Presentation Authors: Tingsheng Lin*, nanjing, China, People's Republic of
Introduction: Poor tumor targeting is a major challenge for the current bladder preservation therapies in muscle invasive bladder cancer (MIBC). Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In this study, we developed tumor-targeting hyaluronic acid (HA) nanoparticles with combined phototherapy and hypoxia-activated chemotherapy for bladder preservation in muscle invasive bladder cancer.
Methods: The HA-IR780-TPZ NPs were prepared. We investigated the O2 consumption of NPs in vitro and in vivo, and hypoxia-activated prodrug tirapazamine (TPZ) antitumor effect under normoxia or hypoxia condition. The muscle invasive bladder cancer model in C57BL/6 mice was established for in vivo study, and therapeutic efficacy of NPs for bladder preservation in muscle invasive bladder cancer was evaluated.
Results: we developed tumor-targeting hyaluronic acid nanoparticles for simultaneous tumor delivery of a photosensitizer IR780 and hypoxia-activated prodrug tirapazamine (TPZ) (HA-IR780-TPZ NPs). CD44 is an HA receptor over-expressed on bladder cancer cells. The hyaluronic acid nanoparticles loaded with IR780 and TPZ showed highly tumor targeting effect in vitro and vivo. IR780-mediated photothermal and photodynamic therapy upon near-IR laser irradiation induced hypoxia (the continuous oxygen consumption by the vascular shutdown effects and the conversion of molecular oxygen to singlet oxygen), which activated antitumor activity of the co-delivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in muscle invasive bladder cancer model. Bladder tumors were effectively inhibited by the HA-IR780-TPZ nanoparticles with bladder preservation.
Conclusions: HA-IR780-TPZ nanoparticles address current clinical challenges, treating locally aggressive lesions and preserving the bladder. They have enormous potential to improve the muscle invasive bladder cancer treatment strategies in clinic.