Targeted Drug Delivery to Surface Receptors

许多肿瘤学家认为，配体靶向药物将给癌症化疗带来革命性变化；然而 很少有配体可以针对一种肿瘤类型，更不用说多种肿瘤了。我们向大家展示了 共价连接到脂质体表面的透明质酸低聚糖结合并内化于 表达CD44的癌细胞株。这是一项重要的成就，因为CD44过度表达 在许多人类肿瘤的表面，包括：乳腺、前列腺、结肠、肺、卵巢、黑色素瘤和脑； 因此，HAL可能是多种肿瘤类型的肿瘤靶向配体。 我们更新的目标是使用计算机辅助配基设计来指导合成 改进了CD44的脂联配体，用于HAL。我们建议优化单次递送特性 包埋在HAL中的药物对CD44表达肿瘤的作用并更好地描述其对正常的毒性 纸巾。拟纳入的药物包括：阿霉素、SN38、顺铂和氟甲酸。我们会 研究在优化的HAL中包裹的单个药物的抗肿瘤活性是 在表达CD44的小鼠肿瘤和人肿瘤中优于非靶向脂质体治疗。 我们将测试这样的假设，即在同一HAL中提供两种药物的适当组合可以 以相加或协同的方式作用，提供比单独使用任何一种药物对CD44更好的细胞毒性 在培养中表达癌细胞。拟研究的药物组合包括：阿霉素和SN38；阿霉素 顺铂；顺铂和SN38；SN38和氟甲酸；氟甲酸和叶酸。要实现 在后一个目标中，我们将开发能够组装成脂质体并提供更好药物的新型脂类 药物组合的保留期。我们将把在低pH值下水解的邻酯类脂类加入到 脂质体能在靶点提供药物组合的触发释放。最后，我们将研究 假设包裹在优化的HAL中的这些药物组合的抗肿瘤活性更好 目的：非靶向脂质体治疗表达CD44的小鼠肿瘤和人肿瘤。 这项研究的成功将为靶向CD44表达的肿瘤提供新的配体，为 配制具有更好的药物滞留和释放特性的脂质体，最重要的是 能够对广泛的人类上皮性癌症进行靶向化疗。

Many oncologists believe that ligand-targeted drugs will revolutionize cancer chemotherapy; however there are few ligands that can target to a single tumor type let alone a variety of tumors. We showed that hyaluronan oligosaccharides covalently attached to the surface of a liposome (HAL) bind to and internalize in CD44 expressing cancer cell lines. This is an important accomplishment because CD44 is over-expressed on the surface of many human tumors including: breast, prostate, colon, lung, ovarian, melanoma and brain; hence HAL could be a cancer targeting ligand for many tumor types. Our objective in the renewal is to use computer-aided ligand design to guide the synthesis of an improved lipid-linked ligand to CD44 for use in HAL. We propose to optimize the delivery properties of single drugs encapsulated in HAL to CD44-expressing tumors and to better delineate the toxicities to normal tissues. The drugs to be incorporated include: doxorubicin, SN38, cis-platinum and fluoroortic acid. We will investigate the hypothesis that anti-tumor activity of individual drugs, encapsulated in optimized HAL are superior to non-targeted liposome therapy in CD44 expressing murine and human tumors in mice. We will test the hypothesis that appropriate combinations of two drugs delivered in the same HAL can act in an additive or synergistic fashion to provide superior cytotoxicity than either drug alone against CD44 expressing cancer cells in culture. Drug combinations to be studied include: doxorubicin & SN38; doxorubicin & cis-platinum; cis-platinum & SN38; SN38 & fluoroortic acid and fluoroortic acid & folinic acid. To achieve this latter goal we will develop novel lipids that can assemble into liposomes and provide better drug retention for combinations of drugs. We will incorporate ortho ester lipids that hydrolyze at low pH into the liposomes to provide triggered release of drug combinations at the target. Finally, we will examine the hypothesis that anti-tumor activity of these drug combinations, encapsulated in optimized HAL are superior to non-targeted liposome therapy in CD44 expressing murine and human tumors in mice. Success in this research will provide new ligands for targeting CD44 expressing tumors, new lipids for formulating liposomes with better drug retention and release characteristics, and most importantly should enable targeted chemotherapy for a broad spectrum of human cancers of epithelial origin.