Chondrosarcoma represents the second most frequent primary malignant bone tumour in adults after osteosarcoma. Because of its abundant chondrogenic extracellular matrix, its poor vascularisation and hypoxic microenvironment, chondrosarcoma is highly resistant to conventional chemo and radio-therapeutic treatments. Today, only effective treatment remains surgical resection. UMR990 Inserm/UdA laboratory develops a new innovative therapeutic targeting strategy which exploits the two characteristics of chondrosarcoma microenvironment: a chondrogenic extracellular matrix (ECM) and a hypoxic tissue. Based on the affinity of the quaternary ammonium (QA) moiety for proteoglycans, we developed a strategy that uses the quaternary ammonium function to selectively address hypoxia activated prodrugs to the ECM of chondrosarcoma, that exhibit a high fixed charged density (FCD). We propose thus, to vectorise, with QA as vectors to PGs of chondrosarcoma, cyclophosphamide derivative hypoxia activated prodrugs with nitroimidazole or nitrofurane cleavable entity. These compounds were studied in vitro and in vivo comparatively to their non-vectorised equivalents and to a vectorised but non cleavable equivalent. The in vitro results, on the HEMC-SS human chondrosarcoma cell line, show that QA derivatives of nitroimidazole prodrug exhibited the best hypoxia versus normoxia differential cytotoxic activity (4.5 times more apoptotic cells in hypoxia than in normoxia). In vivo, on an HEMC-SS xenograft SCID mice model, this molecule causes a significant tumour growth inhibition of 62.1% as compared to only 8% for its non-vectorised equivalent. Interestingly, haematological side effects were less pronounced for the QA-prodrug respectively to the non-vectorised molecule. These highly promising results validate the approach of dual selectivity for chondrosarcoma treatment, especially for the nitroimidazole compound, by increasing its therapeutic index. This new innovative therapeutic strategy offers a real hope for treatment of cartilage cancer, relatively rare pathology, but particularly redoubtable.
Disclosure: The authors declared no competing interests. This work was supported by Ligue Contre le Cancer Auvergne Région and State-Region Planning Contract (CPER).