Title : Redox responsive chlorin e6 polysilsesquioxane nanoparticles for cancer photodynamic therapy in vitro : Investigation of cell death mechanisms
Photodynamic therapy (PDT) has gained prominence in cancer research as a Reactive oxygen species’ (ROS) mediated therapeutic strategy. The principle of PDT relies on the preferential accumulation of a high payload of a photosensitizer (PS) agent in the target tissue, and selective illumination with light, resulting in photo-toxicity and subsequent cell death. This desired target tissue localization can be enhanced by designing a nanocarrier which can deliver large payloads of PS to the diseased site by taking advantage of the enhanced permeation and retention effect (EPR), characteristic of primary tumor vasculature. In the field of nanomedicine, a variety of hybrid nanoparticles including metal organic frameworks and silica-based nanoscale coordination polymers have been investigated for drug delivery, biosensing, and imaging. In our present work, we have synthesized Chlorin e6 (Ce6) functionalized trialkoxysilane-based nanoparticles (PSilQ-Ce6),with a high loading of PS. The size and morphology of these PSilQ-Ce6 nanoparticles were characterized using scanning electron microscopy, and dynamic light scattering. The loading of the PS was determined by means of thermogravimetric analysis and UV-Vis spectroscopy. Our results demonstrate that the synthesized PSilQ-Ce6 nanoparticles afford potent Photodynamic therapy in breast cancer (MDA MB 231) and malignant melanoma (A 375) cells upon irradiation with red light (650nm). The search for closely defined molecular targets of PDT is a multifactorial problem depending on cell and PS type, PS localization and whether there are cellular proteins that are more susceptible to PDT. In the present work, different modes of death that operate on a cellular level are being investigated for nanoparticle mediated PDT in contrast with PDT by free PS.
• We demonstrate the use of a direct microemulsion system as a template to synthesize hybrid nanoparticles with remarkable control in size and drug OR photosensitizer loading.
• In vitro stimuli responsive degradability for payload release is another interesting feature of our material that bolsters its suitability for drug delivery applications
• We report the role of a new iron dependent non apoptotic cell death pathway (Ferroptosis) in nanoparticle mediated photodynamic therapy.
• Additionally, we report how basal levels of ROS characteristic to cancer subtypes affect the therapeutic response of photodynamic therapy.