Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines ...Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug,specifically 6-diazo-5-oxo-L-norleucine(DON),using a thioketal linkage(TK).This system enables imaging,chemotherapy,photodynamic therapy,and on-demand drug release upon radiation exposure.The optimized prodrug,DON-TK-BM3,incorporating cyanine dyes as the fluorophore,displayed potent reactive oxygen species release and efficient tumor cell killing.Unlike the parent drug DON,DON-TK-BM3 exhibited no toxicity toward normal cells.Moreover,DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects,including gastrointestinal toxicity,in mice.This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.展开更多
Here,a methacrylate-modified pyridone derivative(mPYR)was loaded into a porphyrin nanoscale metal-organic framework(porphyrin-nMOF).Then,the loaded mPYR was further polymerized to obtain poly-pyridone(poly-mPYR)to for...Here,a methacrylate-modified pyridone derivative(mPYR)was loaded into a porphyrin nanoscale metal-organic framework(porphyrin-nMOF).Then,the loaded mPYR was further polymerized to obtain poly-pyridone(poly-mPYR)to form poly-mPYR loaded porphyrin-nMOF,which is designated as PLP and used as a reservoir of singlet oxygen(^(1)O_(2)).It was found that PLP could quickly capture^(1)O_(2)in vitro and slowly release^(1)O_(2)in vivo to induce cancer cell death.The release of^(1)O_(2)was light and oxygen independent,and the entire process did not cause intracellular oxygen consumption.PLP also displayed good therapeutic effect in the treatment of both solid tumor and lung metastasis cancer.This strategy of oxygenand light-independent^(1)O_(2)treatment presents great potential for treating refractory cancer.Also,the form of^(1)O_(2)capturing polymer-loaded nMOF expands the biomedical applications of MOFs and polymers,which can be used as a platform for biomedical applications.展开更多
基金support from the National Natural Science Foundation of China(82072058,91859204,82073702)Natural Science Foundation of Jiangsu Province for Excellent Young Scientists(Grant BK20211580,China)Qinglan Project of Jiangsu Province of China.“Double First-Class”university project(CPUQNJC2205,China).
文摘Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug,specifically 6-diazo-5-oxo-L-norleucine(DON),using a thioketal linkage(TK).This system enables imaging,chemotherapy,photodynamic therapy,and on-demand drug release upon radiation exposure.The optimized prodrug,DON-TK-BM3,incorporating cyanine dyes as the fluorophore,displayed potent reactive oxygen species release and efficient tumor cell killing.Unlike the parent drug DON,DON-TK-BM3 exhibited no toxicity toward normal cells.Moreover,DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects,including gastrointestinal toxicity,in mice.This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.
基金This study was supported by the National Natural Science Foundation of China(nos.51833007,51873162,21721005,and 51690152).
文摘Here,a methacrylate-modified pyridone derivative(mPYR)was loaded into a porphyrin nanoscale metal-organic framework(porphyrin-nMOF).Then,the loaded mPYR was further polymerized to obtain poly-pyridone(poly-mPYR)to form poly-mPYR loaded porphyrin-nMOF,which is designated as PLP and used as a reservoir of singlet oxygen(^(1)O_(2)).It was found that PLP could quickly capture^(1)O_(2)in vitro and slowly release^(1)O_(2)in vivo to induce cancer cell death.The release of^(1)O_(2)was light and oxygen independent,and the entire process did not cause intracellular oxygen consumption.PLP also displayed good therapeutic effect in the treatment of both solid tumor and lung metastasis cancer.This strategy of oxygenand light-independent^(1)O_(2)treatment presents great potential for treating refractory cancer.Also,the form of^(1)O_(2)capturing polymer-loaded nMOF expands the biomedical applications of MOFs and polymers,which can be used as a platform for biomedical applications.
