Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs

Abstract

Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of β-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs.

Glycosidase activated prodrugs for targeted cancer therapy

“…4), where the glucose moieties were attached via succinate linkers. 70 Both prodrugs showed improved aqueous solubility and drug-like lipophilicity over the parent drug. Of the two, the single glucose conjugate 15a had a more efficient release in serum, where a high percentage of the parent drug was detected following hydrolysis with β-glucuronidase.…”

A Small Sugar Molecule with Huge Potential in Targeted Cancer Therapy

“…In another study, glycoconjugates of paclitaxel with single or double glucose moieties attached by succinate linkers were reported [ 74 ]. Both the C-2′-single glycosylated paclitaxel (GluSA-PTX) and the double glycosylated paclitaxel ( bis -GluSA-PTX) conjugates showed effective cytotoxicity against breast cancer cells and improved hydro solubility compared to the parent drug.…”

Natural Taxanes: From Plant Composition to Human Pharmacology and Toxicity

“…There is high inter- and intra-species variability in taxane content [ 25 , 26 ], and it has been shown that this variability can depend on the season and taxoid type. The concentration of 10-DAB in first- and second-year needles of T. baccata grown in a Polish garden was highest in January and lowest in April [ 3 ], while in a study in Tehran, Iran [ 6 ], the highest concentration in yew needles was reached in August. The bark of T. baccata grown in the forests of the Czech Republic showed that the highest concentration of PTX and three other taxanes was in October and the lowest in January [ 27 ].…”

“…PTX concentration in T. cuspidata, T. media, and T. mairei is 1.67, 1.22, and 0.66 mg/g, respectively. Paclitaxel (Taxol A) was isolated from Taxus plants and has been widely used since 1984 in the treatment of various cancers (mainly tumours of the breast, ovaries, pancreas or stomach) [ 4 ], while in order to improve the effect, new ways of administering this drug are constantly being developed [ 5 , 6 , 7 , 8 , 9 ]. The reason is mainly the achievement of a better biological effect in the exact target place in different types of tissues [ 10 , 11 ] with the least possible number of side effects and at the same time bypassing various resistant mechanisms of tumour cells (overexpression of multidrug resistance (MDR) efflux transporters or by microtubule alterations) [ 8 , 12 ].…”