Oral delivery of WR-1065 by ROS-responsive PEG-PCL nanoparticles for radioprotection

When a burst of reactive oxygen species (ROS) is induced after radiation exposure, a sufficient radioprotector drug must be quickly released to neutralize the ROS. An oral polymeric carrier of poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) was synthesized via the ROS-response linker thioketal (TK-linked PCEC) and used for delivery of the drug WR-1065. The drug-loaded nanoparticles (PCEC/WR-1065 NPs) had high WR-1065 content (19.7 % w/w) in the core and a particle size of 183 nm. The PCEC/WR-1065 NPs could protect the drug from degradation at gastric pH. More than 70 % of the TK-linked PCEC copolymer could be cleaved in 1 h. Therefore, a sufficient amount of WR-1065 could be quickly released from the PCEC/WR-1065 NPs to neutralize the burst of free radicals generated under irradiation. The in vitro cell uptake results of TK-linked PCEC NPs indicated that the NPs could be efficiently endocytosized by Caco-2 cells. Oral administration of the PCEC/WR-1065 led to survival benefit as well as protective effects on hematopoiesis and main organs with respect to the irradiation and oral free WR-1065 groups after 7.2 and 8.0 Gy total body irradiation, respectively. In vivo biodistribution studies indicated that the PCEC/WR-1065 NPs accumulated mainly in intestinal tissue. These results suggest that the design presented here provides a promising oral ROS-sensitive platform for acute radiation syndrome.