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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

Tissue distribution of parent drug (a) and prodrugs (b) at 4 h after intravenous administration of Taxol®, PTX-VE/VE/VE2-PEG2000/water and water NES PTX-S-S-VE/VE/VE2-PEG2000/ at a PTX equivalent single dose of 20 mg/kg at 4 h (p < 0.05 [*] and p < 0.01 [**]).
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f6: Tissue distribution of parent drug (a) and prodrugs (b) at 4 h after intravenous administration of Taxol®, PTX-VE/VE/VE2-PEG2000/water and water NES PTX-S-S-VE/VE/VE2-PEG2000/ at a PTX equivalent single dose of 20 mg/kg at 4 h (p < 0.05 [*] and p < 0.01 [**]).

Mentions: To evaluate the in vivo performance, the CD1 mice, in the biodistribution study, were administrated intravenously a single dose equivalent of 20 mg/kg PTX. The mice were sacrificed at 4 h and the tissues were harvested. The biodistribution of free PTX and PTX prodrugs are shown in Fig. 6a,b, respectively. For PTX-VE NES, free PTX was only found in the liver, with only a small amount being found in other tissues. This was because of the low cleavage rate of the ester bond, and indicated similar in vivo hydrolytic behavior to that seen in vitro. On the other hand, PTX-VE NES showed high prodrug accumulation, including higher than that of PTX-S-S-VE NES, with liver (3794.0 ± 1241.6 ng/g) being the major distribution tissue followed by spleen (1753.1 ± 666.7 ng/g) and then kidney (1351.4 ± 179.3 ng/g). The reason for this could be attributed to matching properties of VE oil and the VE group in PTX-VE, as well as PTX-VE being less susceptible to hydrolysis than PTX-S-S-VE. Importantly, it exhibited comparable prodrug distribution in tumors for PTX-VE NES and PTX-S-S-VE NES. In the case of PTX-S-S-VE NES, greater free PTX accumulation was seen than for Taxol® in most tissues. The distribution was statistically higher than Taxol® in plasma (p < 0.05), liver (p < 0.05), spleen (p < 0.05), kidney (p < 0.05) and tumor (p < 0.05, Student’s t-test, paired, two sided). This could be because PTX-S-S-VE and VE are molecularly matched resulting in longer circulation of the PTX-S-S-VE NES in the blood and hence longer in vivo retention time than for the Taxol®. In addition, the GSH in blood, despite being of much lower concentration than in the tumor, could start the hydrolytic program to some extent, leading to enhanced hydrolysis. The in vivo distribution results indirectly reflect the hydrolytic properties of the prodrugs.


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)

Tissue distribution of parent drug (a) and prodrugs (b) at 4 h after intravenous administration of Taxol®, PTX-VE/VE/VE2-PEG2000/water and water NES PTX-S-S-VE/VE/VE2-PEG2000/ at a PTX equivalent single dose of 20 mg/kg at 4 h (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

f6: Tissue distribution of parent drug (a) and prodrugs (b) at 4 h after intravenous administration of Taxol®, PTX-VE/VE/VE2-PEG2000/water and water NES PTX-S-S-VE/VE/VE2-PEG2000/ at a PTX equivalent single dose of 20 mg/kg at 4 h (p < 0.05 [*] and p < 0.01 [**]).
Mentions: To evaluate the in vivo performance, the CD1 mice, in the biodistribution study, were administrated intravenously a single dose equivalent of 20 mg/kg PTX. The mice were sacrificed at 4 h and the tissues were harvested. The biodistribution of free PTX and PTX prodrugs are shown in Fig. 6a,b, respectively. For PTX-VE NES, free PTX was only found in the liver, with only a small amount being found in other tissues. This was because of the low cleavage rate of the ester bond, and indicated similar in vivo hydrolytic behavior to that seen in vitro. On the other hand, PTX-VE NES showed high prodrug accumulation, including higher than that of PTX-S-S-VE NES, with liver (3794.0 ± 1241.6 ng/g) being the major distribution tissue followed by spleen (1753.1 ± 666.7 ng/g) and then kidney (1351.4 ± 179.3 ng/g). The reason for this could be attributed to matching properties of VE oil and the VE group in PTX-VE, as well as PTX-VE being less susceptible to hydrolysis than PTX-S-S-VE. Importantly, it exhibited comparable prodrug distribution in tumors for PTX-VE NES and PTX-S-S-VE NES. In the case of PTX-S-S-VE NES, greater free PTX accumulation was seen than for Taxol® in most tissues. The distribution was statistically higher than Taxol® in plasma (p < 0.05), liver (p < 0.05), spleen (p < 0.05), kidney (p < 0.05) and tumor (p < 0.05, Student’s t-test, paired, two sided). This could be because PTX-S-S-VE and VE are molecularly matched resulting in longer circulation of the PTX-S-S-VE NES in the blood and hence longer in vivo retention time than for the Taxol®. In addition, the GSH in blood, despite being of much lower concentration than in the tumor, could start the hydrolytic program to some extent, leading to enhanced hydrolysis. The in vivo distribution results indirectly reflect the hydrolytic properties of the prodrugs.

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