Thermally Triggered Multivalent Targeting of Tumors

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的可行性-热触发多价靶向-提供亲和力靶向的外部控制，以增强抗癌药物向肿瘤血管的选择性递送。这一总体目标的动机是迫切需要改进原发肿瘤的治疗方法，特别是对于脑、胰腺、卵巢和结肠肿瘤，这些肿瘤的死亡率通常是由于治疗无法控制原发肿瘤而导致的。本研究的中心假设是热触发多价靶向将：(1)增强实体肿瘤中药物有效载荷的积累；(2)限制药物在正常组织中的暴露；(3)改善肿瘤治疗。在提出的研究中，一种热响应多肽将被合成，其自组装成纳米级结构-直径约60纳米的多肽胶束-仅在通过外部聚焦热疗轻度加热（~42¿C）的肿瘤内。这些多肽胶束被设计成在胶束的外部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现将增加其亲和力，因此选择性地将抗癌治疗药物递送到肿瘤血管，同时保留正常组织。在纳米尺度上亲和性和尺寸的调制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（ELPs）在AB双块结构中组成。elp是热响应的生物聚合物，在其转变温度（Tt）以上经历热触发的亲水-疏水相变。一种双嵌段ELP共聚物（ELPBC）将在其亲水嵌段末端结合一个血管靶向配体(L)，并在疏水末端与21astatine （21at）偶联，后者是一种放射出强效、短穿透的A粒子的放射性核素。l - elpbc - 2111at缀合物将在加热的肿瘤中自组装成40°C的多价胶束，并通过更大的热触发胶束对肿瘤内皮的亲和力靶向肿瘤内皮，导致肿瘤血管的消融。据我们所知，拟议研究的三个重要意义在于，它将是第一次尝试利用

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