Improving the photodynamic therapy of pyropheophorbide a through the combination of hypoxia-sensitive molecule and infrared light-excited d-TiO2−X nanoparticles

Abstract

Photodynamic therapy (PDT) involving the generation of cytotoxic reactive oxygen species under light in the presence of sufficient oxygen has been widely used in diagnosing and treating cancer. However, the ubiquitous hypoxia in many solid tumors due to their abnormal proliferation and vascularization has greatly compromised the therapeutic effect. We have designed and prepared a tumor therapeutic nanoplatform for improving PDT based on defective TiO[Formula: see text] (d-TiO[Formula: see text] with the consideration that the continuous PDT would cause hypoxic tumor microenvironment (HTM) in which many hypoxia-sensitive drugs might be activated to exert the antitumor activities. The inorganic d-TiO[Formula: see text] nanoparticles (NPs) were firstly prepared and then modified by APTES to obtain the mesoporous d-TiO[Formula: see text]@SiO2NPs. The organic photosensitizer pyropheophorbide-a (PPa) and hypoxic-sensitive agent 6-aminoflavone (AF) were then adsorbed in the mesoporous SiO2, followed by further hydrophilic PEGylation to improve the biocompatibility. Defective d-TiO[Formula: see text] and the PPa could simultaneously consume oxygen after light excitation, while the resulted HTM was utilized to activate the hypoxic-sensitive agent 6-aminoflavone (AF) to trigger anti-cancer effect. The prepared d-TiO[Formula: see text]@SiO2/PPa/AF@PEG NPs were stable in normal physiological environment, and could continuously release PPa and AF under slightly acidic conditions. The in vitro experiments against cancer cells suggested that the combination of PPa and AF displayed significantly enhanced antitumor activities than that of monotherapy. Therefore, this research offered a potential application for 6-aminoflavone in PDT-induced hypoxia to improve the antitumor effects.