Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents

Abstract

7-Ethyl-10-hydroxycamptothecin (SN38), a highly potent metabolite of irinotecan, has an anticancer efficacy 100–1000 folds more than irinotecan in vitro. However, the clinical application of SN38 has been limited due to the very narrow therapeutic window and poor water solubility. Herein, we report the SN38-glucose conjugates (Glu-SN38) that can target cancer cells due to their selective uptake via glucose transporters, which are overexpressed in most cancers. The in vitro antiproliferative activities against human cancer cell lines and normal cells of Glu-SN38 were investigated. One of the conjugates named 5b showed high potency and selectivity against human colorectal cancer cell line HCT116. Furthermore, 5b remarkably inhibited the growth of HCT116 in vivo. These results suggested that 5b could be a promising drug candidate for treating colorectal cancer.

Research Progress of SN38 Drug Delivery System in Cancer Treatment

“…In addition, Glu-SNP and SNP inhibited tumor growth in MKN45 transplanted nude mice by (91.5 ± 1.49)% and (93.9 ± 1.08)%, respectively, which was markedly greater than CPT-11 (20.6 ± 13.2)% ( Figure S6 ). Yang et al 65 prepared three SN38-glucose couples by modifying the 20-hydroxyl group of SN38 (Glu-SN38) [ Figure S7(A )] for targeting overexpressing GLUTs in tumor cells. Adding 100 mM glucose to the medium caused, the IC 50 values of the most active of these SN38-glucose couplers, 5b and irinotecan, were altered 8.3-fold and 1.3-fold, respectively, while 5b showed a higher selectivity for the human colorectal cancer cell-line HCT-116 compared to other negative control cells.…”

Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors

“…However, the efficacy of Cur is limited by its inadequate solubility and bioavailability [ 126 ]. SN38, known for its potent inhibition of DNA topoisomerase I [ 127 ], can induce apoptosis in CRC cells [ [128] , [129] , [130] ]. Similarly, SN38 encounters challenges related to its poor solubility and stability [ 131 ].…”

Structural Modification Endows Small-Molecular SN38 Derivatives with Multifaceted Functions

“…The introduction of glucose to SN38 simultaneously enhanced water solubility and tumor-targeting ability of the SN38 derivatives. Among them, compound 82 exhibited high cytotoxicity and selectivity for HCT-116 cells, which was also demonstrated in an HCT-116 xenograft model [ 70 ]. The design idea is also applicable to structural modification of other hydrophobic chemotherapeutic agents.…”