Gemcitabine hydrochloride is an FDA-approved chemotherapeutic drug used in the treatment of various cancers. Several drawbacks of gemcitabine, including its short in vivo half-life of 8-17 min associated with ar apid excretion by the kidneys and its poor membrane permeability,h ave inspired research on an anodelivery approach. In this study,w er eport ethylene-based periodic mesoporous organosilica nanoparticles (PMOs) for photodynamic therapy and the autonomous delivery of gemcitabine in cancer cells. Porphyrins were used as photosensitizers and were localized in the walls of the PMOs while ah igh loading capacity of gemcitabine was observed in the porous structure. Depending on the nature of the photosensitizer, and its aggregation state, we were able to perform one or two-photon photodynamic therapy.T wo-photon excited photodynamic therapy combinedw ith gemcitabine delivery led to as ynergya nd av ery efficient cancer cell killing.

Background: Bridged silsesquioxane nanoparticles (BSNs) recently described represent a new class of nanoparticles exhibiting versatile applications and particularly a strong potential for nanomedicine. Aims:In this work, we describe the synthesis of BSNs from an octasilylated functional porphyrin precursor (PORBSNs) efficiently obtained through a click reaction. These innovative and very small-sized nanoparticles were functionalized with PEG and mannose (PORBSNs-mannose) in order to target breast tumors in vivo. Methods and Results:The structure of these nanoparticles is constituted of porphyrins J aggregates that allow two-photon spatiotemporal excitation of the nanoparticles. The therapeutic potential of such photoactivable nanoparticles was first studied in vitro, in human breast cancer cells in culture and then in vivo on zebrafish embryos bearing human tumors. These animal models were intravenously injected with 5 nL of a solution containing PORBSNs-mannose. An hour and half after the injection of photoactivable and targeted nanoparticles, the tumor areas were excited for few seconds with a two-photon beam induced focused laser. We observed strong tumor size decrease, with the involvement of apoptosis pathway activation. Conclusion:We demonstrated the high targeting, imaging, and therapeutic potential of PORBSNs-mannose injected in the blood stream of zebrafish xenografted with human tumors. KEYWORDSbridged silsesquioxane nanoparticles, human tumor targeting, photodynamic therapy, two-photon excitation Soraya Dib and Dina Aggad contribute equally to this work.