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

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.