Thermally Triggered Multivalent Targeting of Tumors

描述(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输送。这一总体目标的动机是迫切需要改进原发肿瘤的治疗，特别是脑、胰腺、卵巢和结肠癌的治疗，这些肿瘤的死亡率通常是由于无法控制原发肿瘤的治疗而造成的。这项拟议研究的中心假设是，热触发多价靶向将：(1)促进药物在实体肿瘤中的积累；(2)限制正常组织中的药物暴露；以及(3)改善肿瘤治疗。在这项拟议的研究中，将合成一种热响应性多肽，它将仅在通过外聚焦热疗适度加热(~42℃)的肿瘤内自组装成纳米结构-直径约60 nm的多肽胶束。这些多肽胶束旨在将肿瘤内皮特异性靶向配体的多个副本呈现在胶束的外部--日冕--。靶向配体仅在肿瘤中的多价呈现将增加其亲和力，从而选择性地将抗癌治疗药物输送到肿瘤血管，同时保留正常组织。在纳米尺度上对亲和力和尺寸的调节是这些工程纳米结构的一个独特特征，也是它们性能的关键。热触发胶束形成系统由AB双嵌段结构的弹性蛋白样多肽(ELP)组成。ELPS是一种热响应性生物聚合物，在其转变温度(TT)以上经历热触发的亲水-疏水相变。二嵌段ELP共聚物(ELPBC)将在其亲水嵌段的末端引入血管靶向配体(L)，并在疏水末端与211 Astine(211 At)结合，211 At是一种发射高强度、短穿透a粒子的放射性核素。L-ELPBC-211At结合物在加热的肿瘤中会在40℃的温度下自组装成多价胶束，并通过更大的热引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。这项拟议研究的意义在于，据我们所知，这将是利用

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