1. A camptothecin-based, albumin-binding prodrug enhances efficacy and safety in vivo.
- Author
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Cheng Z, Huang Y, Shen Q, Zhao Y, Wang L, Yu J, and Lu W
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Body Weight drug effects, Camptothecin analogs & derivatives, Camptothecin chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Delivery Systems, Drug Screening Assays, Antitumor, Humans, Mice, Mice, Inbred BALB C, Molecular Structure, Prodrugs chemical synthesis, Prodrugs chemistry, Rats, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Camptothecin pharmacology, Prodrugs pharmacology, Serum Albumin chemistry
- Abstract
The albumin-based drug delivery system is an effective drug delivery strategy for traditional chemotherapeutic drugs that can improve their antitumour efficacies and reduce systemic toxicities. The camptothecin derivative CPTS0001 has excellent antitumour activity in vitro, but it shows toxicity and side effects in vivo. In this study, we report the synthesis and biological evaluation of the β-glucuronidase-reactive albumin-binding prodrug Mal-glu-CPTS0001 based on quaternary ammonium. After intravenous administration, the compound covalently binds to plasma albumin through Michael addition, enabling it to accumulate in tumours, where tumour-associated β-glucuronidase triggers the selective release of CPTS0001. This prodrug significantly reduced the toxicity of the parent drug, and the maximum tolerated dose was increased by 2.5 times. At the same time, this prodrug enhanced the selectivity in vivo and improved the preferential accumulation of prodrug in tumours. Notably, this prodrug exhibited excellent in vivo antitumour effects in a murine breast cancer xenograft model without visible pathological toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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