Targeting the Delivery of Glycan-Based Paclitaxel Prodrugs to Cancer Cells via Glucose Transporters

Abstract

This report describes the synthesis of four novel paclitaxel based prodrugs with glycan conjugation (1-4). Glycans were conjugated using an ester or ether bond as the linker between 2'-paclitaxel and the 2'-glucose or glucuronic acid moiety. These prodrugs showed good water solubility and selective cytotoxicity against cancer cell lines, but showed reduced toxicity toward normal cell lines and cancer cell lines with low expression levels of GLUTs. The ester conjugated prodrug 1 showed the most cytotoxicity among the prodrugs examined and could be transported into cells via GLUTs. Fluorescent and confocal microscopy demonstrated that targeted cells exhibited morphological changes in tubulin and chromosomal alterations that were similar to those observed with paclitaxel treatment. Therefore, these glycan-based prodrugs may be good drug candidates for cancer therapy, and the glycan conjugation approach is an alternative method to enhance the targeted delivery of other drugs to cancer cells that overexpress GLUTs.

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

“…Thus, structural modification of podophyllotoxin for developing new antitumor drugs with increased selectivity and reduced toxicity is highly desirable. In recent years, the altered glucose metabolism in cancer cells has been explored for targeted cancer therapy [18]. Glucose is the main source of metabolic energy of animal cells, generating ATP through glycolysis and oxidative phosphorylation.…”

Anticancer agents interacting with membrane glucose transporters

“…The resulting compound, whose transport was mediated at least in part by GLUT1 as confirmed by fluorescence microscopy studies, showed improved pharmaceutical properties and a comparable cytotoxicity against MCF-7 breast cancer cells without toxicity on normal cells, but it showed a reduced toxicity on most of the tested cancer cell lines compared to the parent compound. 90 …”

Possibilities of Cancer Chemotherapy Based on Transporter-Conscious Drug Design

“…Paclitaxel is an important agent in the treatment of several cancers including breast cancer. Glucoseconjugated paclitaxel derivatives through the ester bond or the ether bond ( Figure 3) were transported into cells against tumor cell lines such as NCI-H838 (lung adenocarcinoma), MES-SA (uterine carcinoma), HCT-116 (colon carcinoma), and NPC-TW01 (nasopharyngeal carcinoma) with the exception of breast cancer cells, based on Glut1-mediated transport, and then exhibited the cytotoxic activity [15]. Similarly, it is suggested that glucose-conjugated paclitaxel derivatives can be transported into breast cancer cells and exhibit the cytotoxic activity there, because GluT1 is overexpressed even in breast cancer cells.…”