Synthesis of novel photolabile alkoxyamines: application in photodynamic therapy for cancer

Photodynamic therapy (PDT) is a method currently used against some cancers. PDT requires a photoactivatable molecule called the photosensitizer (PS) which generates, by action with oxygen impelled by ultraviolet light, the formation of reactive oxygen species including highly reactive singlet oxygen, leading to cell death. Even if PDT is used successfully to treat prostate cancer for example, this methodology poses major drawbacks; 1)- Lack of selectivity of most PSs, 2)- Presence of oxygen to be effective. In order to improve the effect of PDT we report in this work the synthesis of several photolabile alcoxyamines. We also performed the synthesis of a multifunctional platform combining three units: a PS, a specific peptide (KDKPPR) targeting the NRP-1 receptor and an alkoxyamine capable of generating a toxic radicals under the influence of light. The physical and chemical properties of the synthesized alkoxyamines were investigated. Especially we have studied the homolysis of alcoxyamines by light which is the key process of the new therapeutic approach. The study of the photophysical properties of the trimodal platform thus showed that the PS retained its capacity to form singlet oxygen and its affinity for the NRP-1. The free radicals generated by light could be detected thanks the RPE technique (signals obtained and radical trap). The proof of concept of using alkoxyamines in PDT for cancer was thus successfully established. (author)