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.
Protecting the body from radiation damage is a huge medical challenge. Amifostine and curcumin are both effective radioprotectants, but their use has been greatly restricted due to various reasons including low bioavailability. Nanoscale drug delivery systems of poly(ethylene glycol)–poly(ε-caprolactone) copolymers can improve the bioavailability of drugs due to excellent biocompatibility, biodegradability, and long circulation characteristics. In this study, a new reactive oxygen species-sensitive nanocarrier fabricated by linking curcumin and thioketal to poly(ethylene glycol)–poly(ε-caprolactone) polymer was used for delivery of WR-1065 (the active ingredient of amifostine). The content of curcumin in this polymer was about 7.6%, and the drug loading of WR-1065 was 44%. The WR-1065-loaded nanoparticles (NPs) had an average size of 128.6 nm and uniform spherical morphology. These WR-1065-loaded NPs reduced the metabolism of curcumin and WR-1065 in the gastrointestinal tract and could be well absorbed by cells and distributed to multiple organs. Compared with a single drug, oral administration of WR-1065-loaded NPs demonstrated obvious radioprotective effects on the hematopoietic system and prevented intestinal injury. The 30-day survival rate after half-lethal dose (7.2 Gy) of total body irradiation was 100%. In general, WR-1065-loaded NPs improved the oral bioavailability of WR-1065 and curcumin. This multifunctional nanocarrier provides a possibility for combination therapy in treating ionizing radiation damage.
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