Redox-sensitive lipophilic prodrugs: delivering unstable chemotherapeutant for improved cancer therapy

Drug Delivery

Lu Yan¹  Zhao Huang¹  Yue Su¹  Qian Zhang¹  Huitong Chen¹  Yaxin Zheng¹  Jin Li¹  Fu Li¹  Zhengye Huang¹ 

[1] School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, Chin;

关键词: Camptothecin;    lipophilic prodrugs;    antitumor activity;    drug delivery;    redox sensitivity;   

DOI  :  10.1080/10717544.2019.1678696

来源: publisher

【 摘 要 】

Therapeutic application of unmodified camptothecin (CPT) is severely restricted by its extremely low water solubility and the instability of active lactone ring. In this study, a redox-sensitive CPT-OA conjugate containing the disulfide bond (CPT-SS-OA) was used to deliver the lactone-stabilized CPT for the improved antitumor efficacy. A non-sensitive CPT-OA was used as control to illuminate the role of disulfide bond. Both CPT-SS-OA and CPT-OA formulated in cremophor EL micelles (CM) displayed multiple therapeutic advantages: small diameter (∼14 nm), efficient cellular internalization, prolonged blood circulation, and favorable biodistribution. However, only CPT-SS-OA/CM achieved the superior chemotherapeutic efficacy over CPT solution in the Lewis lung carcinoma (LLC) cancer xenograft, which was ascribed to the accelerated release of the active lactone CPT responding to the elevated reductive glutathione in tumor cells. Such redox-sensitive lipophilic prodrugs represent an effective alternative strategy for the delivery of CPT in the active lactone form. This strategy can be used for other chemically unstable chemotherapeutant for the improved therapeutic efficacies.

【 授权许可】

CC BY