Development of glycan-based Paclitaxel prodrugs for targeting delivery to cancer cells
Date Issued
2007
Date
2007
Author(s)
Lin, Yih-Shyan
DOI
en-US
Abstract
Paclitaxel (Taxol), a natural diterpene compound, is a promising anticancer drug that was shown substantial clinical efficacy to solid tumor. However, like other cytotoxic agent, taxol lacks of selectivity and contributes to serious side effects. The conversion of taxol into prodrugs that can be specifically delivered to cancer cells may prevent this shortcoming.
In this study, we designed and synthesized four glycan-based paclitaxel prodrugs. Compound 1 and 2 are glucose-based prodrugs; and 3 and 4 are glucuronic acid-based ones. Given the high level expressions of glucose transporters and -glucuronidase in carcinomas, there is rationale to develop glycan-targeting prodrugs. Within these four compounds, prodrug 1 has the best cytotoxicity against seven human tumor cell lines (NCI-H838, Hep-3B, A498, MES-SA, HCT-116, NPC-Two1, and MKN-45). The cytotoxicity of prodrug 1 is only 2 to 16-fold lower than taxol. In addition, we also tested the toxicity of these drugs to normal cell lines (HUV-EC-C and CHO-K1). Except prodrug 4, the IC50 of other compounds are more than 100 μM. Our prodrugs showed good cytotoxicity and selectivity to cancer cells.
We also confirmed the internalization of prodrugs 1 into cancer cells. In order to trace this drug, we added a chromophore, m-aminobenzoyl group, in C7 position of taxol skeleton. After five hours treatment, the drug was seen in the plasma regions of NPC-TW01 cells. This result suggested that glucose-based prodrug 1 can be taken up by cancer cells within short time treatment. By means of rapid internalization by cancer cells, our prodrug may ease the side effects when administrating to patients.
Microtubule aggregation was observed in NPC-TW01 cells after stimulation with these prodrugs for 24 hours. In our prodrugs, the biological properties of taxol are masked temporarily by blocking its active site with a self-immolative linker. We except that paclitaxel will be liberated after glycan removal and spacer autocleavage.
In confocoal images, microtubules in cells treated with taxol or prodrugs were observed to lose silk structures. This result supported the hypothesis that our prodrugs can be converted into taxol and interference the dynamics of microtubule.
Like taxol, our prodrugs can cause cell death through apoptosis. In contrast to necrosis, apoptosis is a milder cell death pathway. In order to avoid inflammation caused by necrosis, we must demonstrate that these drugs kill cells in apoptosis pathway. Chromosome condensation is a distinct character of programmed cell death; and we found this phenomenon in cells treated with these four compound. This result indicated that apoptosis is the major death mechanism triggered by our prodrugs.
In summary, we have synthesized four glycan-based paclitaxel prodrugs and analyzed their biological characters. These prodrugs showed antitumor effect on promoting microtubule assembly and inducing apoptosis. Within these four drugs, prodrug 1 has the best cytotoxicity and selectivity to cancer cells according to the result of cytotoxicity assay. Furthermore, prodrug 1 was also proved to internalize into cells after five-hour treatment. This compound is a potential candidate for further investigation.
Subjects
紫杉醇
前驅藥物
抗癌
葡萄糖
醛酸
paclitaxel
prodrug
anticancer
glucose
glucuronic acid
SDGs
Type
other