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.

许多肿瘤学家认为，靶向配体的药物会彻底改变癌症化疗。然而很少有配体可以靶向单一肿瘤类型，更不用说各种肿瘤了。我们表明了这一点透明质酸寡糖共同连接到脂质体表面（HAL）与内部结合并内在化 CD44表达癌细胞系。这是一个重要的成就，因为CD44过表达在许多人类肿瘤的表面上，包括：乳腺癌，前列腺，结肠，肺，卵巢，黑色素瘤和大脑；因此，HAL可能是许多肿瘤类型的癌症靶向配体的癌症。我们在更新中的目标是使用计算机辅助配体设计来指导合成改进了脂质连接的配体至CD44，可用于HAL。我们建议优化单个的输送属性封装在HAL中的药物表达CD44的肿瘤，以更好地描述毒性正常组织。要纳入的药物包括：阿霉素，SN38，顺铂和荧光酸。我们将研究以下假设：在优化的HAL中封装的单个药物的抗肿瘤活性在CD44中，在小鼠中表达鼠和人类肿瘤的非靶向脂质体疗法优于非靶向的脂质体疗法。我们将测试以下假设以添加剂或协同的方式起作用，可提供比单独针对CD44的任何一种药物提供优越的细胞毒性在培养中表达癌细胞。要研究的药物组合包括：阿霉素＆sn38;阿霉素＆cis-platinum;顺式 - 铂＆sn38; SN38和氟替代酸和氟替代酸和叶酸。实现后一个目标，我们将开发出可以组装成脂质体并提供更好药物的新型脂质保留药物组合。我们将合并在低pH下水解的正酯脂质脂质体提供了触发靶标的药物组合的释放。最后，我们将研究封装在优化HAL中的这些药物组合的抗肿瘤活性的假设是优越的在CD44中表达小鼠的鼠和人肿瘤的非靶向脂质体疗法。这项研究的成功将为靶向CD44表达肿瘤，新脂质提供新的配体制定具有更好的药物保留和释放特征的脂质体，最重要的是为广泛的上皮起源癌症启用靶向化学疗法。