BIODEGRADABLE NANOCAPULES FOR DELIVERY OF MONENSIN AS POTENTIATOR OF IMMUNOTOXINS

免疫毒素已被用作肿瘤特异性细胞毒剂 学术界和工业界的调查人员。其中一个主要限制是 它们在体内的效力很低。像莫能菌素这样的增效剂已经被使用 在体外取得了巨大的成功，但它们的脂溢性排除了 它们在活体内的使用。脂质体(循环时间长)含有 莫能菌素目前正在作为免疫毒素的增强剂进行研究 在体外和体内。这项研究的主要目的是准备 羧酸离子载体的纳米胶囊，莫能菌素可以绕过 网状内皮系统(称为“隐形纳米胶囊”)。这些 纳米胶囊将用作抗My9免疫毒素的增强剂 目前处于第三阶段临床试验的结合物(IT)。这个 纳米胶囊的包封率将得到充分的表征， 大小、稳定性和药代动力学特征。隐形莫能菌素 纳米胶囊将与IT结合物和不同的人孵化 观察肿瘤细胞株的体外增强作用。全部在体外 莫能菌素纳米胶囊的定性和定量参数 与“隐形”莫能菌素脂质体相比。莫能菌素纳米胶囊将是 在人体肿瘤中进一步测试它们对IT的增强作用 异种移植静脉注射。静脉注射/静脉注射。肿瘤模型(使用裸鼠) 莫能菌素隐形脂质体作为对照。两种不同的人类肿瘤，H- 间皮瘤和HL-60细胞将被用作肿瘤移植瘤。结果是 从上述研究中得出的结果将使我们能够决定给什么药物 使用的系统，基于聚合物或基于脂类。 上述研究的完成将使我们能够选择一种配方 对于第一阶段研究，将与IT结合物结合使用作为 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.