Acta Biomaterialia ( IF 9.4 ) Pub Date : 2023-07-13 , DOI: 10.1016/j.actbio.2023.07.008 Ri Huang 1 , Hong Du 2 , Liang Cheng 1 , Peizhuo Zhang 2 , Fenghua Meng 3 , Zhiyuan Zhong 1
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Pancreatic cancer (PC) stands as a most deadly malignancy due to few effective treatments in the clinics. KRAS G12D mutation is a major driver for most PC cases, and silencing of KRAS G12D is considered as a potential therapeutic strategy for PC, which is nevertheless crippled by lacking a pragmatic delivery system for siRNA against KRAS G12D (siKRAS). Here, we report that cRGD peptide-modified bioresponsive chimaeric polymersomes (cRGD-BCP) mediate highly efficient siKRAS delivery to PANC-1 tumor, potently silencing KRAS G12D mRNA in tumor cells and effectively suppressing PC tumor growth in mice. cRGD-BCP exhibited remarkable encapsulation of siKRAS (loading content > 14 wt.%, loading efficiency > 90%) to form stable and uniform (ca. 68 nm) nanovesicles (cRGD-BCP-siKRAS). Of note, cRGD density greatly impacted the cellular uptake and silencing efficiency of cRGD-BCP-siKRAS in PANC-1 cells, in which an optimal cRGD density of 15.7 mol.% achieved 3.7- and 3.6-fold enhancement of internalization and gene silencing, respectively, compared with non-targeted BCP-siKRAS. cRGD-BCP-siKRAS was practically intact after 3-week storage at 4°C. Intriguingly, cRGD-BCP-siKRAS markedly enhanced the uptake of siKRAS in PANC-1 tumor, and at a siKRAS dose of 3 mg/kg knocked down 90% KRAS G12D gene, resulting in potent tumor inhibition and extraordinary survival benefits (median survival time: 101 days versus 38 (PBS group) and 59 days (BCP-siKRAS)) with 40% mice achieved complete regression. It appears that cRGD-mediated nanodelivery of siKRAS provides a potential cure for pancreatic cancer.
Statement of significance
Small interfering RNA (siRNA) emerges as a specific and powerful biopharmaceuticals against cancers; however, inefficient in vivo delivery impedes its clinical translation. In spite of the fact that KRAS G12D mutation has been identified as a major driver for most pancreatic cancer, its notorious non-druggability renders little success on development of molecular targeted drugs. Pancreatic cancer is deemed as current king-of-cancer. Here, we show that cyclic RGD peptide installed bioresponsive polymersomes are able to efficiently deliver siRNA against KRAS G12D to pancreatic tumor, resulting in 90% gene knock-down and effective tumor inhibition. Strikingly, two out of five mice have been cured. This targeted nanodelivery of siRNA provides a high-efficacy treatment strategy for pancreatic cancer.
中文翻译：
针对 KRAS G12D 的 siRNA 纳米靶向递送可抑制胰腺癌
由于临床上缺乏有效的治疗方法，胰腺癌（PC）是一种最致命的恶性肿瘤。 KRAS G12D突变是大多数 PC 病例的主要驱动因素， KRAS G12D沉默被认为是 PC 的潜在治疗策略，但由于缺乏针对KRAS G12D的siRNA ( siKRAS ) 的实用递送系统， PC 受到削弱。在此，我们报告cRGD肽修饰的生物响应性嵌合聚合物体（cRGD-BCP）介导高效地将siKRAS递送至PANC-1肿瘤，有效沉默肿瘤细胞中的KRAS G12D mRNA并有效抑制小鼠PC肿瘤的生长。 cRGD-BCP表现出对siKRAS的显着封装（负载量> 14 wt.%，负载效率> 90%），形成稳定且均匀（约68 nm）的纳米囊泡（cRGD-BCP- siKRAS ）。值得注意的是，cRGD 密度极大地影响了 PANC-1 细胞中 cRGD-BCP- siKRAS的细胞摄取和沉默效率，其中 15.7 mol.% 的最佳 cRGD 密度实现了内化和基因沉默的 3.7 倍和 3.6 倍增强。分别与非靶向 BCP- siKRAS相比。 cRGD-BCP- siKRAS在 4°C 保存 3 周后几乎完好无损。 有趣的是，cRGD-BCP- siKRAS显着增强了 PANC-1 肿瘤中siKRAS的摄取，并且在 3 mg/kg 的siKRAS剂量下，敲低 90% KRAS G12D基因，从而产生有效的肿瘤抑制和非凡的生存益处（中位生存时间） ：101 天对比38 天（PBS 组）和 59 天（BCP- siKRAS ）），40% 的小鼠实现了完全消退。 cRGD 介导的siKRAS纳米递送似乎为胰腺癌提供了潜在的治疗方法。
重要性声明
小干扰RNA（ siRNA ）作为一种特异性强的抗癌生物药物而出现；然而，体内递送效率低下阻碍了其临床转化。尽管KRAS G12D突变已被确定为大多数胰腺癌的主要驱动因素，但其臭名昭著的非成药性使得分子靶向药物的开发收效甚微。胰腺癌被认为是当前的癌症之王。在这里，我们表明，安装有环状 RGD 肽的生物响应性聚合物囊泡能够有效地将针对KRAS G12D的siRNA递送至胰腺肿瘤，从而实现 90% 的基因敲低和有效的肿瘤抑制。引人注目的是，五分之二的老鼠被治愈了。这种靶向纳米递送siRNA为胰腺癌提供了高效的治疗策略。
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