Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea.
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Korea.
Molecules. 2022 Apr 14;27(8):2529. doi: 10.3390/molecules27082529.
Pancreatic cancer is a highly fatal disease that is becoming an increasingly leading cause of cancer-related deaths. In clinic, the most effective approach to treat pancreatic cancers is the combination treatment of several chemotherapeutic drugs, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), but this approach is not adequate to manage patients due to their severe toxic side effects. Herein, we proposed light-activated monomethyl auristatin E (MMAE) prodrug nanoparticles for combinational photo-chemotherapy and optimized its applications for pancreatic cancer treatment. The photosensitizer (Ce6) and chemotherapeutic drug (MMAE) were conjugated through caspase-3-specific cleavable peptide (KGDEVD). The resulting CDM efficiently promoted the reactive oxygen species (ROS) under visible light irradiation and thereby induced caspase-3 overexpression in pacreatic cancers, which subsequently released the MMAE from the system. Importantly, MMAE released from CDM further amplified the activation of CDM into MMAE by inducing extensive apoptotic cell death in tumor microenvironment for treatment of tumor cells in deep in the tumor tissues as far visible light cannot reach. In addition, CDM formed prodrug nanoparticles via intermolecular π-π stacking and hydrophobic interactions, allowing durable and reliable treatment by preventing fast leakage from the pancreatic cancers via the lymphatic vessels. The CDM directly (intratumoral) injected into pancreatic cancers in orthotopic models through an invasive approach significantly delayed the tumor progression by combinational photo-chemotherapy with less toxic side effects. This study offers a promising and alternative approach for safe and more effective pancreatic cancer treatment via prodrug nanoparticles that combine photodynamic therapy and chemotherapy.
胰腺癌是一种高度致命的疾病，正成为癌症相关死亡的一个越来越主要的原因。在临床上，治疗胰腺癌最有效的方法是几种化疗药物的联合治疗，包括氟尿嘧啶、亚叶酸钙、伊立替康和奥沙利铂（FOLFIRINOX），但由于其严重的毒副作用，这种方法不足以治疗患者。在此，我们提出了光激活单甲基奥瑞他汀 E（MMAE）前药纳米颗粒用于联合光化疗，并优化了其在胰腺癌治疗中的应用。光敏剂（Ce6）和化疗药物（MMAE）通过半胱氨酸天冬氨酸蛋白酶-3（caspase-3）特异性切割肽（KGDEVD）连接。所得的 CDM 在可见光照射下有效地促进了活性氧（ROS）的产生，从而诱导胰腺癌细胞中 caspase-3 的过表达，随后将 MMAE 从系统中释放出来。重要的是，从 CDM 释放的 MMAE 通过诱导肿瘤微环境中广泛的细胞凋亡死亡，进一步放大了 CDM 向 MMAE 的激活，从而治疗肿瘤组织深处的肿瘤细胞，因为可见光无法到达这些细胞。此外，CDM 通过分子间的π-π堆积和疏水相互作用形成前药纳米颗粒，通过防止通过淋巴管从胰腺癌细胞中快速漏出，从而实现持久和可靠的治疗。CDM 通过一种侵入性方法直接（瘤内）注射到原位模型中的胰腺癌中，通过联合光化疗显著延缓了肿瘤的进展，且毒副作用较小。这项研究为通过光动力疗法和化疗相结合的前药纳米颗粒治疗胰腺癌提供了一种有前途的替代方法，具有安全性和更高的疗效。
