Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies,Molecular Pharmaceutics

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Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-25 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00720
Hsiou-Ting Kuo ₁ , Helen Merkens ₁ , Zhengxing Zhang ₁ , Carlos F. Uribe ₁ , Joseph Lau ₁ , Chengcheng Zhang ₁ , Nadine Colpo ₁ , Kuo-Shyan Lin _{1,

2,

3} , François Bénard _{1,

2,

3}

Affiliation

We designed and evaluated a novel albumin-binder-conjugated ¹⁷⁷Lu-PSMA-617 derivative, ¹⁷⁷Lu-HTK01169, with an extended blood retention time to maximize the radiation dose delivered to prostate tumors expressing prostate-specific membrane antigen (PSMA). PSMA-617 and HTK01169 that contained N-[4-(p-iodophenyl)butanoyl]-Glu as an albumin-binding motif were synthesized using the solid-phase approach. Binding affinity to PSMA was determined by in vitro competition-binding assay. ¹⁷⁷Lu labeling was performed in acetate buffer (pH 4.5) at 90 °C for 15 min. SPECT/CT imaging, biodistribution, and endoradiotherapy studies were conducted in mice bearing PSMA-expressing LNCaP tumor xenografts. Radiation dosimetry was calculated using OLINDA software. Lu-PSMA-617 and Lu-HTK01169-bound PSMA with high affinity (K_i values = 0.24 and 0.04 nM, respectively). SPECT imaging and biodistribution studies showed that ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-HTK01169 were excreted mainly via the renal pathway. With fast blood clearance (0.68%ID/g at 1 h postinjection), the tumor uptake of ¹⁷⁷Lu-PSMA-617 peaked at 1 h postinjection (15.1%ID/g) and gradually decreased to 7.91%ID/g at 120 h postinjection. With extended blood retention (16.6 and 2.10%ID/g at 1 and 24 h, respectively), the tumor uptake of ¹⁷⁷Lu-HTK01169 peaked at 24 h postinjection (55.9%ID/g) and remained at the same level by the end of the study (120 h). Based on dosimetry calculations, ¹⁷⁷Lu-HTK01169 delivered an 8.3-fold higher radiation dose than ¹⁷⁷Lu-PSMA-617 to LNCaP tumor xenografts. For the endoradiotherapy study, the mice treated with ¹⁷⁷Lu-PSMA-617 (18.5 MBq) all reached humane end point (tumor volume >1000 mm³) by Day 73 with a median survival of 58 days. Mice treated with 18.5, 9.3, 4.6, or 2.3 MBq of ¹⁷⁷Lu-HTK01169 had a median survival of >120, 103, 61, and 28 days, respectively. With greatly enhanced tumor uptake and treatment efficacy compared to ¹⁷⁷Lu-PSMA-617 in preclinical studies, ¹⁷⁷Lu-HTK01169 warrants further investigation for endoradiotherapy of prostate cancer.

中文翻译：

结合白蛋白结合基序增强¹⁷⁷ Lu-PSMA-617的治疗功效：临床前剂量测定法和放射治疗

我们设计并评估了新型白蛋白-结合物¹⁷⁷ Lu-PSMA-617衍生物¹⁷⁷ Lu-HTK01169，具有延长的血液保留时间，以最大化传递至表达前列腺特异性膜抗原（PSMA）的前列腺肿瘤的放射剂量。使用固相方法合成了包含N- [4-（对碘苯基）丁酰基] -Glu作为白蛋白结合基序的PSMA-617和HTK01169 。通过体外竞争结合测定法测定对PSMA的结合亲和力。¹⁷⁷在90°C的乙酸盐缓冲液（pH 4.5）中进行Lu标记15分钟。在携带表达PSMA的LNCaP肿瘤异种移植物的小鼠中进行了SPECT / CT成像，生物分布和放射治疗研究。使用OLINDA软件计算辐射剂量。Lu-PSMA-617和Lu-HTK01169结合的PSMA具有高亲和力（K _i值分别为0.24和0.04 nM）。SPECT成像和生物分布研究表明，¹⁷⁷ Lu-PSMA-617和¹⁷⁷ Lu-HTK01169主要通过肾脏途径排泄。快速血液清除（注射后1小时内为0.68％ID / g），肿瘤摄取量为¹⁷⁷Lu-PSMA-617在注射后1 h达到峰值（15.1％ID / g），并在注射后120 h逐渐降低至7.91％ID / g。随着血液滞留时间延长（分别在1和24 h时分别为16.6和2.10％ID / g），¹⁷⁷ Lu-HTK01169的肿瘤吸收在注射后24 h达到峰值（55.9％ID / g），并在结束时保持相同水平研究（120小时）。根据剂量学计算，对LNCaP肿瘤异种移植，¹⁷⁷ Lu-HTK01169的放射剂量比¹⁷⁷ Lu-PSMA-617高8.3倍。对于放射治疗研究，到¹⁷⁷天时，用¹⁷⁷ Lu-PSMA-617（18.5 MBq）治疗的小鼠均达到了人性化的终点（肿瘤体积> 1000 mm ³），中位生存期为58天。用^177的18.5、9.3、4.6或2.3 MBq处理的小鼠Lu-HTK01169的中位生存期分别为> 120、103、61和28天。有了大大提高肿瘤摄取和治疗的功效，与¹⁷⁷路，PSMA-617在临床前研究中，¹⁷⁷路，HTK01169权证前列腺癌的endoradiotherapy进一步调查。

更新日期：2018-09-25

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