Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Suzhou GenePharma Co., Ltd., Suzhou 215123, PR China.
Acta Biomater. 2023 Sep 15;168:529-539. doi: 10.1016/j.actbio.2023.07.008. Epub 2023 Jul 13.
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.
胰腺癌（PC）是一种最为致命的恶性肿瘤，因为目前临床上几乎没有有效的治疗方法。KRAS G12D 突变是大多数 PC 病例的主要驱动因素，沉默 KRAS G12D 被认为是 PC 的一种潜在治疗策略，但由于缺乏针对 KRAS G12D 的实用 siRNA 递送系统（siKRAS）而受到阻碍。在这里，我们报告了 cRGD 肽修饰的生物响应性嵌合聚合物囊泡（cRGD-BCP）可将高效的 siKRAS 递送至 PANC-1 肿瘤，在肿瘤细胞中强力沉默 KRAS G12D mRNA，并有效抑制小鼠的 PC 肿瘤生长。cRGD-BCP 能够显著包封 siKRAS（载药量>14wt%，载药效率>90%），形成稳定且均匀的（约 68nm）纳米囊泡（cRGD-BCP-siKRAS）。值得注意的是，cRGD 密度极大地影响了 cRGD-BCP-siKRAS 在 PANC-1 细胞中的细胞摄取和沉默效率，其中最佳的 cRGD 密度为 15.7mol.%，与非靶向 BCP-siKRAS 相比，分别实现了 3.7 倍和 3.6 倍的内化和基因沉默增强。cRGD-BCP-siKRAS 在 4°C 下储存 3 周后几乎保持完整。有趣的是，cRGD-BCP-siKRAS 显著增强了 siKRAS 在 PANC-1 肿瘤中的摄取，在 siKRAS 剂量为 3mg/kg 时，可使 90%的 KRAS G12D 基因失活，从而导致强烈的肿瘤抑制和非凡的生存获益（中位生存时间：101 天，与 PBS 组相比为 38 天和 59 天，与 BCP-siKRAS 相比），40%的小鼠实现了完全消退。这表明 cRGD 介导的 siKRAS 纳米递药为胰腺癌提供了一种潜在的治愈方法。
小干扰 RNA（siRNA）作为一种针对癌症的特异性和强大的生物制药，已崭露头角；然而，其体内递送效率低下，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，但由于其臭名昭著的不可成药性，在开发分子靶向药物方面几乎没有取得成功。胰腺癌被认为是当前的癌症之王。在这里，我们发现环状 RGD 肽修饰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。值得注意的是，有五只老鼠中的两只已经被治愈。这种针对 siRNA 的靶向递药为胰腺癌提供了一种高效的治疗策略。
