Peptide-targeted alpha-particle emitting phage for ovarian cancer therapy.

描述(申请人提供)：这项名为“用于卵巢癌治疗的多肽靶向α粒子发射噬菌体”的研究提案的目标是开发多肽靶向噬菌体(噬菌体)鬼头片或填充纳米颗粒铅-212(212Pb)的幽灵头盔或衣壳，用于定向腹膜内治疗卵巢癌。α粒子是氦4He离子，在发射时会产生高的线性能量转移(LET)，显著高于发射放射性核素或X射线的2粒子的LET。据推测，携带有携带erbB-2亲和肽KCCYSL的T7噬菌体衣壳将靶向过度表达erbB2受体的卵巢肿瘤，导致肿瘤局部治疗剂量的阿尔法辐射，同时最小化不良的放射性核素子再分布。这项研究的具体目的是(1)在表面表达Erb B-2受体亲和肽KCCYSL的T7噬菌体衣壳，(2)制备大量展示噬菌体衣壳的空噬菌体多肽，然后负载凝聚的固态金属纳米颗粒，(3)测定装载212Pb的衣壳的放射化学稳定性和与卵巢癌细胞的结合能力，(4)研究衣壳的免疫原性，并在erbB-2阳性的SK-OV-3卵巢肿瘤移植瘤模型中进行初步的体内生物分布研究。卵巢癌是所有妇科癌症中死亡率最高的，部分原因是它的发现时间较晚。腹膜扩散是该病自然病程中的一个重要特征；未能控制腹膜腔内的疾病是治疗失败的主要原因。预计放射性标记衣壳将被注射到腹膜腔内。衣壳表面显示的KCCYSL多肽将靶向表达erbB-2的卵巢肿瘤，并用阿尔法粒子照射它们。多肽靶向α发射噬菌体是一种靶向放射性核素治疗的新方法，它将α粒子的治疗效果与通过包裹放射性核素显著减少子代再分布的副作用相结合，从而为卵巢癌的治疗提供了一种创新的方法。 公共卫生相关性：卵巢癌是所有妇科癌症中死亡率最高的，这在很大程度上是由于发现较晚，而且大多数患者在确诊时都有骨盆以外的疾病。新型多肽靶向α颗粒噬菌体衣壳的设计和开发将为治疗已经在腹膜内扩散的卵巢癌提供一种创新的方法。

DESCRIPTION (provided by applicant): The goal of the research proposal entitled, "Peptide-targeted alpha-particle emitting phage for ovarian cancer therapy," is to develop peptide targeted bacteriophage (phage) ghost headpieces or capsids filled with nanoparticles of lead-212 (212Pb), the parent of the alpha-particle emitting radionuclide bismuth-212 (212Bi), for directed intraperitoneal ovarian cancer treatment. Alpha particles are helium 4He ions that result in high linear energy transfer (LET) upon emission, significantly higher than the LET of 2-particle emitting radionuclides or x-rays. It is hypothesized that Pb-212 loaded T7 phage capsids displaying the erbB-2 avid peptide KCCYSL will target ovarian tumors over-expressing the erbB2 receptor resulting in a tumor-localized therapeutic dose of alpha radiation, while minimizing undesirable radionuclide daughter redistribution. The specific aims of the proposed research are (1) engineer T7 phage capsids that express the erbB-2 receptor avid peptide KCCYSL on their surfaces, (2) prepare large quantities of empty KCCYSL peptide displaying phage capsids then load them with condensed solid-state metallic 212Pb nanoparticles, (3) determine the radiochemical stability and ovarian cancer cell binding ability of the 212Pb loaded capsids, and (4) investigate the immunogenicity of the capsids and perform initial biodistribution studies of the 212Pb-labeled KCCYSL capsids in vivo in an erbB-2 positive SK-OV-3 ovarian tumor xenograft model. Ovarian carcinoma has the highest mortality of any gynecologic cancer, in part due to its late detection. Peritoneal spread is an important feature in the natural history of the disease; failure to control disease within the peritoneal cavity is a major cause of treatment failure. It is envisioned that radiolabeled capsids would be injected into the peritoneal cavity. The KCCYSL peptides displayed on the surfaces of the capsids will target them to erbB-2 expressing ovarian tumors, irradiating them with alpha-particles. Peptide-targeted alpha emitting phage is a novel approach to targeted radionuclide therapy that couples the therapeutic effectiveness of alpha particles with ability to dramatically reduce side effects from daughter redistribution by encapsulation of the radionuclide, resulting in an innovative approach to ovarian cancer treatment. PUBLIC HEALTH RELEVANCE: Ovarian carcinoma has the highest mortality of any gynecologic cancer, which is largely due to late detection and the fact that most patients have disease outside the pelvis at the time of diagnosis. The engineering and development of novel peptide-targeted alpha particle emitting phage capsids will offer an innovative approach to the treatment of ovarian cancer that has spread intraperitoneally.