NANOCAPSULE CARRIERS--ORAL AMIFOSTINE DELIVERY CONTROL

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Damage to healthy tissues during radio- and/or chemotherapy remains a major clinical problem. Attempts have therefore been made to develop cytoprotective agents that would eliminate and/or restrict healthy tissue damage during chemotherapy and/or radiotherapy. Of numerous types of agents studied as healthy tissue damage during chemotherapy and/or radiotherapy. Of numerous types of agents studied as potential chemoprotectors/radioprotectors, aminothiols and phosphorothiorate compounds are one of the most effective under experimental conditions. The most widely studied of these aminothiols and indeed the only one effective under experimental conditions. The most widely studied of these amino thiols and indeed the only one to be available as FDA approved drug is amifostine. Amifostine has demonstrated the ability to protect the kidney against to protect the kidney against the cytotoxicity of cisplatin without interfering with the desired anti-cancer effect of the latter- hence the FDA approval for such use. As a result, amifostine is being further investigated in other tumor types utilizing different chemotherapeutic combinations, as well as in radiotherapy. The chemoprotective and radioprotective benefits of amifostine, however, are likely to remain grossly underutilized mainly because of limitations of routes of administration (currently i.v. only) which are both effective and easy to use under clinical conditions. The primary objective of this project is to overcome this limitation by developing a biodegradable, orally active sustained-release preparation of amifostine. Development of such a formulation will mark an important advancement in the areas of chemoprotection and radioprotection. Preparation of amifostine loaded biodegradable nanocapsules will be done using the following techniques: the modified solvent evaporation technique and the phase separation technique. The evaluation/optimization of the physiochemical characteristics of nanocapsules will be done using the following parameters: particle size, morphology, efficiency of encapsulation, and in vitro drug release and degradation kinetics. The absorption and tissue distribution characteristics of encapsulated amifostine will be evaluated/optimized in mice following oral administration. Finally, the radioprotective efficacy of encapsulated amifostine against acute and fractionated whole body gamma irradiation in mice will be measured using the following parameters: jejunal crypt cell survival, bone marrow hemopoietic progenitor cell survival, protection from irradiation-induced damage to intestinal permeability, and 30-day survival.