Photodynamic therapy (PDT) using porphyrins has been approved for treatment of several solid tumors due to the generation of cytotoxic reactive oxygen species (ROS). However, low physiological solubility and lack of selectivity towards tumor sites are the main limitations of their clinical use. Nanoparticles are able to spontaneously accumulate in solid tumors through an enhanced permeability and retention (EPR) effect due to leaky vasculature, poor lymphatic drainage, and increased vessel permeability. Herein, we proved the added value of nanoparticle vectorization on anticancer efficacy and tumor-targeting by 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (TPPOH). Using 80 nm silica nanoparticles (SNPs) coated with xylan-TPPOH conjugate (TPPOH-X), we first showed very significant phototoxic effects of TPPOH-X SNPs mediated by post-PDT ROS generation and stronger cell uptake in human colorectal cancer cell lines compared to free TPPOH. Additionally, we demonstrated apoptotic cell death induced by TPPOH-X SNPs-PDT and the interest of autophagy inhibition to increase anticancer efficacy. Finally, we highlighted in vivo, without toxicity, elevated anticancer efficacy of TPPOH-X SNPs through improvement of tumor-targeting compared to a free TPPOH protocol. Our work demonstrated for the first time the strong anticancer efficacy of TPPOH in vitro and in vivo and the merit of SNPs vectorization.

Most photosensitizers (PS) suffer from a lack of water solubility and from a low selectivity toward tumor cells. Delivery systems using nanoparticles make it possible to improve PS water solubility, and also tumor targeting via the enhanced permeability and retention (EPR) effect. Among the organelles, mitochondria are attractive target sites for drug-delivery strategies since they perform a variety of key cellular processes. Our study was aimed at synthesizing nanoparticles consisting of xylan-carrying porphyrins attached to a triphenylphosphonium moiety, in order to enhance the PDT effect through mitochondrial targeting. Hybrid nanoparticles were designed that consisted of a silica core coated with xylan substituted with porphyrin derivatives carrying a triphenylphosphonium moiety. These hybrid nanoparticles have been constructed, along with their counterparts devoid of silica core, taking into consideration the controversy surrounding the use of silica nanoparticles. Phototoxicity experiments, conducted against the HCT-116 and HT-29 colorectal cancer cell lines, showed that nanoparticles with porphyrins bearing a triphenylphosphonium moiety exhibited an enhanced photocytotoxic effect in comparison with free porphyrin or nanoparticles with porphyrins without the triphenylphosphonium moiety.