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Intratumoral Cancer Chemotherapy with a Carrier-Based Immunogenic Cell-Death Eliciting Platinum (IV) Agent
Groer, Chad Zhang, Ti Lu, Ruolin Cai, Shuang Mull, Derek Huang, Aric Forrest, Melanie Berkland, Cory Aires, Daniel Forrest, Marcus Laird
Groer, Chad
Zhang, Ti
Lu, Ruolin
Cai, Shuang
Mull, Derek
Huang, Aric
Forrest, Melanie
Berkland, Cory
Aires, Daniel
Forrest, Marcus Laird
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Abstract
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.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see doi.org/10.1021/acs.molpharmaceut.0c00781.
Date
2020-09-25
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American Chemical Society
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Keywords
Head and neck cancer, Platinum (IV) chemotherapy, Hyaluronic acid, Immunogenic cell death, RNA sequencing, KEGG and GO analysis
Citation
Groer, C., Zhang, T., Lu, R., Cai, S., Mull, D., Huang, A., Forrest, M., Berkland, C., Aires, D., & Forrest, M. L. (2020). Intratumoral Cancer Chemotherapy with a Carrier-Based Immunogenic Cell-Death Eliciting Platinum (IV) Agent. Molecular pharmaceutics, 17(11), 4334–4345. https://doi.org/10.1021/acs.molpharmaceut.0c00781