Targeted Drug Delivery to Surface Receptors

许多肿瘤学家认为，配体靶向药物将彻底改变癌症化疗;然而， 很少有配体能够靶向单一肿瘤类型，更不用说多种肿瘤了。我们发现 共价连接到脂质体（HAL）表面的透明质酸低聚糖结合并内化在 表达CD 44的癌细胞系。这是一项重要的成就，因为CD 44在细胞中过度表达， 在许多人类肿瘤的表面，包括：乳腺癌、前列腺癌、结肠癌、肺癌、卵巢癌、黑色素瘤和脑肿瘤; 因此HAL可能是许多肿瘤类型的癌症靶向配体。 我们更新的目标是使用计算机辅助配体设计来指导合成一种 用于HAL的改进的与CD 44的脂质连接的配体。我们建议优化单一的交付性能 HAL中包裹的药物对表达CD 44的肿瘤的作用，并更好地描述对正常人的毒性。 组织中拟纳入的药物包括：阿霉素、SN 38、顺铂和氟硼酸。我们将 研究了以下假设，即包封在优化的HAL中的单个药物的抗肿瘤活性是 在小鼠中表达CD 44的鼠和人肿瘤中优于非靶向脂质体疗法上级。 我们将检验这样的假设，即在同一HAL中递送的两种药物的适当组合可以 以相加或协同的方式作用，提供比任一单独药物对CD 44的上级细胞毒性 在培养物中表达癌细胞。待研究的药物组合包括：多柔比星和SN 38;多柔比星 顺式铂;顺式铂&SN38; SN 38 & fluoroortic acid和fluoroortic acid & folinic acid。实现 后一个目标，我们将开发新的脂质，可以组装成脂质体，并提供更好的药物 药物组合的保留。我们将在低pH下水解的原酸酯脂质掺入到 脂质体以提供药物组合在靶点处的触发释放。最后，我们将研究 假设包封在优化HAL中的这些药物组合的抗肿瘤活性是上级的 在小鼠中表达CD 44的鼠和人肿瘤中的非靶向脂质体疗法。 这项研究的成功将为靶向表达CD 44的肿瘤提供新的配体， 配制具有更好的药物保留和释放特性的脂质体，最重要的是， 能够对上皮来源的广谱人类癌症进行靶向化疗。

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.