Data underlying the publication: Organochloride mediated prodrug activation induced by ionizing radiation

Boronic acid and ester-caged prodrugs have been widely investigated in cellular-generated hydrogen peroxide triggered release. Although it is well-known that ionizing radiation generates hydrogen peroxide in aqueous solution, using this approach to activate boronic acid or ester-based prodrugs suffers from low H₂O₂ yields and thus low uncaging efficiency. However, the peroxyl radical formed from irradiating aqueous solution of organochloride may increase the uncaging efficiency. In this study, we used a boronic acid-caged coumarin derivative to quantify the yield of oxidation induced by clinical doses of radiation, and boronic acid-caged gemcitabine to assess the activation of a prodrug upon irradiation. Irradiation of the coumarin derivative in phosphate buffered saline shows a low yield of 0.048 µM/Gy, and the prodrug after irradiation has only limited toxicity to U87 cell line, indicating limited uncaging. The oxidation of boronic acid can be greatly enhanced by the peroxyl radical generated from irradiation of dilute PBS-organochloride solutions, with the yield increasing to 0.13 µM/Gy. Moreover, the oxidation by peroxyl radical can be catalyzed by <em>N</em>,<em>N</em>-dimethylaniline derivatives, increasing the yield to 0.19 µM/Gy. Clinical dose irradiation of the caged gemcitabine derivative in a solution of PBS with trichloroethanol and 2-(dimethylamino)benzoic acid shows efficient tumor cell killing and a comparable toxicity with that of the parent drug, indicating efficient uncaging.

硼酸（boronic acid）与酯基笼状前药（ester-caged prodrugs）已被广泛应用于细胞源性过氧化氢触发的释药体系研究。尽管已知电离辐射可在水溶液中产生过氧化氢，但采用该策略激活硼酸或酯基类前药时，存在过氧化氢产率偏低的问题，进而导致笼状结构脱除效率不佳。不过，有机氯化物水溶液经辐照后生成的过氧自由基（peroxyl radical），或可提升笼状结构脱除效率。本研究中，我们采用硼酸笼状香豆素衍生物，量化临床剂量辐射诱导的氧化反应产率；同时使用硼酸笼状吉西他滨（gemcitabine），评估辐照下前药的激活效果。在磷酸盐缓冲盐水（phosphate buffered saline, PBS）中对香豆素衍生物进行辐照，测得其氧化产率仅为0.048 µM/Gy；辐照后的前药对U87细胞株仅表现出微弱毒性，提示笼状结构脱除程度有限。经稀释的PBS-有机氯化物溶液辐照产生的过氧自由基，可大幅强化硼酸的氧化反应，使产率提升至0.13 µM/Gy。此外，N,N-二甲基苯胺（N,N-dimethylaniline）衍生物可催化过氧自由基介导的氧化反应，进一步将产率提升至0.19 µM/Gy。在添加三氯乙醇（trichloroethanol）与2-(二甲氨基)苯甲酸（2-(dimethylamino)benzoic acid）的PBS溶液中，对笼状吉西他滨衍生物进行临床剂量辐照，结果显示其可高效杀伤肿瘤细胞，且毒性与游离母药相当，证实该体系实现了高效的笼状结构脱除。