Smart cell nuclear-localising 125/131I-labelled octreotates for sandwiched beta- and Auger-particle therapy of metastatic neuroendocrine tumours

博士项目目标：建立一个125/ 131i标记的能在神经内分泌肿瘤（NET）细胞核中选择性积累的octreotate对的文库；证明在NET肽受体放射性核素治疗中，连续使用最佳的细胞核定位125/ 131i标记的octreotate对发射β粒子和奥格粒子优于传统的[177Lu]DOTATATE。lutathera （[177Lu]DOTATATE）已成为生长抑素受体2型表达（SSTR2）神经内分泌肿瘤（NET）患者的标准治疗药物。NETTER-1 III期试验显示，卢他拉延长了转移性NETs的无进展生存期（PFS），尽管客观缓解率很低（18%）。我们的分析表明，与病情稳定的患者相比，在出现部分反应的患者中，PFS对卢他拉西的疗效更好。大多数患者使用卢他拉西只能达到病情稳定；同时治疗时间长，费用高。因此，需要更有效的治疗方法。目前基于放射性金属的肽受体放射性核素治疗（PRRT）对NETs的主要限制是肾毒性影响了可实现的治疗效果，高达14%的病例发生严重（4-5级CTC）肾毒性。肾毒性是由肾细胞中残留的放射性金属引起的，这一特性与放射性碘无关。虽然同时输注带正电的氨基酸可以降低肾毒性，但它们也会加重恶心和呕吐。短暂的骨髓毒性是释放β - prrt的另一个重要副作用。PRRT的效果取决于放射性核素的衰变特性。尽管有这些知识，但很少考虑根据肿瘤负荷/大小调整prrt。串联或序贯注射[177Lu]DOTATATE和[90Y]DOTATATE（两者都能释放长路径长度的β -颗粒），考虑了不同的肿瘤负荷反应，并提高了疗效。更实用的131I/125I对尚未研究，可能是由于化学可及性和实施简易放射化学以生产耐脱碘的放射性碘化奥曲酸盐方面的挑战。我们假设，将PRRT与碘-131和碘-125夹在一起，可以有效地靶向放射治疗递送可能不均匀的大肿瘤，以及在达到剂量限制毒性之前的小微转移。这种方法将允许针对个别患者的NET状态进行定制治疗，并且毒性有限。短路径长度的125I有效杀伤肿瘤细胞需要放射性同位素在靠近细胞核的空间定位。这可以通过使用硫醇或酸敏感的连接剂来共轭放射性碘化核定位官能团（NLF）来实现。预计在sstr2依赖性细胞内化之后，细胞内游离硫醇浓度或溶酶体酸度的增加将切割相应的连接体并释放放射性的NLF，这些NLF随后将在细胞核中积累。靠近DNA的碘-125的分解将被密集电离，并产生与高线性能量转移辐射α粒子发射器相当的治疗效果，但具有有限的全身毒性。因此，具有增强细胞核定位能力的[125/131I]-NLF-LINKER-bAG-TOCA对为实现高治疗指数夹夹PRRT提供了一种实用的解决方案。[125/131I]-NLF-LINKER-bAG-TOCApair将通过相同的方法进行放射性合成，这简化了该策略的临床实施。对octreate核心（bAG-TOCA）的结构修饰可能会强烈影响所提出的肽的体内药代动力学。因此，我们将制备正电子发射的[124I]-NLF-LINKER-bAG-TOCAs，并利用PET研究其药代动力学。

Aim of the PhD Project:Develop a library of 125/131I-labelled octreotate pairs that can selectively accumulate in the neuroendocrine tumour (NET) cell nuclei;Demonstrate that the tandem use of the optimal cell nuclear-localising 125/131I-labelled octreotate pair emitting beta-particles and Auger-particles is superior to the conventional [177Lu]DOTATATE in NET peptide receptor radionuclide therapy.Project DescriptionLutathera ([177Lu]DOTATATE) has become the standard treatment of somatostatin receptor type 2-expressing (SSTR2) neuroendocrine tumour (NET) patients. The NETTER-1 Phase III trial showed that Lutathera prolongs progression free survival (PFS) in metastatic NETs, although objective response rate is low (18%). Our analysis shows that PFS to Lutathera is superior in patients showing partial response compared to stable disease. Most patients on Lutathera only achieve stable disease; together with long therapy duration and high cost. Thus, more efficacious therapies are needed.A major limitation of current radiometal-based peptide receptor radionuclide therapy (PRRT) for NETs is renal toxicity compromising achievable therapeutic effectiveness, with severe (CTC grade 4-5) nephrotoxicity occurring in up to 14% of cases. Nephrotoxicity results from residualisation of radiometals in kidney cells, a property that is not associated with radioiodines. While concomitant infusion of positively charged amino acids can decrease renal toxicity, they can also accentuate nausea and vomiting. Transient bone marrow toxicity is another important side-effect of beta-emitting-PRRT.Efficacy of PRRT depends on the radionuclides decay characteristics. Despite this knowledge,there has beenlittle consideration to tailoring PRRTs to tumour burden/size. Tandem or sequential injection of [177Lu]DOTATATE and [90Y]DOTATATE (both of which emit beta-particles over a long path-length), considers differential tumour burden response, and improves efficacy. The more practical 131I/125I pair has not been studied, perhaps due to challenges in chemical accessibility and implementing facile radiochemistry to produce radioiodinated octreotates that are resistant to deiodination. We hypothesise that sandwiched PRRT with iodine-131 and iodine-125 will efficiently target both large tumours where radiotherapeutic delivery may be heterogeneous, and small micrometastases before dose-limiting toxicity is reached. This approach will allow for tailoring therapy to an individual patient's NET status with limited toxicity. Effective tumour cell killing with short path-length 125I requires the radioisotope to be spatially localised close to the nucleus. This would be achieved by using a thiol or acid sensitive linker to conjugate a radioiodinated nuclear-localising functionality (NLF) to octreotate. It is expected that following SSTR2-dependent cellular internalisation, the increased intracellular free thiol concentration or lysosomal acidity will cleave the corresponding linker and release the radioiodinated NLF which will subsequently accumulate in the cell nucleus. The disintegration of iodine-125 close to DNA will be densely ionising and elicit therapeutic effectiveness comparable to high linear energy transfer radiation alpha-particle emitters but with limited systemic toxicity. Thus, the [125/131I]-NLF-LINKER-bAG-TOCA pair with enhanced cell nuclear-localising ability provides a practical solution to achieve high therapeutic-index sandwiched PRRT. The [125/131I]-NLF-LINKER-bAG-TOCApair would be radiosynthesized via identical methods, which simplifies the clinical implementation of this strategy. The structural modifications to the octreotate core (bAG-TOCA) may strongly influence in vivo pharmacokinetics of the proposed peptides. Thus, we will prepare the positron emitting, [124I]-NLF-LINKER-bAG-TOCAs and use PET to investigate their pharmacokinetics.