Polyoxometalate-Based Radiosensitization Platform for Treating Hypoxic Tumors by Attenuating Radioresistance and Enhancing Radiation Response

Radioresistance is one of the undesirable impediments in hypoxic tumors, which sharply diminishes the therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with appreciable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxic tumors. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW₁₀@CS nanosphere) as a radiosensitization system for simultaneous extrinsic and intrinsic radiosensitization, by generating an overabundance of cytotoxic reactive oxygen species (ROS) using high-energy X-ray stimulation and mediating the hypoxia-inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1α expression and suppress broken double-stranded DNA self-healing. Most importantly, the GdW₁₀@CS nanospheres have the capacity to promote the exhaustion of intracellular glutathione (reduced GSH) by synergy W⁶⁺-triggered GSH oxidation for sufficient ROS generation, thereby facilitating the therapeutic efficiency of radiotherapy. As a result, the as-synthesized GdW₁₀@CS nanosphere can overcome radioresistance of hypoxic tumors through a simultaneous extrinsic and intrinsic strategy to improve radiosensitivity. We have demonstrated GdW₁₀@CS nanospheres with special radiosensitization behavior, which provides a versatile approach to solve the critical radioresistance issue of hypoxic tumors.