Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland BT52 1SA, UK.
Department of HPB Surgery, Mater Hospital, Belfast, Northern Ireland BT14 6AB, UK.
J Control Release. 2018 Jun 10;279:8-16. doi: 10.1016/j.jconrel.2018.04.018. Epub 2018 Apr 11.
Pancreatic cancer remains one of the most lethal forms of cancer with a 10-year survival of <1%. With little improvement in survival rates observed in the past 40 years, there is a significant need for new treatments or more effective strategies to deliver existing treatments. The antimetabolite gemcitabine (Gem) is the most widely used form of chemotherapy for pancreatic cancer treatment, but is known to produce significant side effects when administered systemically. We have previously demonstrated the benefit of combined chemo-sonodynamic therapy (SDT), delivered using oxygen carrying microbubbles (OMB), as a targeted treatment for pancreatic cancer in a murine model of the disease. In this manuscript, we report the preparation of a biotin functionalised Gem ligand for attachment to OMBs (OMB-Gem). We demonstrate the effectiveness of chemo-sonodynamic therapy following ultrasound-targeted-microbubble-destruction (UTMD) of the OMB-Gem and a Rose Bengal loaded OMB (OMB-RB) as a targeted treatment for pancreatic cancer. Specifically, UTMD using the OMB-Gem and OMB-RB conjugates reduced the viability of MIA PaCa-2, PANC-1, BxPC3 and T110299 pancreatic cancer cells by >60% (p < 0.001) and provided significant tumour growth delay (>80%, p < 0.001) compared to untreated animals when human xenograft MIA PaCa-2 tumours were treated in SCID mice. The toxicity of the OMB-Gem conjugate was also determined in healthy non-tumour bearing MF1 mice and revealed no evidence of renal or hepatic damage. Therefore, the results presented in this manuscript suggest that chemo-sonodynamic therapy using the OMB-Gem and OMB-RB conjugates, is potentially an effective targeted and safe treatment modality for pancreatic cancer.
胰腺癌仍然是最致命的癌症形式之一，10 年生存率<1%。在过去的 40 年中，生存率几乎没有提高，因此迫切需要新的治疗方法或更有效的策略来提供现有治疗。抗代谢物吉西他滨（Gem）是治疗胰腺癌最广泛使用的化疗形式，但已知全身给药时会产生明显的副作用。我们之前已经证明了使用载氧微泡（OMB）进行联合化疗-声动力学治疗（SDT）作为疾病的一种靶向治疗在胰腺癌的小鼠模型中的益处。在本文中，我们报告了一种用于附着于 OMB 的生物素功能化 Gem 配体的制备（OMB-Gem）。我们证明了在使用 OMB-Gem 和负载 Rose Bengal 的 OMB（OMB-RB）进行超声靶向微泡破坏（UTMD）后，化疗-声动力学治疗的有效性，这是一种针对胰腺癌的靶向治疗。具体而言，使用 OMB-Gem 和 OMB-RB 缀合物进行 UTMD 可使 MIA PaCa-2、PANC-1、BxPC3 和 T110299 胰腺癌细胞的活力降低>60%（p<0.001），并且与未处理的动物相比，当在 SCID 小鼠中治疗人异种移植物 MIA PaCa-2 肿瘤时，提供了显著的肿瘤生长延迟（>80%，p<0.001）。还在健康的非肿瘤 bearing MF1 小鼠中确定了 OMB-Gem 缀合物的毒性，并且没有发现肾脏或肝脏损伤的证据。因此，本文中提出的结果表明，使用 OMB-Gem 和 OMB-RB 缀合物进行化疗-声动力学治疗可能是一种有效的针对胰腺癌的靶向且安全的治疗方式。
