NANOCAPSULE CARRIERS--ORAL AMIFOSTINE DELIVERY CONTROL

纳米胶囊载体--口服氨磷汀递送控制

• 批准号: 6450672
• 负责人: TARUN K MANDAL
• 金额: $ 3.85万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450672
• 关键词: biodegradable product; cytoprotection; drug delivery systems; microcapsule; nanotechnology; oral administration; radioprotective agents

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.

在放疗和/或化疗期间对健康组织的损伤仍然是主要的临床问题。因此，已经尝试开发在化疗和/或放疗期间消除和/或限制健康组织损伤的细胞保护剂。在化疗和/或放疗期间，研究了多种类型的药物作为健康组织损伤。作为潜在的化学保护剂/辐射保护剂，氨基硫醇和硫代磷酸酯化合物研究的许多类型的代理人是在实验条件下最有效的。这是这些氨基硫醇中研究最广泛的，也是唯一一种在实验条件下有效的。这些氨基硫醇中研究最广泛的，实际上也是唯一一种可作为FDA批准的药物的是氨磷汀。氨磷汀已经证明了保护肾脏免受顺铂细胞毒性的能力，而不干扰顺铂的预期抗癌作用-因此FDA批准了这种用途。因此，氨磷汀正在进一步研究其他肿瘤类型，利用不同的化疗组合，以及在放疗。然而，氨磷汀的化学保护和辐射保护益处可能仍然严重未被充分利用，主要是因为给药途径的限制（目前仅静脉内），其在临床条件下既有效又易于使用。本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。这种制剂的开发将标志着化学防护和辐射防护领域的重要进展。负载氨磷汀的可生物降解纳米胶囊的制备将使用以下技术进行：改进的溶剂蒸发技术和相分离技术。将使用以下参数对纳米胶囊的理化特性进行评价/优化：粒度、形态、包封效率以及体外药物释放和降解动力学。将在小鼠经口给药后评价/优化包封氨磷汀的吸收和组织分布特征。最后，将使用以下参数测量包封的氨磷汀对小鼠中急性和分次全身γ辐射的辐射保护功效：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和30天存活。