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Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly.

Fu Q, Wang Y, Ma Y, Zhang D, Fallon JK, Yang X, Liu D, He Z, Liu F - Sci Rep (2015)

Bottom Line: Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency.It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased.The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.

ABSTRACT
Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4(th) injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.

No MeSH data available.


Related in: MedlinePlus

Hemolytic activity of Taxol®, PTX-VE/VE/VE2-PEG2000/water NES, PTX-S-S-VE/VE/VE2-PEG2000/water NES, and Abraxane® at 37 °C for 1 h (data are expressed as the mean ± SD, n = 3 mice for each measurement) (p < 0.05 [*] and p < 0.01 [**]).
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f8: Hemolytic activity of Taxol®, PTX-VE/VE/VE2-PEG2000/water NES, PTX-S-S-VE/VE/VE2-PEG2000/water NES, and Abraxane® at 37 °C for 1 h (data are expressed as the mean ± SD, n = 3 mice for each measurement) (p < 0.05 [*] and p < 0.01 [**]).

Mentions: It is acknowledged that hemolysis is a major drawback for surfactant based formulations, such as Taxol®. In this study, TPGS and VE2-PEG, which can each also cause hemolysis, were used for stabilizing the NES. Therefore, to evaluate the safety of the two NES, we studied the hemolysis effect by incubating erythrocytes with the formulations (Taxol®, PTX-VE/VE/VE2-PEG2000 NES, PTX-S-S-VE/VE/VE2-PEG2000 NES, and Abraxane®) for 1 h at different PTX concentrations. Figure 8 shows hemolysis results for the formulations at various concentrations. At 0.0293 μM of PTX, all formulations were nonhemolytic. As the concentration was increased, hemolysis appeared. At the highest concentration tested (0.117 μM), 91.3% of the erythrocytes were hemolyzed for the Taxol® group, while only 19.5%, 15.6%, and 12.9% of erythrocytes were hemolyzed for PTX-S-S-VE/VE/VE2-PEG2000 NES, PTX-VE/VE/VE2-PEG2000 NES, and Abraxane®, respectively. Therefore, it can be suggested that both of the prodrug NES formulations are safer than Taxol® in terms of membrane toxicity.


Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly.

Fu Q, Wang Y, Ma Y, Zhang D, Fallon JK, Yang X, Liu D, He Z, Liu F - Sci Rep (2015)

Hemolytic activity of Taxol®, PTX-VE/VE/VE2-PEG2000/water NES, PTX-S-S-VE/VE/VE2-PEG2000/water NES, and Abraxane® at 37 °C for 1 h (data are expressed as the mean ± SD, n = 3 mice for each measurement) (p < 0.05 [*] and p < 0.01 [**]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499798&req=5

f8: Hemolytic activity of Taxol®, PTX-VE/VE/VE2-PEG2000/water NES, PTX-S-S-VE/VE/VE2-PEG2000/water NES, and Abraxane® at 37 °C for 1 h (data are expressed as the mean ± SD, n = 3 mice for each measurement) (p < 0.05 [*] and p < 0.01 [**]).
Mentions: It is acknowledged that hemolysis is a major drawback for surfactant based formulations, such as Taxol®. In this study, TPGS and VE2-PEG, which can each also cause hemolysis, were used for stabilizing the NES. Therefore, to evaluate the safety of the two NES, we studied the hemolysis effect by incubating erythrocytes with the formulations (Taxol®, PTX-VE/VE/VE2-PEG2000 NES, PTX-S-S-VE/VE/VE2-PEG2000 NES, and Abraxane®) for 1 h at different PTX concentrations. Figure 8 shows hemolysis results for the formulations at various concentrations. At 0.0293 μM of PTX, all formulations were nonhemolytic. As the concentration was increased, hemolysis appeared. At the highest concentration tested (0.117 μM), 91.3% of the erythrocytes were hemolyzed for the Taxol® group, while only 19.5%, 15.6%, and 12.9% of erythrocytes were hemolyzed for PTX-S-S-VE/VE/VE2-PEG2000 NES, PTX-VE/VE/VE2-PEG2000 NES, and Abraxane®, respectively. Therefore, it can be suggested that both of the prodrug NES formulations are safer than Taxol® in terms of membrane toxicity.

Bottom Line: Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency.It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased.The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.

ABSTRACT
Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4(th) injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.

No MeSH data available.


Related in: MedlinePlus