NANOCAPSULE CARRIERS--ORAL AMIFOSTINE DELIVERY CONTROL

放疗和/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，人们试图开发细胞保护剂，以消除和/或限制化疗和/或放疗期间对健康组织的损害。在化学疗法和/或放射疗法中对健康组织造成损害的多种药物中。在研究了许多类型的潜在化学保护剂/放射性保护剂中，氨基硫醇和磷硫酸盐化合物是实验条件下最有效的一种。这些氨基硫醇中研究最广泛的，也是唯一在实验条件下有效的。在这些氨基硫醇中，研究最广泛的也是唯一被FDA批准的药物是氨磷汀。氨磷汀已经证明了保护肾脏免受顺铂细胞毒性影响的能力，而不会干扰后者预期的抗癌效果，因此FDA批准了这种使用。因此，人们正在进一步研究氨磷汀在其他肿瘤类型中使用不同的化疗组合以及放射治疗中的作用。然而，氨磷汀的化学保护和放射保护作用可能仍未得到充分利用，这主要是由于在临床条件下既有效又易于使用的给药途径的限制（目前仅限静脉注射）。该项目的主要目标是通过开发一种可生物降解、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放射防护领域的重要进步。采用改性溶剂蒸发技术和相分离技术制备载氨磷汀可生物降解纳米胶囊。利用以下参数对纳米胶囊的理化特性进行评价/优化：粒径、形态、包封效率、体外药物释放和降解动力学。在口服给药后，将评价/优化氨磷汀胶囊在小鼠体内的吸收和组织分布特性。最后，通过以下参数测量包封氨磷汀对小鼠急性和分次全身γ辐射的辐射防护效果：空肠隐窝细胞存活、骨髓造血祖细胞存活、对辐射诱导的肠通透性损伤的保护以及30天存活率。

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.