DIFFERENT APPROACHES

Presented by:
Muhammed Fahad

 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 drugs  High dosing required due to transport factors including widespread disposition, rapid metabolism and excretion.

2

Approaches to Drug Targeting  3 different approaches: 1 . B i o l o g i c a l A p p ro a c h 3 . P h y s i c a l o r Me c h a n i c a l A p p ro a c h 2 . C h e m i c a l A p p ro a c h 3 .

Site specificity is due to higher drug concns at the site.PHYSICAL OR MECHANICAL APPROACH  Involves formulation of drug using particulate delivery     device  physical localization  differential release of drug. 4 . Also called ‘passive targeting’  exploit natural fate of particles. Crucial factors—size & surface of particles. nanoparticles or liposomes. Carrier systems may be microspheres.

5 . hence majority of drugs concentrate in liver.Localization of particulate carriers  Liver—main site for clearance.  Oral microspheres—taken up from GI by Peyer’s patches.

Targeting to the mononuclear phagocytic system (MPS)  iv administered liposomes—localize within MPS. 6 .  Functions of MPS:  Clearance of large variety of harmful substances from plasma.  Synthesis and secretion of various effector molecules.  Catabolism of macromolecules.  MPS consists of connective tissues of mesenchymal origin.  Participation in immune response.

 Liposomal delivery of drugs systemically enhances drug concn of antimicrobials.  Liposomal delivery of certain compounds may provide extended retention. Egs:  Targeting of azidothymidine (AZT) to macrophages as nanoparticle carriers by iv & oral routes—18 fold increase in reticuloendothelial system. 7 .

 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. Infections caused by bacteria. viruses & protozoa  difficult to manage with conventional chemotherapy due to limited permeation of drugs into cells.  Used in the treatment of systemic fungal infections such as candidosis. 8 . fungi.

: anticancer drug camptothecin loaded in nanoparticles  increase avg residence time.g.  iv administered microspheres of certain drugs tend to localize in lungs—diagnostic purposes. 9 . Extravascular delivery  Extravasation—ability of particles to leave blood pool.  E.  Solid lipid nanoparticles on iv administration accumulate in the brain.Targeting to the pulmonary region  Liposomes 50 nm in size—retained for many hrs.

treatment of knee arthritis with such carrier drugs required lower dose of drug than conventional therapy. pH sensitive nanoparticle suspension used for targeting in the eye to prevent early drug wash out.  E.g. 10 .  intraarticular administration of liposomes of cortisol—showed increased retention in joints.

Mucosal Delivery of Antigens  Mucosal surface—main site for pathogenic entry.  Cause induction of IgA Ab in gut mucosa as well as other mucosal surfaces like respiratory & genitourinary tracts. microspheres of Staphylococcal enterotoxin B toxoid 11 .  E.  Production of IgA provide immunity for mucosal surface against many pathogens.  Microspheres protect vaccine from acid pH of stomach.g.  Orally administered microspheres are taken up by Peyer’s patches—used for oral administration.

Epidoxorubicin 12 .  Experiments show that microspheres smaller than 5 μm passed onto systemic circulation.  E. those greater than 5 μm ramained in Peyer’s patch for upto 35 days. Size of microspheres also determine the type of immunity offered—systemic or mucosal. Magnetic Drug Targeting  Ferrofluids—magnetic fluids  Anticancer drugs bound to ferrofluids are targeted to tumours by magnetic fields placed outside pateints body.g.

Glycoconjugates functioning as specific ligands for receptors on specific cells that recognize particular sugar residues. 3. Hormones functioning as specific ligands for receptors on specific targets.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. Endogenous carbohydrate-binding proteins (lectins).  4 approaches: Antibodies directed against specific cell surface antigens. 2. 13 . 1. and 4.

 E. 14 .  Done by coupling antigen with a ligand of strong binding affinity for molecules of MHC.g. coupling of viral antigens to monoclonal antibodies against a mouse Class II MHC.  Targeting without use of carriers.000 fold increase in efficiency achieved.  Advantage:  Preparation of safer vaccines.Antibodies for Antigen Targeting  higher immune response—when antigens are directed to antigen presenting cells (APCs) & lymphocytes.  Targeted antigen required only in 1st injection.  Upto 1.

15 .  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.Lectins as Targeting Agents  Endogenous carbohydrate-binding proteins of tumours are known as lectins.

g. 16 .  E.  Neoglycoproteins—alternatives to monoclonal antibodies as carriers. lectin conjugated prodrug of doxorubicin showed 160% increase in cytostatic activity. Selective lectin-mediated uptake of therapeutically active glycoproteins by the infected tumour cells.  Advantage: high drug loading by chemical conjugation without loss of activity.

17 .Low Molecular Weight Proteins for Renal Drug Targeting  E.  Captopril conjugated with lysozymes—6 times more retention in kidneys observed.:  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.g.  Polysaccharides such as dextran also show high potential as oral drug carriers.

 Sugar.and-charge modified albumins provide opportunities for development of effective therapeutic strategies. Receptor-mediated targeting of cytosine b-D arabinoside. to liver using glycosylated dextran as macromolecular carrier. onto derivatized dextran for intracellular infections. 18 .  Inulin hydrogels as carrier for colonic drug targeting are also used.  Polymeric prodrug of streptomycin coupled via glycine hydrazide.

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. 19 .

localized delivery. 20 . CDS is produced by chemical reactns with target drug.  Targeting to active biological molecules based on predictable enzymatic activation.  Allow sustained release of drugs also.CHEMICAL APPROACH  Incorporates targeting consideration into the drug design process—for design of safe.  covalently coupled with carrier & protective moieties  convert to CDS1 CDS2 … CDSn.

The concentration of important precursors & intermediates will be significantly higher at the site of action than rest of the body. 21 .

ester derivatives of chlorambucil and cromolyn  hydrolyze in lungs rapidly into active parent drugs  enhance delivery and retention time to lung tissue. 22 .  BBB is impermeable to hydrophilic substances  prevent loss of neurotransmitters to the plasma after synthesis in brain  hence chemical methods are used. Drug Targeting to Brain  Blood-brain barrier (BBB)  obstruct free flow of blood b/w brain and rest of the body.g.Drug Targeting to Lungs  E.

 Redox chemical delivery system  used to deliver drugs that are impermeable to BBB. eg dopamine  which readily cross BBB  E.  2 types  which do not cross BBB.g. dopamine was delivered using the N1-substituted dihydropyridine-pyridinium salt-type redox system—15 fold increase of dopamine levels in brain.  Converting a lipophilic drug to hydrophilic form  prevent its efflux from brain. 23 .

g. In rats showed rapid uptake and enhanced halflife of estradiol as compared to free estradiol.Osteotropic Drug Delivery  E. 24 . bisphosphonic (BP) prodrug for 17 β-estradiol (E2)  estrogen replacement therapy in patients of post menopausal oesteoporosis.

CONCLUSION  Targeted delivery assist the drug molecule to reach preferably to the desired site. 25 .  Microparticles serve as future mode of delivery for oral route especially proteins.  Particulate drug carriers get accumulated in the liver cells due to their smaller size than blood capillaries. liposomes are potential mode of delivery for the treatment of intracellular infections since MPS cells take up liposomes easily.  Among particulate drug carriers.  Reduction in dose and side effects of the drug.

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

F.REFERENCE  Targeted and Controlled drug delivery (Novel carrier systems). page no:5-20. CBS publishers. Meijer. page no: 40-67.  Drug Targeting Organ-Specific Strategies Edited by Grietje Molema and Dirk K. S P Vyas and R K Khar. CBS publishers. page no: 365369.  Progress in Controlled and Novel drug delivery systems by N K Jain. 27 .

28 .