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Silica‐based nanoplatforms are highly versatile and attractive delivery systems for cancer treatment. These platforms have been used for the effective delivery of pharmacological agents in preclinical settings. Though silicon oxide is found naturally in the human body, a major limitation associated with silica‐based nanoparticles is their slow biodegradability. Therefore, the potential risks related to the longer bioaccumulation of these materials can be significant. In this work, the synthesis and application of a novel silica‐based nanoplatform, polysilsesquioxane nanoparticles (PSilQ NPs) is reported. The developed PSilQ material contains stimuli‐responsive properties, and improves biodegradability for the efficient delivery of a clinically relevant photosensitizer, protoporphyrin IX. Herein, it is demonstrated that the PSilQ nanoplatform is biocompatible and exhibits enhanced biodegradability in an immune‐competent mouse model. In addition, PSilQ NPs show phototherapeutic efficiency for reducing the tumor burden in an orthotopic model of triple‐negative breast cancer. These results may pave the way for the future clinical evaluation of this silica‐based nanoplatform.

 

The use of nanoparticle-based materials to improve the efficacy of photodynamic therapy (PDT) to treat cancer has been a burgeoning field of research in recent years. Polysilsesquioxane (PSilQ) nanoparticles with remarkable features, such as high loading of photosensitizers, biodegradability, surface tunability, and biocompatibility, have been used for the treatment of cancer in vitro and in vivo using PDT. The PSilQ platform typically shows an enhanced PDT performance following a cell death mechanism similar to the parent photosensitizer. Ferroptosis is a new cell death mechanism recently associated with PDT that has not been investigated using PSilQ nanoparticles. Herein, we synthesized a protoporphyrin IX (PpIX)-based PSilQ platform (PpIX-PSilQ NPs) to study the cell death pathways, with special focus on ferroptosis, during PDT in vitro. Our data obtained from different assays that analyzed Annexin V binding, glutathione peroxidase activity, and lipid peroxidation demonstrate that the cell death in PDT using PpIX-PSilQ NPs is regulated by apoptosis and ferroptosis. These results can provide alternative approaches in designing PDT strategies to enhance therapeutic response in conditions stymied by apoptosis resistance.