Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes
Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes
复制标题
通过脂质体-微泡复合物超声控制释放阿霉素诱导增强的免疫原性细胞死亡
DOI：
10.1080/2162402x.2018.1446720
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Tan, Guang-Hong
中科院分区：
文献类型：
--
作者：
Huang, Feng-Ying;Lei, Jing;Tan, Guang-Hong
免疫原性细胞死亡(ICD)是一种特殊的细胞死亡，刺激免疫系统对抗癌细胞。超声(US)控制的脂质体-微泡复合体靶向释放药物是一种很有前途的方法，因为它具有非侵入性和通过超声成像的可见性。然而，目前尚不清楚这种方法是否能增强阿霉素等药物所致的ICD。在这里，我们制备了阿霉素-脂质体-微泡复合体(MbDox)，然后对所得MbDox进行了表征和测试，用于美国控制的Dox释放(MbDox+US治疗)，以增强在LL/2和CT26癌细胞和同基因小鼠模型中ICD的诱导。我们发现，MbDox+US处理后，肿瘤细胞对Dox的摄取和核积聚增加，肿瘤组织中的Dox积聚增多。在体外和体内均可增强ICD的诱导作用。MbDox+US处理可诱导肿瘤细胞更多的凋亡，更强的膜暴露以及ER应激蛋白和DAMs的释放，并促进DC的体外成熟。此外，MbDox+US治疗对免疫活性小鼠的治疗效果也强于免疫缺陷小鼠。此外，MbDox+US对ICD的增强作用还表现为肿瘤组织中活化的CD8(+)T淋巴细胞比例较高，而Treg比例较低。综上所述，我们的结果表明，利用脂质体-微泡复合体将ICD诱导剂在美国控制下释放到细胞核中，可能是一种有效的方法来增强ICD在肿瘤治疗中的诱导作用。
Immunogenic cell death (ICD) is a specific kind of cell death that stimulates the immune system to combat cancer cells. Ultrasound (US)-controlled targeted release of drugs by liposome-microbubble complexes is a promising approach due to its non-invasive nature and visibility through ultrasound imaging. However, it is not known whether this approach can enhance ICD induced by drugs, such as doxorubicin. Herein, we prepared a doxorubicin-liposome-microbubble complex (MbDox), and the resultant MbDox was then characterized and tested for US-controlled release of Dox (MbDox+US treatment) to enhance the induction of ICD in LL/2 and CT26 cancer cells and in syngeneic murine models. We found that MbDox+US treatment caused more cellular uptake and nuclear accumulation of Dox in tumor cells, and more accumulation of Dox in tumor tissues. Enhanced induction of ICD occurred both in vitro and in vivo. MbDox+US treatment induced more apoptosis, stronger membrane exposure and the release of ER stress proteins and DAMPs in tumor cells, and increased DC maturation in vitro. In addition, MbDox+US treatment also resulted in stronger therapeutic effects in immunocompetent mice than in immunodeficient mice. Moreover, MbDox+US enhancement of ICD was also evidenced by a higher proportion of activated CD8(+) T-lymphocytes but lower Treg in tumor tissues. Taken together, our results demonstrate that US-controlled release of ICD inducers into nuclei using liposome-microbubble complexes may be an effective approach to enhance the induction of ICD for tumor treatment.