TARGETED DRUG DELIVERYDIFFERENT APPROACHES

Presented by:

Muhammed Fahad

TARGETED DELIVERY OF DRUGS

Delivery of drugs to specific part of the body.Significantly reduce overall drug toxicity

while maintaining therapeutic benefits.Improve therapeutic index of drugs. eg. peptide drugsHigh dosing required due to transport factors

including widespread disposition, rapid metabolism and excretion.

Approaches to Drug Targeting

3 different approaches:

1. Physical or Mechanical Approach2. Biological Approach3. Chemical Approach

PHYSICAL OR MECHANICAL APPROACHInvolves formulation of drug using

particulate delivery device physical localization differential release of drug.

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

Also called ‘passive targeting’ exploit natural fate of particles.

Carrier systems may be microspheres, nanoparticles or liposomes.

Crucial factors—size & surface of particles.

Localization of particulate carriersLiver—main site for clearance; hence

majority of drugs concentrate in liver.

Oral microspheres—taken up from GI by

Peyer’s patches.

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.

Egs:Targeting of azidothymidine (AZT) to

macrophages as nanoparticle carriers by iv & oral routes—18 fold increase in reticuloendothelial system.

Liposomal delivery of certain compounds may provide extended retention.

Liposomal delivery of drugs systemically enhances drug concn of antimicrobials.

Infections caused by bacteria, fungi, viruses & protozoa difficult to manage with conventional chemotherapy due to limited permeation of drugs into cells.

Administration of antimicrobial drugs in liposomes solves this.

Drug-loaded liposomes are readily taken up by phagocytic cells help drug delivery directly to site of action.

Used in the treatment of systemic fungal infections such as candidosis.

Targeting to the pulmonary regionLiposomes 50 nm in size—retained for many hrs.iv administered microspheres of certain drugs

tend to localize in lungs—diagnostic purposes.

Extravascular deliveryExtravasation—ability of particles to leave blood

pool.Solid lipid nanoparticles on iv administration

accumulate in the brain.E.g.: anticancer drug camptothecin loaded in

nanoparticles increase avg residence time.

pH sensitive nanoparticle suspension used

for targeting in the eye to prevent early drug

wash out.

intraarticular administration of liposomes of

cortisol—showed increased retention in

joints.

E.g. treatment of knee arthritis with such

carrier drugs required lower dose of drug

than conventional therapy.

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Mucosal Delivery of AntigensMucosal surface—main site for pathogenic

entry.Production of IgA provide immunity for

mucosal surface against many pathogens.Orally administered microspheres are taken up

by Peyer’s patches—used for oral administration.

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

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Size of microspheres also determine the type of immunity offered—systemic or mucosal.

Experiments show that microspheres smaller than 5 μm passed onto systemic circulation; those greater than 5 μm ramained in Peyer’s patch for upto 35 days.

Magnetic Drug TargetingFerrofluids—magnetic fluidsAnticancer drugs bound to ferrofluids are

targeted to tumours by magnetic fields placed outside pateints body.

E.g. Epidoxorubicin

BIOLOGICAL APPROACHInvolves 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 Targetinghigher 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.

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Selective lectin-mediated uptake of therapeutically active glycoproteins by the infected tumour cells.

E.g. lectin conjugated prodrug of doxorubicin showed 160% increase in cytostatic activity.

Neoglycoproteins—alternatives to monoclonal antibodies as carriers.Advantage: high drug loading by chemical

conjugation without loss of activity.

Low Molecular Weight Proteins for Renal Drug TargetingE.g.: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.

Receptor-mediated targeting of cytosine b-D arabinoside, to liver using glycosylated dextran as macromolecular carrier.

Polymeric prodrug of streptomycin coupled via glycine hydrazide, onto derivatized dextran for intracellular infections.

Sugar- and-charge modified albumins provide opportunities for development of effective therapeutic strategies.

Inulin hydrogels as carrier for colonic drug targeting are also used.

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 APPROACHIncorporates targeting consideration into the

drug design process—for design of safe, localized delivery.

Targeting to active biological molecules based on predictable enzymatic activation. CDS is produced by chemical reactns with target drug, covalently coupled with carrier & protective moieties convert to CDS1 CDS2 … CDSn.

Allow sustained release of drugs also.

The concentration of important precursors & intermediates will be significantly higher at the site of action than rest of the body.

Drug Targeting to LungsE.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 BrainBlood-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.

Redox chemical delivery system used to deliver drugs that are impermeable to BBB.

Converting a lipophilic drug to hydrophilic form prevent its efflux from brain.

2 types which do not cross BBB; eg dopamine

which readily cross BBBE.g. dopamine was delivered using the N1-

substituted dihydropyridine-pyridinium salt-type redox system—15 fold increase of dopamine levels in brain.

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.

CONCLUSIONTargeted delivery assist the drug molecule to

reach preferably to the desired site.Reduction in dose and side effects of the drug.Particulate drug carriers get accumulated in the

liver cells due to their smaller size than blood capillaries.

Among particulate drug carriers, liposomes are potential mode of delivery for the treatment of intracellular infections since MPS cells take up liposomes easily.

Microparticles serve as future mode of delivery for oral route especially proteins.

Orally delivered microparticles are taken up by Peyer’s patches cause induction of immune response.

Biological approach is more specific but at the same time the biology is known for variations and mutations.

Highly specific monoclonal antibodies may also show cross-reactivity.

REFERENCETargeted and Controlled drug delivery (Novel carrier

systems), S P Vyas and R K Khar, CBS publishers, page no: 40-67.

Drug Targeting Organ-Specific Strategies Edited by Grietje Molema and Dirk K. F. Meijer, page no:5-20.

Progress in Controlled and Novel drug delivery systems by N K Jain, CBS publishers, page no: 365-369.

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