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'Chasing Ehrlich's dream: the quest for magic bullets'

by Sandip K Basu,
National Institute of Immunology

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CDC-NII Malaria Vaccine. Tools of cell biology and genetic engineering are being used for replacing existing vaccines, with safer and more effective versions and are improving the prospects of new vaccines against AIDS, cancer, malaria and other parasitic infections. For instance, Dr Hasnain at NII has made a composite gene by stitching together several gene fragments for proteins exprissed in various stages of malaria parasite's development, and expressed this engineered gene in baculoviruses. Studies at CDC with this artificial protein look highly promising as a new lead towards a candidate vaccine against malaria.

Towards the medicines of tomorrow: targeted drugs. Despite such welcome developments, the fact is that effective treatments against new and re-emerging diseases are proving ever harder to invent. New drugs becoming increasingly difficult to come by, we Sought alternative means so that molecules with desired curative potential that are currently unusable due to toxic side effects can be made therapeutically useful. Let me illustrate our approach towards such medicines of tomorrow.

Advantages of Site specific drug delivery. Why drugs often produce toxic reactions? Current pharmacological practice is based on the central dogma that the .effect of a drug depends on its concentration in the blood or other body fluids. Of about 1013 cells comprising the human body, only a small fraction needs intervention with drugs to cure or curb a specific disease, Having no special affinity for the diseased target cells, most drugs in current use can access normal cells as well. Since most drugs enter cells by passive diffusion, a relativelyhigh dose of the drug needs to be administered to attain therapeutically effective drug concentration inside. the cells, which aggravates the problem of toxicity. Ever since Paul Ehrlich introduced the concept of magic bullets in 1906, a common priority goal of therapeutics has been the designing of vehicles containing exclusive signals for recognizing the target cells, and delivering drugs selectively to these cells.

Targets on cell surface. Two general targets on the surface of mammalian cells are exploitable for such site-specific drug delivery: 1) antigens against which specific, non-cross-reactive antibodies can be developed, and 2)receptor molecules capable of efficient transport of macromolecular ligands. The carrier for targeting a drug to specific cells thus can either be an antibody specific for the target cell, or a ligand for the receptor molecules present only on the target cells (Basu 1990). Ehrlich himself proposed the use of a specific antibody as the carrier of the chemotherapeutic agent.

Disadvantages of Anti body-med iated targeting: The antibody-mediated targeting approachr raised great hopes after fine discovery of hybridorna technology for production of highly specific monoclonal antibodies. However, it has still not been possible to solve many of the problems of this approach.

Receptor-tirtediated transport of LDL. The receptor-mediated approach is of more recent vintage and derives from our work on the role of low-density lipoprotein in atherosclerosis. This work delineated how specific receptor molecules on the surface of rnammalian cells bind macromolecules, leading to their internalisation and processing in specific intracellular compartments. This process is now called receptor-mediated endocytosis and is universally recognised as a major transport mechanism utilised by mammalian cells for a variety of purposes.

LDL receptor work established. We had great fun working out the mysteries of this process during 1975-83 but the story is textbook matter now.

Characteristics of Receptor-mediated endocytosis important for drug delivery. Twenty years ago, thanks to late Professor B.K Bachhawat, I got a job in India. Not having much of a lab to begin with, I had all the time to ponder over how to build a scientific career in India. There was no point working on LDL as my seniors in the LDL receptor adventure, Goldstein and Brown, were already on the verge of a Nobel Prize which came in 1985. Eventually I realized the potential of the process of receptor-mediated endocytosis for the purposes of drug delivery.

Macrophages pivotal cells. I also understood that macrophages in animals mount multipronged defensive responses that protect them against a variety of invading microorganisms and developing cancers. However, in many instances these defensive responses are overwhelmed, circumvented or even misdirected so that these protective cells become the focal points in a large number of diseases - infectious, metabolic or neoplastic, which affect millions of people world wide. Therefore, a generalised targeting regimen specific for macrophages would be extremely useful.

Characteristics of Scavenger receptor system: To target macrophages we needed a receptor restricted to these cells. In the course of my earlier work on lipoprotein metabolism we discovered a receptor system present primarily on cells of marophage lineage. It appears that God created scavenger receptors for my career development in India.

Pathway of receptor-mediated drug delivery. We went about exploiting the principles of receptor-mediated endocytosis for selective drug delivery. We chemically attached the desired molecule to maleylated albumin or polyguanylic acid so that the conjugate is specifically recognized by the scavenger receptors present primarily on macrophages.

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