Controllable hydrogen release for gas-assisted chemotherapy and ultrasonic imaging of drug-resistant tumors

Gas-assisted therapy and diagnosis of tumors have attracted extensive interest due to their low toxicity and convenience, but are severely limited by the uncontrollable gas release. In this work, we proposed a kind of ammonia borane (AB) and doxorubicin (DOX) co-loaded and PEGylated Hollow Mesoporous Polydopamine (AB/DOX@HMPDA-PEG) nanoparticles for acid-sensitive hydrogen (H₂)-assisted ultrasonic (US) imaging and chemotherapy of drug-resistant tumors. The in vitro experiment showed that as a high H₂-storage molecule, AB can controllably release massive H₂ in an acidic environment. For one thing, the H₂ release in the acidic tumor environment and lysosomes of tumor cells in vivo helped to improve the US imaging performance; for another, it facilitated the lysosomal escape of nanoparticles, DOX release from nanoparticles, and blockage of mitochondrial respiratory chain. Furtherly, the blockage of mitochondrial respiratory chain reduced the production of triphosadenine (ATP), thereby decreasing the expression of heat shock protein 90 (HSP90) and promoting the therapeutic effect of DOX on drug-resistant tumors. Therefore, the nanoparticles provided an effective platform for controllable H₂-assisted chemotherapy and US imaging of the drug-resistant tumors.