A Novel Multiple Ligand Approach to Targeting Tumors

一种靶向肿瘤的新型多配体方法

• 批准号: 0201891
• 负责人: Ravi Bellamkonda
• 金额: $ 32.27万
• 依托单位: Case Western Reserve University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0201891&HistoricalAwards=false
• 关键词: Novel; Multiple; Ligand; Approach; Targeting

0201891BellamkondaInability to successfully target chemotherapeutic agents to tumors, specifically gliomas of the brain, has been a major obstacle for successful treatment and prognosis. While liposomal delivery to gliomas has been promising, non-specific delivery of chemotherapeutic agent(s) remains high. The investigators propose a novel, multiple-ligand approach to target drug-laden liposomes to brain tumors in an efficient manner while minimizing non-specific uptake at the same time. The approach is based on the following hypotheses: A) The overall affinity between receptor targeted drug delivery vehicle and tumors can be increased by using multiple weak interactions generated by multiple targeting ligands on the delivery vehicle that target multiple differentially (but not exclusively) expressed receptors on tumors, and B) Specificity of targeting can be achieved by delivery vehicles presenting sub-optimal levels of each ligand (with optimal being maximum possible affinity for a given ligand), so that non-specific uptake by healthy cells is reduced because they do not coincidently over-express all of the targeted receptors that are differentially expressed on gliomas.Based on these hypotheses, the specific aims are to: 1) Design and fabricate multiple-ligand presenting liposomal vehicles; 2) Determine doxorubicin loaded multiple ligand vehicles' targeting capacity when tumor and non-tumor cells are co-cultured; and 3) Determine the in vivo performance of these vehicles in a rodent model of glioma.

0201891Bellamkonda 无法成功地将化疗药物靶向肿瘤，特别是脑胶质瘤，一直是成功治疗和预后的主要障碍。虽然脂质体递送至神经胶质瘤的前景良好，但化疗药物的非特异性递送仍然很高。研究人员提出了一种新颖的多配体方法，以有效的方式将载有药物的脂质体靶向脑肿瘤，同时最大限度地减少非特异性摄取。该方法基于以下假设：A) 通过使用递送载体上的多个靶向配体产生的多种弱相互作用，可以增加靶向药物递送载体和肿瘤之间的总体亲和力，所述相互作用靶向肿瘤上多个差异（但不排他）表达的受体；B) 靶向的特异性可以通过呈现每个配体的次优水平的递送载体来实现（最佳是对给定的最大可能亲和力） 配体），从而减少健康细胞的非特异性摄取，因为它们不会同时过度表达在神经胶质瘤上差异表达的所有靶向受体。基于这些假设，具体目标是：1）设计和制造多配体呈递脂质体载体； 2) 测定肿瘤细胞与非肿瘤细胞共培养时负载阿霉素的多配体载体的靶向能力； 3) 确定这些载体在神经胶质瘤啮齿动物模型中的体内性能。