Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
J Control Release. 2021 Jul 10;335:306-319. doi: 10.1016/j.jconrel.2021.05.040. Epub 2021 May 31.
Chemo-immunotherapy based on immunogenic cell death (ICD) is a promising strategy for cancer therapy. However, the effective ICD requires a high dosage of ICD stimulus, which could be associated to a dose-dependent toxicity. Therefore, in this study, a liposome remote-loaded with shikonin (a potent ICD stimulus) was developed, with the ability to effectively induce ICD at high dosage in vivo. However, a hepatotoxic effect was observed. To circumvent this problem, shikonin was combined with the anthracycline mitoxantrone or doxorubicin to develop co-loaded liposomes inducing a synergistic ICD effect and cytotoxicity to tumor cells. Cytotoxicity and uptake experiment in vitro were performed to analyze the optimal synergistic ratio of shikonin and anthracyclines based on a "formulated strategy". Interestingly, copper mediated co-loaded liposomes resulted in a pH and GSH dual-responsive release property. More importantly, pharmacokinetics and tumor biodistribution studies revealed an outstanding capacity of ratiometric delivery of dual drugs. Thus, the dual-loaded liposome enhanced the antitumor effect by the stimulation of a robust immune response at lower doses of the drugs with a higher safety compared to single-loaded liposomes. Summarized, the current work provided a reference for a rational design and development of liposomal co-delivery system of drugs and ICD-induced chemo-immunotherapy, and established a potential clinical application of shikonin-based drug combinations as a new chemo-immunotherapeutic strategy for cancer treatment.
基于免疫原性细胞死亡 (ICD) 的化疗免疫治疗是癌症治疗的一种有前途的策略。然而，有效的 ICD 需要高剂量的 ICD 刺激，这可能与剂量依赖性毒性有关。因此，在这项研究中，开发了一种脂质体远程负载紫草素（一种有效的 ICD 刺激物），能够在体内以高剂量有效诱导 ICD。然而，观察到了肝毒性。为了解决这个问题，将紫草素与蒽环类药物米托蒽醌或阿霉素联合开发共载脂质体，以诱导协同 ICD 效应和细胞毒性肿瘤细胞。进行了体外细胞毒性和摄取实验，以根据“配方策略”分析紫草素和蒽环类药物的最佳协同比例。有趣的是，铜介导的共载脂质体具有 pH 和 GSH 双重响应释放特性。更重要的是，药代动力学和肿瘤组织分布研究揭示了双药物的比率传递具有出色的能力。因此，与单载脂质体相比，双载脂质体通过刺激更强的免疫反应以更低的药物剂量增强了抗肿瘤作用，具有更高的安全性。总之，本工作为药物和 ICD 诱导的化疗免疫治疗的脂质体共递药系统的合理设计和开发提供了参考，并为以紫草素为基础的药物组合作为癌症治疗的新化疗免疫治疗策略建立了潜在的临床应用。
