Liposomal Delivery of Mitoxantrone and a Cholesteryl Indoximod Prodrug Provides Effective Chemo-immunotherapy in Multiple Solid Tumors.
Liposomal Delivery of Mitoxantrone and a Cholesteryl Indoximod Prodrug Provides Effective Chemo-immunotherapy in Multiple Solid Tumors.
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DOI：
10.1021/acsnano.0c05194
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发表时间：
2020-10-27
期刊：
影响因子：
17.1
通讯作者：
Nel AE
中科院分区：
文献类型：
--
作者：
Mei KC;Liao YP;Jiang J;Chiang M;Khazaieli M;Liu X;Wang X;Liu Q;Chang CH;Zhang X;Li J;Ji Y;Melano B;Telesca D;Xia T;Meng H;Nel AE
我们开发了一种定制设计的脂质体载体，用于共同递送强效免疫原性细胞死亡（ICD）刺激物和吲哚胺2，3-双加氧酶（IDO-1）途径的抑制剂，以建立同基因小鼠实体瘤的化学免疫治疗方法。通过远程输入蒽醌化疗剂米托蒽醌（MTO）到脂质体中来构建载体，脂质体进一步在脂质双层中赋予胆固醇缀合的吲哚西莫德（IND）前药。对于原理验证测试，我们在CT 26结肠癌模型中使用MTO/IND脂质体的IV注射来证明稳健免疫应答的产生，其特征在于ICD标志物（CRT和HMGB-1）的出现以及由穿孔素和颗粒酶B介导的细胞毒性癌细胞死亡的证据。值得注意的是，细胞毒性效应涉及自然杀伤细胞（NK），这表明一种新型ICD反应。IND前药的共递送显著增强了免疫治疗应答，这诱导了额外的CRT表达，减少了Foxp 3 + Treg的数量并增加了穿孔素释放，此外还延长了动物存活率，超过了仅MTO脂质体的效果。该结果反映了通过载体将MTO递送至癌症部位的改善的药代动力学。鉴于在CT 26模型中的成功，我们还评估了平台在过表达IDO-1的其他乳腺癌（EMT 6和4 T1）和肾癌（RENCA）模型中的功效。在所有肿瘤模型中，在NK参与下，包封的MTO递送对于诱导化学免疫治疗应答是高度有效的。此外，在EMT 6和4 T1肿瘤中，通过IND共递送增强了MTO的生长抑制作用。考虑到所有因素，我们的数据支持使用包封的MPO递送进行化学免疫治疗，并且有可能通过共同递送IDO-1途径抑制剂来增强免疫反应。
We developed a custom-designed liposome carrier for co-delivery of a potent immunogenic cell death (ICD) stimulus plus an inhibitor of the indoleamine 2,3-dioxygenase (IDO-1) pathway to establish a chemo-immunotherapy approach for solid tumors in syngeneic mice. The carrier was constructed by remote import of the anthraquinone chemotherapeutic agent, mitoxantrone (MTO), into the liposomes, which were further endowed with a cholesterol-conjugated indoximod (IND) prodrug in the lipid bilayer. For proof-of-principle testing, we used IV injection of the MTO/IND liposome in a CT26 colon cancer model to demonstrate the generation of a robust immune response, characterized by the appearance of ICD markers (CRT and HMGB-1) as well as evidence of cytotoxic cancer cell death, mediated by perforin and granzyme B. Noteworthy, the cytotoxic effects involved natural killer (NK), which suggests a novel type of ICD response. The immunotherapy response was significantly augmented by co-delivery of the IND prodrug, which induced additional CRT expression, reduced number of Foxp3+ Treg and increased perforin release, in addition to extending animal survival beyond the effect of an MTO-only liposome. The outcome reflects the improved pharmacokinetics of MTO delivery to the cancer site by the carrier. In light of the success in the CT26 model, we also assessed the platform efficacy in further breast cancer (EMT6 and 4T1) and renal cancer (RENCA) models, which overexpress IDO-1. Encapsulated MTO delivery was highly effective for inducing chemo-immunotherapy responses, with NK participation, in all tumor models. Moreover, the growth inhibitory effect of MTO was enhanced by IND co-delivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by co-delivery of an IDO-1 pathway inhibitor.
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影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
--
作者：
Bayraktar, Soley;Batoo, Sameer;Gluck, Stefan
通讯作者：
Gluck, Stefan
影响因子：
4.7
作者：
Fox E;Oliver T;Rowe M;Thomas S;Zakharia Y;Gilman PB;Muller AJ;Prendergast GC
通讯作者：
Prendergast GC
影响因子：
7.3
作者：
Castro F;Cardoso AP;Gonçalves RM;Serre K;Oliveira MJ
通讯作者：
Oliveira MJ
影响因子：
8.8
作者：
Chang CW;Barber L;Ouyang C;Masin D;Bally MB;Madden TD
通讯作者：
Madden TD