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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

In vitro hydrolytic profiles and cytotoxicity against KB-3-1 cell line for PTX-S-S-VE (data are expressed as the mean ± SD, n = 5 wells for each formulation at each concentration).These studies were carried out at 37 °C.
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f4: In vitro hydrolytic profiles and cytotoxicity against KB-3-1 cell line for PTX-S-S-VE (data are expressed as the mean ± SD, n = 5 wells for each formulation at each concentration).These studies were carried out at 37 °C.

Mentions: On the basis of the analysis above and considering the redox nature of the tumor microenvironment33, we undertook to synthesize PTX-S-S-VE (PTX conjugated with VE via a disulfide bond) because the sufficient GSH3435 in tumor cells will cleave the bridge and promote the hydrolysis to free PTX. As shown in Fig. 4, the hydrolysis rate was accelerated with GSH concentration increased. In addition, compared with PTX-VE, the in vitro hydrolysis was improved and its anticancer activity was increased.


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)

In vitro hydrolytic profiles and cytotoxicity against KB-3-1 cell line for PTX-S-S-VE (data are expressed as the mean ± SD, n = 5 wells for each formulation at each concentration).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

f4: In vitro hydrolytic profiles and cytotoxicity against KB-3-1 cell line for PTX-S-S-VE (data are expressed as the mean ± SD, n = 5 wells for each formulation at each concentration).These studies were carried out at 37 °C.
Mentions: On the basis of the analysis above and considering the redox nature of the tumor microenvironment33, we undertook to synthesize PTX-S-S-VE (PTX conjugated with VE via a disulfide bond) because the sufficient GSH3435 in tumor cells will cleave the bridge and promote the hydrolysis to free PTX. As shown in Fig. 4, the hydrolysis rate was accelerated with GSH concentration increased. In addition, compared with PTX-VE, the in vitro hydrolysis was improved and its anticancer activity was increased.

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