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（由申请人提供）：拟议研究的总体目标是证明一种新的肿瘤选择性靶向方法（热触发多价靶向）的可行性，该方法提供亲和靶向的外部控制，以增强抗癌药物向肿瘤的选择性递送这一总体目标的动机是迫切需要改进原发性肿瘤的治疗，特别是脑、胰腺、卵巢和结肠肿瘤，这些肿瘤的死亡通常是由于治疗无法控制肿瘤的发生而导致的。该研究的中心假设是热触发的多价靶向将：（1）增强药物有效负载在实体瘤中的积累；（2）限制正常组织中的药物暴露；（3）改善肿瘤治疗。拟议的研究中，将合成一种热响应性多肽，该多肽可自组装成纳米级结构 - 直径约为 60 nm 的多肽胶束 - 仅在轻度加热的肿瘤内（约 42°） C)通过外部聚焦热疗。这些多肽胶束被设计为在胶束的外部-冠上呈现肿瘤内皮特异性靶向配体的多个拷贝，仅在肿瘤中靶向配体的多价呈现将增加其亲和力，因此选择性地。在纳米尺度上调节亲和力和尺寸是这些工程纳米结构的独特特征，也是实现这一目标的关键。热触发胶束形成系统由 AB 二嵌段结构中的弹性蛋白样多肽 (ELP) 组成，ELP 是热响应生物聚合物，在高于其转变温度 (Tt) 时会发生热触发亲水-疏水相变。共聚物（ELPBC）将在其亲水性嵌段末端结合血管靶向配体（L），并将在疏水性末端缀合至211砹 (211At) 是一种放射性核素，可发射高效、短穿透性的 L-ELPBC-211At 缀合物，在 40° 时会自组装成多价胶束。 C在加热的肿瘤中并通过胶束对肿瘤内皮的更大的热触发亲合力靶向肿瘤内皮，从而导致肿瘤脉管系统的消融，据我们所知，这将是利用该研究的首次尝试。