NANOCAPSULE CARRIERS--ORAL AMIFOSTINE DELIVERY CONTROL

放射和/或化疗期间对健康组织的损害仍然是一个主要的临床问题。因此，已经尝试开发细胞保护剂，以消除和/或限制化疗和/或放射治疗期间的健康组织损害。在化疗和/或放射治疗期间被研究为健康组织损害的多种类型的药物。在被研究为潜在的化学保护剂/辐射保护剂的众多类型的试剂中，氨基硫醇和硫代磷酸盐化合物是在实验条件下最有效的药物之一。这些氨基硫醇中研究最广泛的，实际上也是在实验条件下唯一有效的。这些氨基硫醇中研究最广泛的，实际上也是唯一一种可以作为FDA批准的药物使用的是氨磷汀。氨磷汀已经证明有能力保护肾脏免受顺铂的细胞毒性的影响，而不会干扰顺铂的预期抗癌作用--因此FDA批准了这种用途。因此，阿米福汀正在利用不同的化疗组合以及放射治疗进一步研究其他类型的肿瘤。然而，主要由于给药途径的限制(目前静脉注射)，氨磷汀的化学防护和辐射防护益处可能仍未得到充分利用。仅限)，在临床条件下既有效又易于使用。该项目的主要目标是通过开发一种可生物降解的、口服活性的氨磷汀缓释制剂来克服这一限制。这种配方的开发将标志着化学防护和辐射防护领域的重要进展。采用改进的溶剂挥发法和相分离技术制备氨磷汀生物可降解纳米胶囊。评价/优化纳米胶囊的物理化学特性将使用以下参数：颗粒大小、形态、包封率以及体外药物释放和降解动力学。阿米福汀胶囊在小鼠体内的吸收和组织分布特征将在口服后进行评估/优化。最后，阿米福汀胶囊对小鼠急性和分次全身伽玛射线照射的辐射防护效果将通过以下参数来衡量：空肠隐窝细胞存活率、骨髓造血祖细胞存活率、对辐射引起的肠道通透性损害的保护以及30天存活期。

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.