Drug Targeting I PDF

Targeted drug delivery-Recall Approach in which the drug is concentrated selectively at a particular tissue and is able to deliver cytotoxic drugs safely and effectively by making use of various carriers such as lipidic nanocarriers,metallic nanoparticles, liposomes, proteins, and antibodies. ...

Targeted drug delivery-Recall Approach in which the drug is concentrated selectively at a particular tissue and is able to deliver cytotoxic drugs safely and effectively by making use of various carriers such as lipidic nanocarriers,metallic nanoparticles, liposomes, proteins, and antibodies.  Drug Targeting-Definitions Drug Targeting, i.e.  Predominant drug accumulation in the target zone independently on the method and route of drug administration.  Ability of the drug to accumulate in the target organ or tissue selectively and quantitatively, independent of the site and methods of its administration  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 systems essentially required for effective transportation of loaded drug up to the pre selected sites.  Targeted nanoparticles Platform Targeting Drug (Carrier) ligand PEGlylated F(ab′) 2 Doxorubicin liposome fragment of human antibody GAH NGPE Transferrin Oxaliplatin liposome Liposome Single-chain P53 gene antibody fragment PEGylated Peptide Docetaxel PLGA NP GAH = Recombinant monoclonal antibody NGPE = N-glutaryl phosphatidylethanolamine PLGA = Poly lactic-co-glycolic acid P53 gene = p53 tumor suppressor protein  Carriers Resealed erythrocytes have emerged as one of the most effective biocarriers studied recently because of their easy preparation and drug loading, biodegradability, and possess long circulation half-life.  Applications of Resealed Erythrocytes Disease Name of Drug(s) Purpose Liver Tumors Bleomycin, Targeting to hepatic Adriamycin, Carcinoma Carboplatin, Gentamycin Parasitic diseases Pentamidine Macrophage containg loaded leishmania lgG coated erythrocytes, Glutaradehyde treated erythrocytes  Important Properties Influencing Drug Targeting Drug Concentration, Particulate location and Distribution, Molecular Weight, Physicochemical properties, Drug Carrier Interaction Carrier Type, Amount of Excipients, Surface Characterisations, Size, Density In vivo Environment pH, Polarity, Ionic Strength, Surface Tension, Viscosity, Temperature, Enzyme  Rationale for Drug Targeting 1/3 1. Drug instability 2. Low absorption 3. Short half-life 4. Low therapeutic index 5. Large volume of distribution of pharmaceuticals throughout the body. Activity against certain diseases or disease sites is not based on their ability to accumulate selectively in the pathological organ, tissue or cell. Usually, the pharmaceutical agent is rather evenly distributed within the body. 6. Low or lack of drug specific affinity toward a pathological site.  Rationale for Drug Targeting 2/3 7. Moreover, to reach the site of action, the drug has to cross many biological barriers, such as other organs, cells and intracellular compartments, where it can be inactivated or express undesirable influence on organs and tissues that are not involved in the pathological process.  As a result, to achieve a required therapeutic concentration of a drug in a certain body compartment, it has to administer the drug in large quantities.  Rationale for Drug Targeting 3/3 8. The necessity of a large total dose of a drug to achieve high local concentration. 9. Consequences: Non-specific toxicity and other adverse side-effects due to high drug doses.  Under these circumstances, cytotoxic and/or antigenic drugs can become the cause of many negative side effects.  Key solution of above problems is: Drug targeting  Drug Targeting  Drug targeting can bring a solution to all previous problems.  Recall: As mentioned, drug targeting: the ability of the drug to accumulate in the target organ or tissue selectively and quantitatively, independent of the site and methods of its administration.  Ideally, under such conditions, the local concentration of the drug at the disease site(s) should be high, while its concentration in other non-target organs and tissues should be below certain minimal level to prevent any negative side-reactions.  Drug Targeting Concept  The concept of drug targeting, is considered as a hypothetical ‘magic bullet’ as an entity consisting of two actions — the first one should recognize and bind the target, while the second one should provide a therapeutic action in this target.  Currently, the concept of magic bullet includes a coordinated behavior of three components: (a) Drug (b) Targeting moiety (c) Pharmaceutical carrier used to multiply the number of drug molecules per single targeting moiety.  Properties of Ideal Targeted Drug Deliver-Recall  Nontoxic, biocompatible and physicochemical stable in vivo and in vitro  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  Simple or easy to be prepared, reproductive and cost effective  Advantages of Drug Targeting 1/2 1. Drug administration protocols may be simplified 2. Drug quantity required to achieve a therapeutic effect may be greatly reduced as well as the cost of therapy 3. Drug concentration in the required sites can be sharply increased without negative effects on non-target compartments. The same is, for the great extent, true for the use of many diagnostic agents.  Advantages of Drug Targeting 2/2 4. Overcome biological & Pharmaceutical barriers which separate the site of administration from the site of action of drug 5. Enhance efficacy of drug, e.g. the administration of the methoxy methyl ester of Hetacillin (derivative of ampicillin) gave more distribution of ampicillin in the tissues than occurs on administration of ampicillin itself. 6. Prodrugs are decrease toxic side effects by restricting the action of a drug to a spicific target site in the body Hetacillin Ampicillin  Strategy for Drug Targeting  The concept of drug targeting allow the development of drugs which are potent and non-toxic and targeted drug to its particular site of action through:  Use cell-specific enzymes and ligands  Development of prodrug-based technologies  Use of smart polymeric systems  Targeted Drug Delivery in vivo  Recall- Pharmaceutical carriers have been successfully developed & used for targeted drug delivery in vivo include:  Soluble polymers  Microcapsules  Microparticles  Cells  Ghost Cells  Liposomes  Micelles  Targeting of Pharmaceuticals within the Cardiovascular System  Possible targets within the cardiovascular system may include:  blood elements -Tumors are usually also accessed from the blood flow.  damaged areas of vascular wall  vascular bed itself  thrombi  atherosclerotic plaques  Infarcts  damaged cardiomyocytes  Applications of Drug Targeting 1/3 1. Delivery of toxic drugs to tumors  highly toxic drugs that are too dangerous to deliver in a systemic manner,  e.g. potent radionuclides, cellular toxins ƒ  allow smaller doses to be used 2. Delivery of DNA vectors to target cell type for genetic correctionsƒ  Applications of Drug Targeting 2/3 3. Targeting to vasculature  cancer treatment  target to neovasculature forming around tumors  pulmonary, cardiovascular, and inflammatory diseases 4. Targeting to pathogen-infected cells infected cells undergo changes in cell-surface molecule expression 5. Crossing blood-brain barrier Applications of Drug Targeting 3/3  TYPES OF DRUG TARGETS  A drug will not work unless it is bound  Common Drug Targets: ion channels, carrier molecules, enzymes, cell receptors, DNA Use carrier Blocks protein transporter TYPES OF DRUG TARGETS