Strategies for targeting and release of active anti-cancer and anti-microbial drugs from lipophilic prodrugs and from microparticles

• Autorzy: Yatvin M. B. , Meredith M.J. , Jangi M.S. , Shenoy M.A.
• Języki publikacji: EN

Abstrakty

EN

Many anti-cancer and antiviral drugs currently used are either unable, or inefficient in their ability to pass through the blood brain-barrier and to enter and maintain therapeutic drug levels in brain. The low bioavailability of these drugs is a limiting factor in their use. In order to overcome these limitations, we ester-linked various anti-cancer and antiviral drugs to ceramide and phosphatidylcholine and created prodrugs possessing therapeutic attributes lacking in the parent compounds. This resulted in greater cellular uptake and prolonged retention of these prodrugs in vitro. Likewise, prodrug concentration was greater and retention time longer than the parent drug in the brain, testes and thymus of mice. Another major goal in drug development is discovering compounds that have efficacy against a specific microorganism or virus without significant side effects. For example, many potentially good drugs cannot be used because they are either toxic to uninfected cells or they cannot be restricted to a certain part of the body. If a drug could remain inert unless and until it is inside an infected cell, many of the common problems associated with drug treatments would be solved. In an attempt to address this problem we are developing a method by which a drug will be released only in cells that are infected with a particular microorganism or virus. The methodology makes use of the fact that microparticles are ingested by macrophages. Cell-specific treatment can be achieved by combining a drug with a microparticle using microorganism-specific enzyme substrates. Thus, release of active drug will occur only in the presence of enzymes specific to the target virus or microorganism. In the uninfected macrophage drug remains bound to the microparticle and is inactive. In the infected cell active drug is released by enzymatic hydrolysis. Potential applications for this technology include all diseases in which pathogens are resident in macrophages and other phagocytic cells.

Słowa kluczowe

EN

enzymatic hydrolysis; antiviral drug; drug level; anticancer drug; brain; lipophilic prodrug; blood-brain barrier; antimicrobial drug; phosphatidylcholine

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2000
• Tom: 05
• Numer: 1
• Opis fizyczny: p.119-132,fig.

Twórcy

autor

Yatvin M. B.

autor

Meredith M.J.

autor

Jangi M.S.

autor

Shenoy M.A.

Bibliografia

• 1. Wirtz, K.W. Transfer of phospholipids between membranes Biochim. Biophys. Acta. 344 (1974) 95-117.
• 2. Hansch, C., Steward, A. R., Anderson, S. M. and Bentley, D. The parabolic dependence of drug action upon lipophilic character as revealed by a study of hypnotics J. Med. Chem 11 (1968) 1-11.
• 3. Schrager, L. K., and D’Souza, MP. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent anti-retroviral combination therapy. JAMA 280 (1998) 67-71.
• 4. Rappaport, S. I., Ohno, K., and Pettigrew, K. D. Drug entry into the brain. Brain Res. 172 (1979) 354-359.
• 5. Rail, D. P. and Zubrod, C. G. Mechanism of drug absorption and excretion. Passage of drugs in and out of central nervous system. Ann. Rev. Pharmacol. 2 (1962) 109-128.
• 6. Pantaleo, G., Grazioci, C., Demarest, J. F., Butini, L., Montroni, M., Fox, C. H., Orenstein, J. M., Kotler, D. P. and Fauci, A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature (London) 362 (1993) 355-358.
• 7. Driscoll, J. S., Siddiqui, M. A., Ford, H., Kelley, J. A., Roth, J. S., Mitsuya, H., Tanaka, M. and Marquez, V. E. Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 3. 6-Amino prodrugs of 2'-beta-fluoro-2',3'-dideoxyinosine. J. Med, Chem. 39 (1996) 1619-1625.
• 8. Klecker, R. W., Collins, J. M., Yarchoan, R., Thomas, R., Jenkins, J. F., Broder, S. and Myers C. E. Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin. Pharmacol. Ther. 41 (1987) 407-412.
• 9. Richman, D. D. Antiviral therapy of HIV infection. Ann. Rev. Med. 42 (1991) 69-90.
• 10. Sandberg, J. A. and Slikker, W. Developmental pharmacology and toxicology of anti-HIV therapeutic agents: dideoxynucleosides. FASEB J. 9. (1995) 1157-1163.
• 11. Yarchoan, R. R., Klecker, W., Weinhold, K. J., Markham, P. D., Lyerly, H. K., Durack, D. T., Gelman, E., Nusinhoff-Lehrman, S., Blum, R. M., Barry, R.. W., Shearer, G. M., Fischl, M. A., Mitsuya, H., Gallo, R. C., Collins, J. M., Bolognesi, D. P., Meyers, C. E. and Broder S. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet, 1 (1986) 575-580.
• 12. Hostetler K. Y., Kini GD, Beadle J. R., Aldern K. A., Gardner M. F., Border, R., Kumar R., Barshak, L., Sridhar, C. N., Wheeler, C. J. and Richman, D. D. Lipid prodrugs of phosphonoacids: greatly enhanced antiviral activity of 1-O-octadecyl-sn-glycero-3-phosphonoformate in HIV-1, HSV-1 and HCMV- infected cells, in vitro. Antiviral Res. 1-2 (1996) 59-67.
• 13. Yatvin, M. B., Li, W., Stowell, M. B. H., Gallicchio, V. S., Shaw, W. A. and Burgess, S. W. Increased intracellular uptake, half-life improved antiviral action, decreased marrow toxicity and central nervous system uptake and retention by a prodrug of AZT. in: AIDS Monograph Band 5, Economed Vertagsgesellschaft AG & Co. KG, Landsberg/Loch, Germany, (1996), 278-281.
• 14. Li, W., Meredith, M. J. and Yatvin, M. B. Linking AZT to ceramide improves it’s antiviral action, decreases marrow toxicity and increases brain uptake and retention. Current Topics in Biophysics 20 (1996) 94-98.
• 15. Barlkis, E. W. and Yatvin, M. B. The life cycle of retroviruses: the influence of hyperthermia and membrane organization, in: Membrane Interactions of HIV, Volume 6 (Editors Roland C. Aloia and Cyril C. Curtain) Wiley-Liss, Inc., New York, (1992), 215-236.
• 16. Yatvin, M. B., Li, W., Meredith, M. J. and Shenoy, M. A. Improved uptake and retention of lipophilic prodrug to improve treatment of HIV. J. Adv. Drug Deliv Rev. 39 (1999) 165-182.