To date, surgery remains the only option for the treatment of chondrosarcoma (CHS), which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognostic, improving the management of CHS still remains a challenge. Our team develops an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan(PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by Surface Plasmon Resonance. In the orthotopic model of swarm rat CHS, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabelled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [3H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA active targeting of CHS. The antitumoral effects were characterized by tumor volume assessment, in vivo 99mTc-NTP 15-5 scintigraphic imaging of PG, 1H-HRMAS NMR spectroscopy and histology. The conjugation of a QA function to Mel doesn't hampered its in vivo efficiency and strongly improves tolerability of Mel leading to a significant decrease of side effects (hematological analyses and body weight monitoring). Thus QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with CHS.
- Received January 9, 2016.
- Revision received August 1, 2016.
- Accepted August 3, 2016.
- Copyright ©2016, American Association for Cancer Research.