College of Pharmacy and Bionanocomposite Research Center, Kyung Hee University, Seoul 02447, Republic of Korea.
Department of Biomedical & Health Science, Konkuk University, Chungju 27478, Republic of Korea.
J Control Release. 2021 Mar 10;331:434-442. doi: 10.1016/j.jconrel.2021.01.031. Epub 2021 Jan 27.
Despite recent advances in chemotherapy, pancreatic cancer remains a leading cause of cancer-related deaths. Moreover, although targeted therapy has shown promising therapeutic efficacy in many types of cancers, no such effective targeting strategy for treatment of pancreatic cancer, which is in desperate need for new treatment approaches. Here, we developed claudin-4-targeting Clostridium perfringens enterotoxin (CPE) peptide-conjugated polysialic acid nanoparticles (C-SNPs) for pancreatic cancer-targeted therapy. Doxorubicin-loaded C-SNPs (DOX-C-SNPs) higly accumulated in the targeted pancreatic cancer via enhanced peameability and retention (EPR) effect, targeting claudin-4 in pancreatic cancer that becomes superficially exposed owing to the disruption of tight junctions. Notably, DOX-C-SNP accumulation in the non-targeted, normal pancreas was significantly reduced because of hindered access to claudin-4 in tight junctions. As a result, DOX-C-SNPs substantially suppressed tumor growth in an orthotopic pancreatic cancer model while exerting minimal toxicity against non-targeted, normal tissues. Collectively, these findings indicate that claudin-4-targeting DOX-C-SNPs may have promise in treating pancreatic cancers through targeting of exposed claudin-4.
尽管化疗在最近取得了进展，但胰腺癌仍然是癌症相关死亡的主要原因。此外，尽管靶向治疗在许多类型的癌症中显示出了有希望的治疗效果，但针对胰腺癌却没有这样的有效靶向治疗策略，因此迫切需要新的治疗方法。在这里，我们开发了针对紧密连接蛋白 4 的产气荚膜梭菌肠毒素（CPE）肽偶联聚唾液酸纳米粒（C-SNPs）用于胰腺癌的靶向治疗。载多柔比星的 C-SNPs（DOX-C-SNPs）通过增强通透性和滞留（EPR）效应高度积聚在靶向胰腺癌中，靶向由于紧密连接破坏而表面暴露的胰腺癌中的紧密连接蛋白 4。值得注意的是，由于难以进入紧密连接中的紧密连接蛋白 4，DOX-C-SNP 在非靶向的正常胰腺中的积聚显著减少。结果，DOX-C-SNPs 在原位胰腺癌模型中显著抑制了肿瘤生长，同时对非靶向的正常组织的毒性最小。总的来说，这些发现表明，针对紧密连接蛋白 4 的 DOX-C-SNPs 通过靶向暴露的紧密连接蛋白 4，可能在治疗胰腺癌方面具有潜力。
