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SN38-based albumin-binding prodrug for efficient targeted cancer chemotherapy
Journal of Controlled Release  (IF9.776),  Pub Date : 2021-10-04, DOI: 10.1016/j.jconrel.2021.09.040
Ying Huang, Lei Wang, Zhiyang Cheng, Biyu Yang, Jiahui Yu, Yi Chen, Wei Lu

Developing new therapeutic strategies that damage tumour cells without harming normal tissues is among the primary obstacles in chemotherapy. In this study, a novel β-glucuronidase-sensitive albumin-binding prodrug was designed and synthesized to selectively deliver the drug SN38 to tumour sites and maximize its efficacy. After intravenous administration, the prodrug Mal-glu-SN38 covalently bound to plasma albumin through the Michael addition, enabling it to accumulate in the tumour and release SN38 when triggered by extracellular β-glucuronidase. Compared to irinotecan, Mal-glu-SN38 displayed a slower plasma clearance and increased drug exposure over time. Moreover, Mal-glu-SN38 caused an increase in tumour-site accumulation of both the albumin-prodrug conjugate and free SN38 released from albumin conjugate when compared with irinotecan. After administration of multiple doses, Mal-glu-SN38 also significantly delayed the tumour growth, resulting in an impressive reduction or even disappearance of tumours (67% of mice cured) without causing any observable side effects.