INNOVATIVE DRUGS IN PHOTODYNAMIC THERAPY

Valentina Rapozzi

Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy

Abstract

Photodynamic Therapy (PDT) is a clinically approved, minimally invasive therapeutic treatment that exerts a selective cytotoxic activity towards cancer cells. This technique involves the administration of a photosensitizer (PS) and its irradiation at a wavelength within the PS absorbance band. In the presence of oxygen, a cascade of stress oxidative reactions leads to direct tumor cell death, damage to the microvasculature and induction of a local inflammatory reaction. According to Tayyaba Hasan, one of the major experts of PDT, “with PDT no matter what you do, if you are lucky, there is a prodeath response, simultaneously, there is a prosurvival molecular response, which mitigates the desidered outcome with PDT”. An important challenge for basic science researchers and clinicians is to address these opposing PDT responses and improve the efficary of the treatment. A strategy is to design PSs which are more selective for tumor tissues and which incorporate specific functions to reduce cell recurrence.

As PDT induces iNOS/NO in both tumor and microenvironment, we examined the role of nitric oxide (NO) in cytotoxicity and cytoprotection. Our findings show that NO mediates its cellular effects by acting on the NF-kB/YY1/RKIP loop, which controls cell growth and apoptosis. The cytoprotective effect of PDT-induced NO is observed at low NO levels, which activate the pro-survival antiapoptotic NF-kB and YY1, and inhibit the anti-survival/pro-apoptotic and metastasis suppressor RKIP. This finding reveals a critical role played by NO in PDT and suggests that the use of bifunctional PDT agents composed of a photosensitizer and a NO-donor could strenghen the phototreatment. A successful therapeutic use of NO is obtained when its concentration in the target tissue is controlled. To achieve this, we proposed as PDT agent, a bimolecular conjugate called DR2, composed of a photosensitizer (pheophorbide α) and a non-steroidal anti-androgen molecule capable of releasing NO under the exclusive control of light.

Our results showed that this approach is promising and suggest the importance of studying the host molecular pathways in the PDT response in order to synthetize new more effective photosensitizers.

Keywords: Photodynamic, response, molecule, cytoprotection, invasive.