Dual Integrin and GRPR Targeted Radiotherapy of Prostate Cancer

描述（由申请人提供）：本SBIR提案的最终目标是开发新的放射性多肽作为前列腺癌内部放疗的靶向药物。前列腺癌是影响美国男性的最常见癌症。目前，早期前列腺癌的治疗方法是手术、外部束辐射或放射性粒子植入。激素疗法、化学疗法和放射疗法用于晚期疾病的治疗。然而，对于雄激素依赖型前列腺癌，目前尚无有效的治疗方法。在开发用于治疗目的的放射标记抗体方面，已经进行了重大的努力。这些放射性标记大分子的临床应用通常不令人满意，因为靶向表位的肿瘤特异性较低，渗透到肿瘤中有限，并且引起抗小鼠免疫球蛋白反应。这些考虑有利于使用在肿瘤中摄取较高的非免疫原性小分子。多肽满足这些标准。一些肽如胃泌素释放肽（GRP）及其受体已被发现在肿瘤细胞中高表达，包括前列腺、乳腺、肠道和胰腺。最近，bombesin （BBN）肽衍生物被标记为177Lu和90Y，有望用于前列腺癌治疗。尽管这些方法取得了成功，但这些肽示踪剂在前列腺癌中的肿瘤摄取和保留相对较低，体内动力学也不理想。我们最近发展了双受体靶向的概念。我们设计了一种BBN-RGD肽异源二聚体，可以结合GRPR和整合素。3，具有突出的肿瘤靶向疗效和影像学特点。在雄激素受体（AR）阴性的PC-3肿瘤模型中，双受体结合在体内的肿瘤摄取和保留方面产生了超过加性效应。因此，在本SBIR提案中，我们希望将这一概念扩展到开发临床可翻译肽受体靶向放疗（PRTR）。前六个月的第一阶段将集中于开发和合成肽放射性示踪剂，并对其受体结合亲和力、亲水性和细胞毒性进行体外表征。该提案的第二阶段将侧重于放射性示踪剂的药代动力学和药效学。计算90y标记BBN-RGD治疗肽的小鼠剂量。90Y标记的BBN-RGD放射性药物的最大耐受剂量（MTD）将通过剂量递增研究确定。评估不同肿瘤模型的治疗效果。这项提议的创新之处在于开发了一种新的策略，为开发有效的靶向放疗产品提供了令人兴奋的前景，这种产品可以应用于各种类型的癌症。

DESCRIPTION (provided by applicant): The ultimate goal of this SBIR proposal is to develop novel radiopeptides as targeting agents for internal radiotherapy of prostate cancer. Prostate cancer is the most common cancer affecting men in the United States. Currently, early stage prostate cancer is treated with surgery, external beam radiation or radioactive seed implants. Hormonal therapy, chemotherapy and radiation are used for the treatment of advanced disease. However, no effective treatment is available for androgen independent prostate cancers. Significant effort has been expanded in attempts to develop radiolabeled antibodies for therapeutics purposes. Clinical applications of these radiolabeled macromolecules have generally been unsatisfactory due to low tumor specificity of targeted epitopes, limited penetration into tumors, and the provocation of anti-mouse immunoglobulin responses. These considerations favor the use of nonimmunogenic small molecules with higher uptake in tumors. These criteria are fulfilled by peptides. Some peptides such as gastrin releasing peptide (GRP) and its receptor has been found highly expressed in tumor cells, including prostate, breast, gut and pancreas. Recently, bombesin (BBN) peptide derivatives have been labeled with 177Lu and 90Y for prostate cancer therapy with promise. Despite the success of such approaches, these peptide tracers have relatively low tumor uptake and retention in prostate cancer and suboptimal in vivo kinetics. We recently developed the concept of dual receptor targeting. We designed a BBN-RGD peptide heterodimer that binds to both GRPR and integrin ?v?3, which showed outstanding tumor targeting efficacy and imaging characteristics. Dual-receptor binding results in more than an additive effect in vivo in terms of tumor uptake and retention in an androgen-receptor (AR)-negative PC-3 tumor model. Therefore, in this SBIR proposal, we would like to extend this concept to develop a clinically translatable peptide receptor targeted radiotherapy (PRTR). The first six- month phase I of this proposal will focus on developing and synthesizing the peptide radiotracers and in vitro characterization for their receptor binding affinity, hydrophilicity and cytotoxicity. The second phase of the proposal will focus on the pharmacokinetics and pharmacodynamics of the radiotracers. Mouse dosimetry of therapeutic 90Y-labeled BBN-RGD peptides will be calculated. The maximum tolerable dose (MTD) for 90Y- labeled BBN-RGD radiopharmaceuticals will be determined by dose escalation studies. Treatment efficacy on different tumor models will be assessed. The innovation in this proposal is developing a novel strategy which provides exciting promise to develop efficient targeted radiotherapy products that can be applied to various types of cancers. PUBLIC HEALTH RELEVANCE: We will develop the novel clinically translatable dual integrin and GRPR targeted radiotherapy of prostate cancer. Because the agent targets preferentially to specific receptors on cancer cells, we anticipate that the new tracers for radiotherapy will have better efficacy and reduced peripheral toxicity. The same strategy should also be applicable to other cancer therapeutics.