Proteoglycan-targeting applied to hypoxia-activated prodrug therapy in chondrosarcoma: first proof-of-concept
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Aurélien Voissiere1, Valérie Weber1, Yvain Gerard1, Françoise Rédini2, Florian Raes3, Jean-Michel Chezal1, Françoise Degoul1, Caroline Peyrode1 and Elisabeth Miot-Noirault1
1Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Clermont-Ferrand, France
2Nantes Atlantique Université, INSERM, UMR1238, Sarcomes osseux et remodelage des tissus calcifiés, Nantes, France
3PHENOMIN-TAAM-UPS44, CIPA (Centre d’Imagerie du Petit Animal), CNRS Orléans, France
Aurélien Voissiere, email: [email protected]
Keywords: chondrosarcoma; proteoglycan; hypoxia-activated prodrug; quaternary ammonium; extracellular matrix
Received: January 26, 2017 Accepted: July 09, 2017 Published: September 27, 2017
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.
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