靶向递送AR-V7 siRNA的双价PSMA适配体，有效抑制恩扎鲁胺耐药前列腺癌的生长
Targeted Delivery of AR-V7 siRNA with Bivalent PSMA Aptamers Effectively Suppresses the Growth of Enzalutamide-Resistant Prostate Cancer
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影响因子:4.5
分区:医学2区 / 药学2区 医学：研究与实验3区
发表日期:2024 Nov 04
作者:
Lu Xue, Xiaolin Yu, Lijing Zhao, Aria Garrett, Daqing Wu, Hong Yan Liu
DOI:
10.1021/acs.molpharmaceut.4c00743
摘要
雄激素剥夺治疗一直是晚期前列腺癌（PCa）的主要治疗策略。但大多数患者随着时间推移会发展为去势抵抗性。对于FDA已批准的第二代雄激素受体（AR）拮抗剂，包括恩扎鲁胺（ENZ）和阿比特龙（AA），最初对其有反应的患者最终会产生耐药。对ENZ/AA耐药的关键机制涉及AR剪接变异体（AR-Vs），特别是AR-V7。目前的AR拮抗剂由于缺乏C端配体结合域（LBD），而保留AR的N端结构（NTD），仍能激活雄激素响应基因，因此无法针对AR-V7。因此，靶向AR的NTD和AR-V7对于克服ENZ耐药性至关重要。不幸的是，由于难以定义其三维（3D）结构，AR NTD一直被认为是“不可药物靶向”的目标。在此背景下，siRNA非常适合解决这一难以药物化的靶点。然而，siRNA无法自由扩散进入细胞，需要载体。核酸适配体在体内靶向递送siRNA方面非常适用。在本研究中，我们开发了一种血清稳定的双价前列腺特异性膜抗原（PSMA）适配体-AR-V7 siRNA嵌合体（PAP）。结果显示，PAP可以在表达PSMA的去势抵抗性细胞中敲低全长AR和AR-V7。它能在细胞系和前列腺癌异种移植物中重新敏感化ENZ。ENZ联合PAP可以显著抑制小鼠中22Rv1异种移植物的生长，无需进行去势治疗。由于毒性低，PAP具有提供一种新型抗雄激素治疗以应对当前ENZ耐药前列腺癌的潜力。
Abstract
Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.