glycoproteins or neoglycoproteins act as carriers drug incorporated in glycoproteins carbohydrate on glycoprotein cause its uptake by lectin drug released intracellularly during proteolysis of carrier.

Low Molecular Weight Proteins for Renal Drug Targeting

EXAMPLE

Targeting of naproxen using lysozyme as carrier since it is taken up & catabolized in proximal tubules of kidney—Showed 70 fold increase in retention in kidneys compared to free naproxen.

Captopril conjugated with lysozymes—6 times more retention in kidneys observed.

Polysaccharides such as dextran also show high potential as oral drug carriers.

Hormones Functioning as Specific Ligands for Receptors on the Specific Targets

Insulin used as enzyme carrier for correcting enzyme deficiency disease in fibroblasts from patients with cholesterol storage disease.

CHEMICAL APPROACH

Incorporates targeting consideration into the drug design process—for design of safe, localized delivery.

Targeting to active biological molecules based on predictable enzymatic activation.

Allow sustained release of drugs also.

Drug Targeting to Lungs

• E.g. ester derivatives of chlorambucil and cromolyn hydrolyze in lungs rapidly into active parent drugs enhance delivery and retention time to lung tissue.

Drug Targeting to Brain

• Blood-brain barrier (BBB) obstruct free flow of blood b/w brain and rest of the body.• BBB is impermeable to hydrophilic substances prevent loss of neurotransmitters to the plasma after synthesis in brain hence chemical methods are used.

Osteotropic Drug Delivery

E.g. bisphosphonic (BP) prodrug for 17 β-estradiol (E2) estrogen replacement therapy in patients of post menopausal oesteoporosis.

In rats showed rapid uptake and enhanced halflife of estradiol as compared to free estradiol.

FUTURE PERSPECTIVES In the Future, targeted drug delivery systems may also prove

particularly valuable to enable the use of a drug seems to be ineffective or toxic, if delivered systemically

E.g. Neural growth factor which need to cross BBB or Vaccines which need to taken up by antigen presenting cells

At the Current pace of Gene Cloning and Recombinant-Protein Production within biopharmaceutical industry, many more site specific drug delivery products will be clinically investigated and implemented in near future.

REFERENCES

Targeted and Controlled drug delivery (Novel carrier systems), S P Vyas and R K Khar, CBS publishers, page no: 38-61.

Progress in Controlled and Novel drug delivery systems by N K Jain, CBS publishers, page no: 362-366.

Drug Targeting Organ-Specific Strategies Edited by Grietje Molema and Dirk K. F. Meijer, page no:1-16.

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