BIODEGRADABLE NANOCAPULES FOR DELIVERY OF MONENSIN AS POTENTIATOR OF IMMUNOTOXINS

免疫毒素已被各种肿瘤特异性细胞毒性剂用作肿瘤特异性细胞毒性剂。 学术界和工业界的调查人员。 其中一个主要的限制是 它们在体内的效力很低。 像莫能菌素这样的增效剂 在体外获得了巨大成功，但它们的亲脂性质已经排除了 它们在体内的应用。 脂质体（循环时间长），含有 莫能菌素作为免疫毒素的增强剂目前正在研究中 在体外和体内。 这项研究的主要目的是准备 羧基离子载体的纳米胶囊，莫能菌素，其可以绕过 网状内皮系统（被称为“隐形纳米胶囊”）。 这些 纳米胶囊将用作抗My 9免疫毒素的增强剂 目前处于III期临床试验中的缀合物（IT）。 的 纳米胶囊将被充分表征其包封效率， 大小、稳定性和药代动力学特征。 隐形莫能菌素 将纳米帽与IT缀合物和不同的人免疫球蛋白一起孵育。 肿瘤细胞系，以观察体外增强作用。 所有体外 莫能菌素纳米胶囊的定性和定量参数将是 与“隐形”莫能菌素脂质体相比。 莫能菌素纳米胶囊将 使用人肿瘤进一步测试它们在体内的IT增强作用 i.p/i.v.和i.v./静脉内肿瘤模型（使用裸鼠）， 隐形莫能菌素脂质体作为对照。 两种不同的人类肿瘤 间皮瘤和HL-60细胞将用作肿瘤异种移植物。 结果 从上述研究中得出的结论将使我们能够决定 使用基于聚合物或基于脂质的系统。 上述研究的完成将使我们能够选择一种配方 对于I期研究，与IT缀合物联合使用作为 增效剂。

Immunotoxins have been used as tumor-specific cytotoxic agents by various investigators in academics and industry. One of the major limitations has been their low potency in vivo. Potentiators like monensin have been used with great success in vitro but their lipophillic nature has precluded their use in vivo. Liposomes (with long circulating times) containing monensin are being currently investigated as potentiators of immunotoxins in vitro and in vivo. The main objective of this research is to prepare nanocapsules of a carboxylic ionophore, monensin which can bypass the reticuloendothelial system (to be termed as 'stealth nanocapsules'). These nanocapsules will be used as potentiators of the anti My9 immunotoxin conjugate (IT) which is presently in Phase III clinical trials. The nanocapsules will be fully characterized for their entrapment efficiency, size, stability and pharmacokinetics profile. Stealth monensin nanocapsules will be incubated with the IT conjugate and different human tumor cell lines to see the in vitro potentiation. All in vitro qualitative and quantitative parameters of monensin nanocapsules will be compared to 'stealth' monensin liposomes. Monensin nanocapsules will be further tested for their potentiation of IT in vivo using human tumor xenografts in a i.p/i.v. and i.v./i.v. tumor model (using nude mice) with stealth monensin liposomes as controls. Two different human tumors, H- mesothelioma and HL-60 cells will be used as tumor xenografts. The results emanating from the above studies will allow us to decide what drug delivery system to use, polymer based or lipid based. The completion of the above studies will allow us to choose one formulation for Phase I studies to be used in combination with the IT conjugate as a potentiator.