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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

Inhibition of tumor growth by Taxol®, PTX-VE/VE/VE2-PEG2000/water and PTX-S-S-VE/VE/VE2-PEG2000/water NES in KB-3-1 cell subcutaneous xenografts.The formulations were administered intravenously at an equivalent dose of 5 mg/kg of PTX every second day for 5 injections in total (data are expressed as the mean ± SD, n = 5 mice for each formulation) (p < 0.05 [*] and p < 0.01 [**]).
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f7: Inhibition of tumor growth by Taxol®, PTX-VE/VE/VE2-PEG2000/water and PTX-S-S-VE/VE/VE2-PEG2000/water NES in KB-3-1 cell subcutaneous xenografts.The formulations were administered intravenously at an equivalent dose of 5 mg/kg of PTX every second day for 5 injections in total (data are expressed as the mean ± SD, n = 5 mice for each formulation) (p < 0.05 [*] and p < 0.01 [**]).

Mentions: To evaluate the in vivo therapeutic effect of the formulations, tumor growth inhibition was studied in a KB-3-1 cells subcutaneous model in Balb/C nude mice. As shown in Fig. 7, the control group showed very rapid tumor growth. There was no significant reduction of the tumor volume in mice treated with PTX-VE/VE/VE2-PEG2000 NES (p > 0.05, Student’s t-test, paired, two sided). However, the mean tumor volume was slightly smaller than for the controls. Not surprisingly, the greatest antitumor activity was observed when the mice were treated with PTX-S-S-VE/VE/VE2-PEG2000 NES. For this formulation, the tumors were diminished before the fifth injection. Similarly, Taxol® also showed a strong tumor inhibition effect and only one mouse was found to still bear the tumor by the 15th day. In addition, no weight loss occurred in all groups (Fig. S10).


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)

Inhibition of tumor growth by Taxol®, PTX-VE/VE/VE2-PEG2000/water and PTX-S-S-VE/VE/VE2-PEG2000/water NES in KB-3-1 cell subcutaneous xenografts.The formulations were administered intravenously at an equivalent dose of 5 mg/kg of PTX every second day for 5 injections in total (data are expressed as the mean ± SD, n = 5 mice for each formulation) (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

f7: Inhibition of tumor growth by Taxol®, PTX-VE/VE/VE2-PEG2000/water and PTX-S-S-VE/VE/VE2-PEG2000/water NES in KB-3-1 cell subcutaneous xenografts.The formulations were administered intravenously at an equivalent dose of 5 mg/kg of PTX every second day for 5 injections in total (data are expressed as the mean ± SD, n = 5 mice for each formulation) (p < 0.05 [*] and p < 0.01 [**]).
Mentions: To evaluate the in vivo therapeutic effect of the formulations, tumor growth inhibition was studied in a KB-3-1 cells subcutaneous model in Balb/C nude mice. As shown in Fig. 7, the control group showed very rapid tumor growth. There was no significant reduction of the tumor volume in mice treated with PTX-VE/VE/VE2-PEG2000 NES (p > 0.05, Student’s t-test, paired, two sided). However, the mean tumor volume was slightly smaller than for the controls. Not surprisingly, the greatest antitumor activity was observed when the mice were treated with PTX-S-S-VE/VE/VE2-PEG2000 NES. For this formulation, the tumors were diminished before the fifth injection. Similarly, Taxol® also showed a strong tumor inhibition effect and only one mouse was found to still bear the tumor by the 15th day. In addition, no weight loss occurred in all groups (Fig. S10).

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