A Leucine Aminopeptidase-Activated Theranostic Prodrug for Cancer Diagnosis and Chemotherapy.

Abstract

Currently, chemotherapy is a widely used and important treatment for cancer. However, almost all of the treatments have shortcomings associated with poor specificity and high toxicity, which results in severe side effects to normal cells and tissue. This is a very important problem, and yet, it currently remains unanswered. Therefore, the development of the method for the more effective delivery of anticancer drugs to their targets and real-time monitoring of the localization of the drugs are very important. Herein, we designed a theranostic prodrug: CPT-p-Leu, which was constructed using fluorescent camptothecin (CPT), a self-immolative linker and leucine (Leu) residue. Upon exposure to LAP (leucine aminopeptidase: LAP), the amide bond in CPT-p-Leu will be cleaved, followed by an intramolecular 1,6-elimination, which triggers the active anticancer drug (CPT) release and recovers the fluorescence of CPT. With our design, the anticancer drug, CPT, can be used as both a drug and a fluorescence reporter, making our system suitable to accurately and effectively track the released CPT distribution. Based on this strategy, CPT-p-Leu could achieve the chemoselective detection of LAP and monitoring of the anticancer drug release. Furthermore, it also provides a very convenient way to accurately determine the location of the released drug in living samples. In addition, CPT-p-Leu shows a good cell membrane permeability and enhanced cytotoxicity toward LAP overexpressing cancer cells. We anticipate that our research will facilitate the development of improved theranostic systems for cancer therapy.

• Authors: Feiyi Wang, Sisi Hu, Qi Sun, Qiang Fei, Chao Ma, Cuifen Lu, Junqi Nie, Zuxing Chen, Jun Ren, Guo-Rong Chen, Guichun Yang, Xiao-Peng He, Tony D James
• Journal: ACS applied bio materials (ACS Appl Bio Mater) Vol. 2 Issue 11 Pg. 4904-4910 (Nov 18 2019) ISSN: 2576-6422 [Electronic] United States
• PMID: 35021490 (Publication Type: Journal Article)