Thermally Triggered Multivalent Targeting of Tumors

热触发肿瘤多价靶向

基本信息

批准号：
7568204
负责人：
Ashutosh Chilkoti
金额：
$ 34.94万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568204
关键词：
Ablation Affinity Animals Antineoplastic Agents Architecture Astatine Autoradiography Avidity Binding Biodistribution Biopolymers Blood Vessels Body Temperature Body Weight decreased Brain Neoplasms Caliber Chemistry Colon Dose Drug Exposure Elastin Endothelium Engineering Fever Fluorescence Genes Growth Heating Human Integrins Knowledge Label Laser Scanning Confocal Microscopy Ligands Measurement Methods Micelles Nanostructures Normal tissue morphology Nude Mice Organ Outcome Ovary Pancreas Penetration Performance Pharmaceutical Preparations Phase Transition Primary Neoplasm Property Pyrenes Quantitative Autoradiography Radiation Radiation therapy Radioactive Radioisotopes Recombinant Proteins Recombinants Research Research Personnel Resolution Scheme Solid Carcinoma Solid Neoplasm Spatial Distribution Spectrophotometry Structure System Temperature Therapeutic Therapeutic Studies Transition Temperature Treatment Efficacy alanine aminopeptidase anti-cancer therapeutic copolymer covalent bond design hyperthermia treatment improved in vivo light scattering mortality nanoscale overexpression particle polypeptide programs protein expression receptor retinal rods self assembly submicron therapeutic evaluation treatment duration tumor tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): The overall objective of the proposed research is to demonstrate the feasibility of a new tumor selective targeting approach - thermally triggered polyvalent targeting - that provides external control of affinity targeting to enhance the selective delivery of anticancer drugs to the tumor vasculature. This overall objective is motivated by the rationale that there is an urgent need for improved therapy of primary tumors, especially for tumors of the brain, pancreas, ovary and colon, where mortality is typically caused by the inability of therapy to control the primary tumor. The central hypothesis of the proposed research is that thermally triggered polyvalent targeting will: (1) enhance accumulation of the drug payload in solid tumors; (2) limit drug exposure in normal tissues; and (3) improve tumor therapy. In the proposed research, a thermally responsive polypeptide will be synthesized that self-assembles into a nanoscale structure - a polypeptide micelle with a diameter of ~60 nm - only within a tumor that is mildly heated (~42¿C) by externally focused hyperthermia. These polypeptide micelles are designed to present multiple copies of a tumor endothelial specific targeting ligand on the exterior - corona - of the micelle. The polyvalent presentation of targeting ligands only in the tumor will increase its avidity and therefore selectively deliver the anticancer therapeutics to the tumor vasculature while sparing normal tissues. The modulation of both affinity and size at the nanoscale is a unique feature of these engineered nanostructures, and is the key to their performance. The thermally triggered micelle forming system consists of elastin-like polypeptides (ELPs) in an AB diblock architecture. ELPs are thermally responsive biopolymers that undergo a thermally triggered hydrophilic-hydrophobic phase transition above their transition temperature (Tt). A diblock ELP copolymer (ELPBC) will incorporate a vascular targeting ligand (L) at the end of its hydrophilic block and will be conjugated at the hydrophobic end to 211 Astatine (211At), a radionuclide which emits highly potent, short penetration a-particles. L-ELPBC-211At conjugates will self-assemble into polyvalent micelles at 40¿C in heated tumors and target the tumor endothelium by a greater thermally triggered avidity of the micelle to tumor endothelium, leading to ablation of tumor vasculature. Thee significance of the proposed research is that it will be, to our knowledge, the first attempt to harness

描述（由适用提供）：拟议研究的总体目标是证明新型肿瘤选择性靶向方法的可行性 - 热触发的多价靶向 - 提供了对亲和力靶向的外部控制，以增强抗癌药物为肿瘤脉管系统的选择性递送。这一整体目标是由迫切需要改善原发性肿瘤治疗的理由，尤其是针对大脑，胰腺，卵巢和结肠的治疗，在这种肿瘤中，死亡率通常是由于无法控制原发性肿瘤的治疗而导致的。拟议的研究的中心假设是，热触发的多价靶向将：（1）在实体瘤中增强药物有效载荷的积累；（2）限制正常组织中的药物暴露；（3）改善肿瘤疗法。在拟议的研究中，将合成一个热响应的多肽，即自组合成纳米级结构 - 直径约为60 nm的多肽胶束 - 仅在肿瘤内通过外部聚焦的高温（〜42¿ c）。这些多肽胶束的设计旨在呈现胶束外部的肿瘤内皮特异性靶向配体的多个副本。仅在肿瘤中靶向配体的多价表示会增加其亲和疗法，从而选择性地将抗癌疗法提供给肿瘤脉管系统，同时避免正常组织。纳米级的亲和力和大小的调节是这些工程纳米结构的独特功能，并且是其性能的关键。热触发的胶束形成系统由AB二嵌段结构中的弹性蛋白样多肽（ELP）组成。 ELP是热响应的生物聚合物，它经历了高于其过渡温度（TT）的热触发的亲水性 - 养生相变。二嵌段ELP共聚物（ELPBC）将在其亲水块末端结合一个血管靶向配体（L），并将在疏水端连接至211 astatine（211AT），这是一种放射性的放射线，它发出了高潜在的潜在潜力，短穿透性a派。 L-ELPBC-211AT结合物将在加热肿瘤中在40°C处自组装成多价胶束，并通过更大的热触发胶束对肿瘤内皮的热触发的肿瘤内皮靶向，从而导致肿瘤脉管结束。拟议的研究的意义是，据我们所知，它将是首次利用的尝试