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

智能细胞核定位 125/131I 标记的奥曲酸盐用于转移性神经内分泌肿瘤的夹心 β 和俄歇粒子治疗

• 批准号: 2424334
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2424334
• 关键词: Smart; cell; nuclear; localising; 125

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.

博士项目的目的：开发一个125/131 I标记的奥曲酸对库，可以选择性地在神经内分泌肿瘤（NET）细胞核中积累;证明在NET肽受体放射性核素治疗中，最佳细胞核定位125/131 I标记的奥曲酸盐对发射β粒子和Auger粒子的串联使用上级传统的[177 Lu]DOTATATE。项目描述Lutathera（[177 Lu]DOTATATE）已成为生长抑素受体2型表达（SSTR 2）神经内分泌肿瘤（NET）患者的标准治疗。NETTER-1 III期试验显示，Lutathera可延长转移性NET的无进展生存期（PFS），尽管客观缓解率较低（18%）。我们的分析显示，与疾病稳定患者相比，Lutathera的PFS在显示部分缓解的患者中更优上级。大多数使用Lutathera的患者只能达到疾病稳定;加上治疗时间长、费用高。因此，需要更有效的疗法。目前用于NET的基于放射性核素的肽受体放射性核素疗法（PRRT）的主要限制是肾毒性，其损害了可实现的治疗效果，在高达14%的病例中发生严重（CTC 4-5级）肾毒性。肾毒性由肾细胞中放射性金属的残留引起，这是一种与放射性碘无关的性质。虽然伴随输注带正电荷的氨基酸可以降低肾毒性，但它们也可以加重恶心和呕吐。瞬时骨髓毒性是β-发射-PRRT的另一个重要副作用，PRRT的疗效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/大小定制PRRT。串联或顺序注射[177 Lu]DOTATATE和[90 Y]DOTATATE（两者均在较长的路径长度上发射β粒子），考虑了不同的肿瘤负荷反应，并提高了疗效。更实用的131 I/125 I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产生抗脱碘的放射性碘化奥曲酸盐的挑战。我们假设，碘-131和碘-125的夹心PRRT将有效地靶向大肿瘤，其中放射性递送可能是异质性的，并且在达到剂量限制性毒性之前靶向小的微转移。这种方法将允许针对个体患者的NET状态定制治疗，毒性有限。使用短路径长度的125 I有效杀死肿瘤细胞需要放射性同位素在空间上定位在细胞核附近。这将通过使用硫醇或酸敏感性接头将放射性碘标记的核定位官能团（NLF）缀合至奥曲肽来实现。预期在SSTR 2依赖性细胞内化后，增加的细胞内游离巯基浓度或溶酶体酸度将切割相应的接头并释放放射性碘标记的NLF，其随后将在细胞核中积累。碘-125在DNA附近的崩解将是密集电离的，并引起与高线性能量转移辐射α粒子发射体相当的治疗效果，但全身毒性有限。因此，具有增强的细胞核定位能力的[125/131 I]-NLF-接头-bAG-TOCA对提供了实现高治疗指数夹心PRRT的实用解决方案。[125/131 I]-NLF-LINKER-bAG-TOCA对将通过相同的方法放射合成，这简化了该策略的临床实施。奥曲酸核心（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，我们将制备发射正电子的[124 I]-NLF-连接体-bAG-TOCA，并使用PET研究其药代动力学。

项目成果

Highly effective liquid and solid phase extraction methods to concentrate radioiodine isotopes for radioiodination chemistry.

• DOI: 10.1002/jlcr.3994
• 发表时间: 2022-08
• 期刊: JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS
• 影响因子: 1.8
• 作者: Davis, Christopher;Li, Chun;Nie, Ruirui;Guzzardi, Norman;Dworakowska, Barbara;Sadasivam, Pragalath;Maher, John;Aboagye, Eric O.;Lu, Zhi;Yan, Ran
• 通讯作者: Yan, Ran