Thermally Triggered Multivalent Targeting of Tumors

热触发肿瘤多价靶向

• 批准号: 7391269
• 负责人: Ashutosh Chilkoti
• 金额: $ 34.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/7391269
• 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; Disease regression; Dose; Drug Exposure; Elastin; Endothelium; Engineering; Evaluation; Fever; Fluorescence; Genes; Genus Cola; Growth; Heating; Human; Integrins; Knowledge; Label; Laser Scanning Confocal Microscopy; Ligands; Measurement; Methods; Micelles; Nanostructures; Normal tissue morphology; Nude Mice; Numbers; Organ; Outcome; Ovary; Pancreas; Penetration; Performance; Pharmaceutical Preparations; Phase Transition; Primary Neoplasm; Property; Protein Overexpression; Pyrenes; Quantitative Autoradiography; RGD (sequence); 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; desire; hyperthermia treatment; improved; in vivo; light scattering; mortality; nanoscale; particle; polypeptide; programs; protein expression; pyrene; receptor; retinal rods; self assembly; size; submicron; treatment duration; tumor; tumor xenograft; uptake

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，该方法提供亲和力靶向的外部控制，以增强抗癌药物向肿瘤血管系统的选择性递送。这一总体目标的动机是迫切需要改善原发性肿瘤的治疗，特别是脑、胰腺、卵巢和结肠的肿瘤，其中死亡率通常是由治疗无法控制原发性肿瘤引起的。这项研究的中心假设是，热触发多价靶向将：（1）增强药物有效载荷在实体瘤中的积累;（2）限制药物在正常组织中的暴露;（3）改善肿瘤治疗。在拟议的研究中，将合成一种热响应多肽，这种多肽自组装成纳米级结构-直径约60 nm的多肽胶束-仅在通过外部聚焦热疗温和加热（约42 ℃）的肿瘤内。这些多肽胶束被设计为在胶束的外冠上呈现肿瘤内皮特异性靶向配体的多个拷贝。靶向配体仅在肿瘤中的多价呈递将增加其亲合力，因此选择性地将抗癌治疗剂递送至肿瘤脉管系统，同时保留正常组织。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，也是其性能的关键。热触发胶束形成系统由弹性蛋白样多肽（ELP）的AB二嵌段结构。ELP是热响应性生物聚合物，其在其转变温度（Tt）以上经历热触发的疏水-疏水相变。二嵌段ELP共聚物（ELPBC）将在其亲水性嵌段的末端掺入血管靶向配体（L），并将在疏水性末端与211 Astatine（211 At）缀合，211 Astatine是一种放射性核素，其发射高度有效的短穿透α-颗粒。L-ELPBC-211 At偶联物在40 ℃下在加热的肿瘤中自组装成多价胶束，并通过胶束对肿瘤内皮的更大热触发亲合力靶向肿瘤内皮，导致肿瘤血管消融。据我们所知，这项研究的重要性在于，它将是第一次尝试利用