Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma.

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR).

Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy.

The tumor microenvironment in chondrosarcoma (CHS), a chemo- and radio-resistant cancer provides unique hallmarks for developing a chondrosarcoma targeted drug-delivery system. Tumor targeting could be achieved using a quaternary ammonium function (QA) as a ligand for aggrecan, the main high negative charged proteoglycan of the extracellular matrix of CHS, and a 2-nitroimidazole as trigger that enables hypoxia-responsive drug release. In a previous work, ICF05016 was identified as efficient proteoglycan-targeting hypoxia-activated prodrug in a human extraskeletal myxoid chondrosarcoma model in mice and a first study of the structure-activity relationship of the QA function and the alkyl linker length was conducted.

Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma.

Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia.

Proteoglycan-targeting applied to hypoxia-activated prodrug therapy in chondrosarcoma: first proof-of-concept.

Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo- and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate.