PSMAi-PARPi combination agents for the targeted Auger and alpha therapy of metastatic castration-resistant prostate cancer

前列腺癌（PC）是第二大常见癌症，也是第二大癌症相关死亡原因 在男人身上。美国癌症协会估计，248，530例新的前列腺癌病例和34，130例 前列腺癌相关死亡将在2021年发生。雄激素剥夺治疗（ADT）-化学或 去势或睾丸切除术-被用作PC的初始治疗;然而，大多数患者发生转移， 去势抵抗性PC（mCRPC）。mCRPC患者存活5年的机会不到16%， 使得更好的治疗选择成为一个关键的需求。放射性标记的前列腺特异性膜抗原抑制剂 （PSMAi）正在研究用于PC患者的治疗。一种这样的试剂，用β发射体177 Lu标记 （177 Lu-PSMA-617）处于III期临床评价的后期阶段。虽然它已经显示出希望，剂量限制 由于其长程β-粒子的弥漫性红骨髓浸润而引起的血液学毒性是一个问题。因为 它们产生DNA双链断裂的能力高于β粒子，高线性能量转移（LET） α粒子（AP）应该更有效地治疗耐药肿瘤。此外，由于其短距离 在组织中，它们应该是治疗微转移病灶的理想选择。用AP发射225 Ac标记的PSMAi 产生的应答率显著高于177 Lu-PSMA-617， 毒性然而，由于它们主要在唾液腺和泪腺中非特异性摄取， 和干眼症是重要问题。俄歇电子（AE）是高LET辐射时，位于附近 DNA和有非常短的范围。当它们在肿瘤细胞核中时可以是致命的，但将具有最小的脱靶 毒性聚ADP-核糖聚合酶1（PARP 1）是一种DNA修复蛋白，在癌症中高度表达， 在正常组织中程度较低。由于PARP 1定位于邻近DNA，我们建议发展AE 用于靶向AEE的PSMAi和PARP 1抑制剂（PARPi）的发射体（AEE）标记的共价缀合物 mCRPC患者的治疗。假设缀合物的PSMA i部分可以实现特异性结合 PARP-1是一种核蛋白，PARPi部分将有助于AEE在PC细胞中的定位。 AEE最有效的肿瘤细胞核。除了AP，重卤素211 At发射高LET 反冲核，在组织中的平均射程为82和105 nm，当衰变发生时具有高度细胞毒性 在细胞核内。它每次衰变还发射约6个AE，在10 nm内比AP沉积更多的辐射剂量 腐烂的地方。由于这些原因，211 At标记的类似物也应该对这些缀合物有效。 具体目的是：1）合成用于俄歇和阿尔法治疗的PARPi-PSMAi放射性缀合物; 2）在 放射性缀合物的体外评价; 3）放射性缀合物的体内生物分布。成功完成 预计该项目将确定一种药物，用于进一步广泛评估靶向放射治疗， mCRPC。希望这样的试剂可以潜在地优于当前的177 Lu-和225 Ac-标记的PSMA 通过以最小的脱靶毒性产生更好的治疗效果来治疗药物。

Prostate cancer (PC) is the second most common cancer and the second leading cancer-related cause of death in men. The American Cancer Society has estimated that 248,530 new cases of prostate cancer and 34,130 prostate cancer-related deaths will occur in 2021. Androgen deprivation therapy (ADT) — either chemical castration or orchiectomy — is used as an initial therapy for PCs; however, most patients develop metastatic castration-resistant PC (mCRPC). Patients with mCRPC have less than a 16% chance of surviving for five years, making better therapeutic options a critical need. Radiolabeled prostate-specific membrane antigen inhibitors (PSMAi) are being investigated for the treatment of PC patients. One such agent, labeled with the β-emitter 177Lu (177Lu-PSMA-617) is in late stage of its Phase III clinical evaluation. Although it has shown promise, dose-limiting hematological toxicity due to diffuse red marrow infiltration of its long-range β-particles is a problem. Because of their higher capability to generate DNA double strand breaks than β-particles, high linear energy transfer (LET) alpha-particles (AP) should be more effective for treating resistant tumors. Furthermore, due to their short range in tissue, they should be ideal for treatment of micrometastatic lesions. PSMAi labeled with AP-emitting 225Ac have yielded response rates significantly higher than that of 177Lu-PSMA-617 with less severe bone marrow toxicity. However, due to their predominantly nonspecific uptake in salivary and lachrymal glands, xerostomia and xerophthalmia were significant issues. Auger electrons (AE) are high LET radiation when positioned near DNA and have very short range. They can be lethal when in the tumor cell nuclei but will have minimal off-target toxicity. Poly ADP-ribose polymerase 1 (PARP1) is a DNA repair protein that is highly expressed in cancers and to a lesser degree in normal tissues. Because PARP1 localizes adjacent to DNA, we propose to develop AE emitter (AEE)-labeled covalent conjugates of PSMAi and inhibitors of PARP1 (PARPi) for the targeted AEE therapy of mCRPC patients. The hypothesis is that the PSMAi part of the conjugate can achieve specific binding to PSMA in the PC cells and, PARP-1 being a nuclear protein, the PARPi moiety will help localize AEE in the tumor cell nuclei where the AEE will be most effective. In addition to AP, the heavy halogen 211At emits high LET recoil nuclei with a mean range in tissue of 82 and 105 nm, which is highly cytotoxic when the decay occurs within the nucleus. It also emits ~6 AEs per decay, which deposits more radiation dose than its AP within 10 nm of the decay site. For these reasons, 211At-labeled analogues also should be effective with these conjugates. The Specific Aims are: 1) Syntheses of PARPi-PSMAi radioconjugates for Auger and Alpha therapy; 2) In vitro evaluation of radioconjugates; 3) In vivo biodistribution of radioconjugates. Successful completion of this project is expected to identify an agent for its further extensive evaluation for targeted radiotherapy of mCRPC. It is hoped that such an agent can be potentially better than the current 177Lu- and 225Ac-labeled PSMA agents by yielding better therapeutic efficacy with minimal off-target toxicity.