Kim Hongsik, Woo Chang-Gok, Son Seung-Myoung, Lee Yong-Pyo, Kim Hee-Kyung, Yang Yaewon, Kwon Jihyun, Lee Ki-Hyeong, Lee Ho-Chang, Lee Ok-Jun, Han Hye-Sook
Department of Internal Medicine, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea.
Department of Pathology, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea.
Medicina (Kaunas). 2025 Mar 26;61(4):598. doi: 10.3390/medicina61040598.
: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is involved in pancreatic cancer progression and is an attractive therapeutic target for pancreatic cancer. In this study, we evaluated the therapeutic efficacy of small-interfering RNA (siRNA) targeting CEACAM6 (siCEACAM6) and the CEACAM6-suppressive microRNA-29a (miR-29a) in a pancreatic ductal adenocarcinoma xenograft mouse model using pH-low insertion peptide (pHLIP) technology, which targets the acidic tumor microenvironment. : The delivery vectors for siRNA and miRNA were constructed by conjugating the peptide nucleic acid forms of siCEACAM6 and miR-29a to a peptide with a pHLIP, enabling the transport of siRNA and miRNA across the plasma membrane. The tumor-suppressive effects of pHLIP-siCEACAM6 and pHLIP-miR-29a were assessed in vivo using a BALB/c xenograft mouse model with the injection of the CFPAC-1 human pancreatic ductal adenocarcinoma cell line. : The treatment of CFPAC-1 cells with pHLIP-siCEACAM6 and pHLIP-miR-29a under acidic pH conditions suppressed CEACAM6 expression and decreased cell viability. In a xenograft mouse model, the intravenous injection of pHLIP-siCEACAM6 and pHLIP-miR-29a suppressed tumor growth by up to 25.1% ( < 0.01) and 21.2% ( < 0.01), respectively, compared to the control mice treated with pHLIP-scr. : Our results demonstrated the efficacy of the pHLIP-mediated delivery of siCEACAM6 and miR-29a as a promising therapeutic strategy in a pancreatic ductal adenocarcinoma xenograft mouse model. The pHLIP technology, which targets the acidic tumor microenvironment, represents an innovative approach to the delivery of small RNAs to pancreatic ductal adenocarcinoma cells, providing new potential strategies for pancreatic cancer treatment.
癌胚抗原相关细胞黏附分子6（CEACAM6）参与胰腺癌进展，是胰腺癌颇具吸引力的治疗靶点。在本研究中，我们使用靶向酸性肿瘤微环境的pH-低插入肽（pHLIP）技术，在胰腺导管腺癌异种移植小鼠模型中评估了靶向CEACAM6的小干扰RNA（siRNA，即siCEACAM6）和抑制CEACAM6的微小RNA-29a（miR-29a）的治疗效果。
通过将siCEACAM6和miR-29a的肽核酸形式与具有pHLIP的肽偶联，构建了siRNA和miRNA的递送载体，从而使siRNA和miRNA能够跨质膜转运。使用注射CFPAC-1人胰腺导管腺癌细胞系的BALB/c异种移植小鼠模型在体内评估pHLIP-siCEACAM6和pHLIP-miR-29a的肿瘤抑制作用。
在酸性pH条件下用pHLIP-siCEACAM6和pHLIP-miR-29a处理CFPAC-1细胞可抑制CEACAM6表达并降低细胞活力。在异种移植小鼠模型中，与用pHLIP-scr处理的对照小鼠相比，静脉注射pHLIP-siCEACAM6和pHLIP-miR-29a分别使肿瘤生长抑制高达25.1%（<0.01）和21.2%（<0.01）。
我们的结果证明了在胰腺导管腺癌异种移植小鼠模型中，pHLIP介导的siCEACAM6和miR-29a递送作为一种有前景的治疗策略的有效性。靶向酸性肿瘤微环境的pHLIP技术代表了一种将小RNA递送至胰腺导管腺癌细胞的创新方法，为胰腺癌治疗提供了新的潜在策略。
