Intratumoral Cancer Chemotherapy with a Carrier-Based Immunogenic Cell-Death Eliciting Platinum (IV) Agent,Molecular Pharmaceutics

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Intratumoral Cancer Chemotherapy with a Carrier-Based Immunogenic Cell-Death Eliciting Platinum (IV) Agent
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-09-25 , DOI: 10.1021/acs.molpharmaceut.0c00781
Chad Groer ₁ , Ti Zhang ₁ , Ruolin Lu ₂ , Shuang Cai ₁ , Derek Mull _{1,

2} , Aric Huang ₂ , Melanie Forrest ₁ , Cory Berkland _{2,

3} , Daniel Aires _{1,

4} , Marcus Laird Forrest _{1,

2}

Affiliation

A carrier-based, immunogenic cell death (ICD)-eliciting platinum(IV) chemotherapeutic agent was synthesized via complexation between an axially derivatized Pt(IV)-tocopherol and hyaluronan (HA)–tocopherol nanocarrier. The resultant HA-Pt(IV) complex demonstrated antiproliferative activity and induced calreticulin translocation, an indicator of ICD, in murine and human head and neck cancer (HNC) cells. The intratumorally administered HA-Pt(IV) treatments were tolerable and efficacious in both immunocompetent and immunodeficient mice with HNC, partially because of the direct cytotoxicity. Superior efficacy and survival were observed in the immunocompetent group, suggesting a possible Pt(IV)-induced immunological response, which would only manifest in animals with an intact immune system. Subsequent imaging of tumor tissues demonstrated increased macrophage infiltration in the HA-Pt(IV)-treated tumors compared to the nontreated controls and the cisplatin-treated tumors, suggesting favorable inflammatory activation. RNA sequencing of HA-Pt(IV)-treated tumors indicated that carbohydrate and vitamin metabolisms were the most important Kyoto Encyclopedia of Genes and Genomes pathways, and molecular function, biological process, and cellular component were highly enriched gene ontology categories.

中文翻译：

使用基于载体的免疫原性细胞死亡诱导铂 (IV) 剂进行肿瘤内癌症化疗

通过轴向衍生的 Pt(IV)-生育酚和透明质酸 (HA)-生育酚纳米载体之间的络合，合成了一种基于载体的、免疫原性细胞死亡 (ICD) 引发的铂 (IV) 化疗剂。由此产生的 HA-Pt(IV) 复合物在小鼠和人类头颈癌 (HNC) 细胞中显示出抗增殖活性并诱导钙网蛋白易位，这是 ICD 的指标。瘤内给药的 HA-Pt(IV) 治疗在具有 HNC 的免疫活性和免疫缺陷小鼠中均是可耐受和有效的，部分原因是直接的细胞毒性。在免疫活性组中观察到了卓越的疗效和存活率，这表明可能存在 Pt(IV) 诱导的免疫反应，这只会在具有完整免疫系统的动物中表现出来。随后的肿瘤组织成像表明，与未治疗的对照和顺铂治疗的肿瘤相比，HA-Pt(IV) 治疗的肿瘤中巨噬细胞浸润增加，表明有利的炎症激活。HA-Pt(IV) 治疗肿瘤的 RNA 测序表明碳水化合物和维生素代谢是最重要的京都基因和基因组途径百科全书，分子功能、生物过程和细胞成分是高度丰富的基因本体类别。

更新日期：2020-11-02

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