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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

Hydrolytic release profiles in pH 7.4 PBS containing 7% DMSO and 0.1% Tween 80 (a) and in vitro cytotoxicity against KB-3-1 cell line for PTX-VE, PTX-SEE, and PTX-SA (b). These studies were carried out at 37 °C.
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f3: Hydrolytic release profiles in pH 7.4 PBS containing 7% DMSO and 0.1% Tween 80 (a) and in vitro cytotoxicity against KB-3-1 cell line for PTX-VE, PTX-SEE, and PTX-SA (b). These studies were carried out at 37 °C.

Mentions: In the hydrolysis study, the PTX-VE was not hydrolyzed until 48 h. The reason for the poor hydrolysis of PTX-VE might be that the hydrolytic site (C-2' hydroxyl group in PTX) is sterically shielded by the VE. To test this hypothesis, PTX-SEE (the VE group substituted by a methyl group) was synthesized. Both PTX-VE and PTX-SEE are hydrophobic. As shown in Fig. 3a, approximately 20.7% of PTX-SEE was hydrolyzed to free PTX by 48 h, a much higher percentage than for PTX-VE. This indicates that steric hindrance could be a major reason for impeded hydrolysis.


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)

Hydrolytic release profiles in pH 7.4 PBS containing 7% DMSO and 0.1% Tween 80 (a) and in vitro cytotoxicity against KB-3-1 cell line for PTX-VE, PTX-SEE, and PTX-SA (b). These studies were carried out at 37 °C.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Hydrolytic release profiles in pH 7.4 PBS containing 7% DMSO and 0.1% Tween 80 (a) and in vitro cytotoxicity against KB-3-1 cell line for PTX-VE, PTX-SEE, and PTX-SA (b). These studies were carried out at 37 °C.
Mentions: In the hydrolysis study, the PTX-VE was not hydrolyzed until 48 h. The reason for the poor hydrolysis of PTX-VE might be that the hydrolytic site (C-2' hydroxyl group in PTX) is sterically shielded by the VE. To test this hypothesis, PTX-SEE (the VE group substituted by a methyl group) was synthesized. Both PTX-VE and PTX-SEE are hydrophobic. As shown in Fig. 3a, approximately 20.7% of PTX-SEE was hydrolyzed to free PTX by 48 h, a much higher percentage than for PTX-VE. This indicates that steric hindrance could be a major reason for impeded hydrolysis.

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