Preclinical Development and Validation of Translational Temperature Sensitive Iodized Oil Emulsion Mediated Transcatheter Arterial Chemo-Immuno-Embolization for the Treatment of Hepatocellular Carcinoma,Advanced Healthcare Materials

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Preclinical Development and Validation of Translational Temperature Sensitive Iodized Oil Emulsion Mediated Transcatheter Arterial Chemo-Immuno-Embolization for the Treatment of Hepatocellular Carcinoma
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2023-05-10 , DOI: 10.1002/adhm.202300906
Heegon Kim ₁ , Bongseo Choi ₁ , Samdeep K Mouli _{1,

2} , Hyunjun Choi _{1,

3} , Kathleen R Harris ₁ , Laura M Kulik ₁ , Robert J Lewandowski _{1,

2} , Dong-Hyun Kim _{1,

2,

3,

4}

Affiliation

Herein a practical strategy for augmenting immune activation in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) is presented. Pluronic F127 (PF127) is incorporated with Lipiodol (LPD) to achieve safe and effective delivery of therapeutic agents during transcatheter intra-arterial (IA) local delivery. Enhanced emulsion stability, IA infusion, embolic effect, safety, pharmacokinetics, and tumor response of Doxorubicin loaded PF127-LPD (Dox-PF127-LPD) for TACE in both in vitro and in vivo preclinical VX2 liver cancer rabbit model and N1S1 HCC rat model are demonstrated. Then, transcatheter arterial chemo-immuno-embolization (TACIE) combining TACE and local delivery of immune adjuvant (TLR9 agonist CpG oligodeoxynucleotide) is successfully performed using CpG-loaded Dox-PF127-LPD. Concurrent and safe local delivery of CpG and TACE during TACIE demonstrate leveraged TACE-induced immunogenic tumor microenvironment and augment systemic anti-tumor immunity in syngeneic N1S1 HCC rat model. Finally, the broad utility and enhanced therapeutic efficacy of TACIE are validated in the diethylnitrosamine-induced rat HCC model. TACIE using clinically established protocols and materials shall be a convenient and powerful therapeutic approach that can be translated to patients with HCC. The robust anti-cancer immunity and tumor regression of TACIE, along with its favorable safety profile, indicate its potential as a novel localized combination immunotherapy for HCC treatment.

中文翻译：

转化温度敏感碘油乳剂介导的经导管动脉化疗免疫栓塞治疗肝细胞癌的临床前开发和验证

在此，提出了一种在肝细胞癌（HCC）的经导管动脉化疗栓塞（TACE）中增强免疫激活的实用策略。Pluronic F127 （PF127）与碘醇（LPD）结合，可在经导管动脉内（IA）局部输送过程中实现治疗剂的安全有效输送。证明了载有阿霉素的 PF127-LPD （Dox-PF127-LPD）用于 TACE 在体外和体内临床前 VX2 肝癌兔模型和 N1S1 HCC 大鼠模型中增强的乳剂稳定性、IA 输注、栓塞效应、安全性、药代动力学和肿瘤反应。然后，使用负载 CpG 的 Dox-PF127-LPD 成功进行经导管动脉化疗免疫栓塞术（TACIE）结合免疫佐剂（TLR9 激动剂 CpG 寡脱氧核苷酸）的局部递送。在 TACIE 期间同时安全地局部递送 CpG 和 TACE 证明了利用 TACE 诱导的免疫原性肿瘤微环境，并在同基因 N1S1 HCC 大鼠模型中增强了全身抗肿瘤免疫。最后，TACIE 的广泛用途和增强的治疗效果在二乙基亚硝胺诱导的大鼠 HCC 模型中得到验证。使用临床建立的方案和材料的 TACIE 应是一种方便而有效的治疗方法，可以转化为 HCC 患者。TACIE 强大的抗癌免疫和肿瘤消退，以及其良好的安全性，表明其作为 HCC 治疗的新型局部联合免疫疗法的潜力。

更新日期：2023-05-10

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