School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
Mol Cancer. 2021 Jan 6;20(1):10. doi: 10.1186/s12943-020-01297-0.
FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu.
A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies.
Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice.
This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.
FOLFOX 是一种包含亚叶酸（FnA，FOL）、氟尿嘧啶（5-Fu，F）和奥沙利铂（OxP，OX）的联合方案，长期以来一直被认为是结直肠癌（CRC）和肝细胞癌（HCC）的标准治疗方法。最近，纳米递药系统的发展为提高抗癌疗效和缓解 FOLFOX 的副作用提供了深远的前景。此前，我们实验室使用纳米沉淀技术开发了一种包含 OxP 衍生物和 FnA 的纳米制剂（称为 Nano-Folox）。Nano-Folox 诱导 OxP 介导的免疫原性细胞死亡（ICD）相关抗肿瘤免疫，当与游离 5-Fu 联合给药时，可显著抑制原位 CRC 小鼠模型中的肿瘤生长。
我们使用纳米沉淀技术新开发了一种包含 FdUMP（5-Fu 活性代谢物）的纳米制剂（称为 Nano-FdUMP），并将其与 Nano-Folox 联合用于 CRC 和 HCC 治疗。
在原位 CRC 和 HCC 小鼠模型中实现了协同疗效。这主要是由于 Nano-FdUMP 介导了活性氧（ROS）的形成，从而增强了 Nano-Folox 诱导的 ICD 疗效。此外，Nano-Folox/Nano-FdUMP 联合抗 PD-L1 抗体显著抑制 CRC 肝转移，使小鼠长期存活。
本研究提供了概念验证，即两种纳米递药系统的联合可以成功治疗 FOLFOX 相关的 CRC 和 HCC。在剂量和时间方面进一步优化将增强该联合策略对患者的临床潜力。
