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

用于卵巢癌治疗的肽靶向α粒子发射噬菌体。

• 批准号: 8242588
• 负责人: LIAOHAI CHEN
• 金额: $ 20.37万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242588
• 关键词: Adverse effects; Affinity; Alpha Particles; Antibodies; Bacteriophage T7; Bacteriophages; Binding; Biodistribution; Bismuth; Capsid; Capsid Proteins; Cloning; Couples; DNA; Daughter; Detection; Development; Diagnosis; Disease; Dose; Engineering; Enzyme-Linked Immunosorbent Assay; Failure; Genes; Goals; Greater sac of peritoneum; Helium; Image; In Vitro; Infection; Intraperitoneal Injections; Ions; Label; Laboratories; Lead; Libraries; Linear Energy Transfer; Liver; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Missouri; Modeling; Mus; Nude Mice; Oligonucleotides; Ovarian Carcinoma; Parents; Patients; Pelvis; Peptides; Peritoneal; Phage Display; Phase III Clinical Trials; Preparation; Property; Proteins; Radioisotopes; Radiolabeled; Radionuclide therapy; Research; Research Proposals; Site; Specificity; Spleen; Staging; Surface; Surface Plasmon Resonance; System; Targeted Radiotherapy; Therapeutic; Time; Toxic effect; Treatment Failure; Universities; Xenograft Model; Xenograft procedure; cancer cell; cancer therapy; disease natural history; disorder control; erbB-2 Receptor; extracellular; immunogenicity; in vivo; innovation; intraperitoneal; mortality; mouse model; nano container; nanocapsule; nanoparticle; neoplastic cell; novel; novel strategies; ovarian neoplasm; particle; pre-clinical research; radiochemical; radiotracer; receptor; solid state; therapeutic effectiveness; tumor; tumor xenograft; vector

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.

描述（由申请人提供）：题为“用于卵巢癌治疗的肽靶向α粒子发射噬菌体”的研究提案的目标是开发肽靶向噬菌体（噬菌体）鬼头或填充铅-212 （212Pb）纳米粒子的衣壳，铅-212 （212Pb）是α粒子发射放射性核素铋-212 （212Bi）的母体，用于直接腹腔内卵巢癌治疗。α粒子是氦4He离子，在发射时产生高的线性能量转移（LET），明显高于2粒子发射放射性核素或x射线的LET。据推测，装载Pb-212的T7噬菌体衣壳显示erbB2渴求肽KCCYSL，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α辐射，同时最大限度地减少不希望的放射性核素子代再分布。本研究的具体目标是：(1)设计表面表达erbB-2受体肽KCCYSL的T7噬菌体衣壳，(2)制备大量展示KCCYSL肽的空衣壳，然后将浓缩的固态金属212Pb纳米粒子装入衣壳，(3)确定装载212Pb的衣壳的放射化学稳定性和卵巢癌细胞结合能力。(4)研究衣壳的免疫原性，并对212pb标记的KCCYSL衣壳在erbB-2阳性的SK-OV-3卵巢肿瘤异种移植模型中的体内生物分布进行初步研究。卵巢癌是所有妇科癌症中死亡率最高的，部分原因是发现较晚。腹膜扩散是本病自然史的重要特征；腹膜腔内疾病控制失败是治疗失败的主要原因。设想将放射性标记衣壳注射到腹膜腔中。显示在衣壳表面的KCCYSL肽将它们靶向表达erbB-2的卵巢肿瘤，用α粒子照射它们。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封放射性核素而显著减少子代再分布的副作用的能力结合起来，从而成为卵巢癌治疗的一种创新方法。