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Targeted Drug Delivery to Surface Receptors

靶向药物递送至表面受体

基本信息

批准号：
7903801
负责人：
FRANCIS C. SZOKA
金额：
$ 18.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903801
关键词：
7-ethyl-10-hydroxycamptothecin Acids Binding Binding Sites Brain Breast CD44 gene Cancer cell line Categories Cell Culture Techniques Cells Characteristics Chemical Structure Chemicals Chemotherapy-Oncologic Procedure Cisplatin Colon Computer Assisted Data Docking Doxorubicin Drug Combinations Drug Delivery Systems Drug Formulations Encapsulated Epithelial Esters Exhibits Funding Goals Heart Human Hyaluronan Hydrolysis Immune system Individual Kidney Kinetics Length Leucovorin Ligand Binding Ligands Link Lipids Liposomes Liver Lung Malignant Neoplasms Measures Mediating Modeling Mus Normal tissue morphology Oligosaccharides Oncologist Ovarian Pharmaceutical Preparations Property Prostate Research Safety Structure Surface Testing Therapeutic Toxic effect cancer cell chemotherapy cytotoxicity density design improved late endosome melanoma neoplastic cell novel receptor success tumor

项目摘要

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.

许多肿瘤学家相信配体靶向药物将彻底改变癌症化疗；然而很少有配体可以靶向单一肿瘤类型，更不用说多种肿瘤了。我们证明了共价连接到脂质体 (HAL) 表面的透明质酸寡糖结合并内化表达 CD44 的癌细胞系。这是一项重要的成就，因为 CD44 过度表达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、黑色素瘤和脑癌；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改进的 CD44 脂质连接配体用于 HAL。我们建议优化单一的交付属性封装在 HAL 中的药物作用于表达 CD44 的肿瘤，并更好地描述对正常细胞的毒性组织。待掺入的药物包括：阿霉素、SN38、顺铂和氟乳酸。我们将研究封装在优化 HAL 中的单个药物的抗肿瘤活性的假设在小鼠表达 CD44 的小鼠和人类肿瘤中优于非靶向脂质体疗法。我们将测试以下假设：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发挥作用，比单独使用任何一种药物针对 CD44 提供更好的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SN38；阿霉素 & 顺铂；顺铂 & SN38； SN38 & 氟乳清酸和氟乳清酸 & 亚叶酸。达到对于后一个目标，我们将开发可以组装成脂质体并提供更好药物的新型脂质药物组合的保留。我们将在低 pH 值下水解的原酸酯脂质加入到脂质体可在目标处触发药物组合的释放。最后，我们将检查假设封装在优化 HAL 中的这些药物组合的抗肿瘤活性更优异对表达 CD44 的小鼠和人类肿瘤的小鼠进行非靶向脂质体治疗。这项研究的成功将为靶向表达 CD44 的肿瘤提供新的配体，为配制具有更好药物保留和释放特性的脂质体，最重要的是应该能够对多种上皮来源的人类癌症进行靶向化疗。