Journal of Scientific & Industrial Research Vol. 63, March 2004, pp 230-247 Targeted drug delivery (Site specific drug delivery) Archana Pandey 1 , Satyendra Mishra 2 , Alka Tiwari 3 and Krishna Misra 2 * 1 Chemistry Department, C M P Degree College, University of Allahabad, Allahabad 211 002 The conventional drugs used so far are small organic molecules meant to degrade the diseased protein, formed as a result of the interference of pathogens at cellular level. A high concentration of these drugs in the cells is necessary for desired therapeutic effect. This aggravates the problem of toxicity. Ever since the unraveling of human genome, attempts are being made to target the drugs selectively to the affected sites in order to increase their efficiency and simultaneously decrease their side effects. ‘Proteomics’ and ‘genomics’ have emerged as new disciplines. The ‘target identification’ for any ligand (drug) can now be achieved by identification of ‘right gene’, ‘right pathway’ and ‘right target,’ and the ‘right drug’ for ‘right patient’ can be developed. Genomics information decides the target validation, which is, in fact the association between particular target and disease process. Target validation can be achieved either at DNA level using gene knockout strategies and triplex formation, at RNA level using RNA interference (RNAi), at m-RNA level using antisense concept, at ribozyme level or at any other intermediate growth promoter site. Target validation is also possible via DNA- microarrays, stem cells or monoclonal antibodies. Recently, stem cells are being used for target identification and drug development. The application of aptamers, i.e., nucleic acids having well defined 3-D shape is gaining importance in target validation of drugs. The application of the knowledge of ‘Proteomics’, Transproteomics and ‘Genomics’ together with the array approach is likely to decide the future of drug development. Keywords: Targeted validation, Genomics, Proteomics, Aptamers, Ribozymes and DNA, Micro array IPC: Int Cl. 7 : A 61 P 43/00 Introduction Since the very existence of man on this planet earth, his constant struggle with pathogens is continuing in research labs concerning discovery of new drugs. Till the late 1960s, we had many discoveries in chemotherapy. Significant antibiotics and chemically synthesised drugs seemed to have no end. But it was soon realized that these drugs are associated with unacceptable side effects. Not only this the organism against which we once had very effective drugs began to display resistance. As we approached the 21 st century the situation got really grim. To cite just one example – AIDS in which the sufferers become highly susceptible to other infections, the emergence of drug resistance to microbes added a really fearful dimension. Another problem is of toxicity of drugs. Why a large number of organic molecules with the desired activity spectrum cannot be used due to their toxic effects? In any diseased condition, only a relatively small fraction of the total 10 13 cells of human body need intervention with drugs to cure or contain the disease. Unfortunately, most of the drugs in use have no special affinity for the diseased target cells. Ingested drug, therefore, can get equal access to normal function producing toxic side reactions, often unacceptably severe. The problem becomes, especially acute when one deals with intracellular infections in which the drug must get inside the cells for killing microorganism which multiply within the cells such as, those causing malaria or Kala - azar. Since most drugs are transported into the cells through passive diffusion, a relatively high dose of the drug needs to be present in the body fluids in order to attain therapeutically effective concentration of the drug inside the cells, thus aggravating the problem of toxicity. Therefore, targeting of drug selectively to the cells where the pharmacological action is desired is expected to increase their therapeutic efficiency as well as decrease the side effects resulting from the interaction of the drug with normal cells 1 (Figure 1). __________ *Author for correspondence E-mail: Krishnamisra@hotmail.com Phone: (91)-0532-2465462/2467154/2460816/2461377-80 Fax: (91)-0532-2461376/2608469 2 Nucleic Acids Research Laboratory, Chemistry Department University of Allahabad, Allahabad 211 002 3 Pharmacology Department, M L N Medical College, Allahabad, Allahabad 210 002