具有双重PSMA适体的AR-V7 siRNA的靶向递送有效地抑制了耐恩扎拉胺的前列腺癌的生长
Targeted Delivery of AR-V7 siRNA with Bivalent PSMA Aptamers Effectively Suppresses the Growth of Enzalutamide-Resistant Prostate Cancer
影响因子:4.50000
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
摘要
雄激素剥夺疗法一直是晚期前列腺癌（PCA）的主要治疗策略。但是大多数患者会随着时间的流逝而产生cast割的阻力。对于FDA批准的第二代雄激素受体（AR）拮抗剂，包括enzalutamide（ENZ）和阿比拉特酮（AA），最初对它们做出反应的患者最终会产生抗药性。抵抗ENZ/AA的关键机制涉及AR剪接变体（AR-VS），特别是AR-V7。当前的AR拮抗剂由于缺乏C末端配体结合结构域（LBD）而无法靶向AR-V7，但仍可以保持AR N末端结构域（NTD），该结构域（NTD）仍然可以激活雄激素反应基因。因此，靶向AR 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，因此AR NTD被认为是“不可能”的目标。在这种情况下，siRNA非常适合解决这一不良目标。但是，siRNA不能自由扩散到细胞中，需要载体。在这方面，基于核酸的适体非常适合体内siRNA的细胞类型递送。在这项研究中，我们开发了一种血清稳定的二价前列腺特异性膜抗原（PSMA）Aptamer-AR-V7 siRNA Chimera（PAP）。结果表明，PAP可以在表达PSMA的castration耐药细胞中击倒AR-FULL长度和AR-V7。它可以在细胞系和PCA异种移植物中恢复ENZ。 ENZ与PAP结合可以显着抑制小鼠的22RV1异种移植的生长而不会经历cast割。由于毒性低，PAP具有为当前耐ENZ耐药PCA提供新的抗二氧化碳处理。
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.