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. This derivative, named as 8-QA, was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-
hypoxia activated. Firstly binding to
aggrecan was confirmed from dissociation constant determined by Surface Plasmon Resonance. In vitro, in HEMC-SS
chondrosarcoma cells cultured in monolayer and in spheroids, 8-QA showed higher cytotoxic activity in
hypoxia versus normoxia, and led to a strong accumulation of cells in S phase and apoptosis. In vivo, a HEMC-SS xenograft model was implanted on SCID mice and characterized for
hypoxia by photoacoustic imaging as well as
proteoglycan content. When HEMC-SS bearing mice were given 8-QA at 47 μmol/kg according to a q4d x 6 schedule, a significant 62.1% inhibition of
tumor growth was observed, without associated hematological side effects. Mechanistic studies of treated
tumors highlighted decrease in mitotic index associated to increase in both p21 and p53S15 markers. Interestingly, 8-QA treatment induced an increase of
DNA damages as measured by γH2AX predominantly found in
pimonidazole-positive hypoxic areas. These preclinical results are the first to demonstrate the interest of addressing
hypoxia-activated
prodrugs selectively to
proteoglycan of chondrogenic
tumor tissue, as a promising therapeutic strategy.