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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

Chemical structures of PTX, PTX-VE, PTX-SEE, PTX-SA, and PTX-S-S-VE.
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f1: Chemical structures of PTX, PTX-VE, PTX-SEE, PTX-SA, and PTX-S-S-VE.

Mentions: In our group, PTX-VE (Fig. 1) has been synthesized by conjugating PTX and vitamin E (VE) together via an ester bond, and it has been encapsulated in the VE/VE2-PEG2000/water nanoemulsions (NES) because PTX-VE, VE, and VE2-PEG2000 were molecularly matched. Based on this, we have codelivered PTX and 5-fluoroucacil in a same nanoparticle by their conjugation with the VE29. What is more, using the same strategy, theranostic (PTX, and sulforhodamine B) has been also achieved30. However, PTX-VE did not release active PTX in vitro within 48 h, resulted in negotiated cytotoxicity. Thus, the aim of this paper was to find out a substitute for PTX-VE. We initially demonstrated that its hydrolysis was impeded by steric hindrance and improved by sufficient polarity, by grafting different groups onto PTX. Then, we proposed and synthesized PTX-S-S-VE, PTX conjugated with VE via a disulfide bond, a redox sensitive bridge (Fig. 2). This bridge would be broken in tumor cells because of the sufficient glutathione (GSH) concentration (2–8 mM)31, to promote the hydrolysis. In addition, the PTX-S-S-VE can also be encapsulated and assembled as PTX-S-S-VE/VE/VE2-PEG2000/water NES for administration because of favourable hydrophobic interactions between the prodrug and the nanocarrier. The tissue distribution, in vivo antitumor activity and hemolytic activity were evaluated for PTX-S-S-VE/VE/VE2-PEG2000/water NES, with PTX-VE/VE/VE2-PEG2000/water NES and Taxol® as reference formulations.


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)

Chemical structures of PTX, PTX-VE, PTX-SEE, PTX-SA, and PTX-S-S-VE.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Chemical structures of PTX, PTX-VE, PTX-SEE, PTX-SA, and PTX-S-S-VE.
Mentions: In our group, PTX-VE (Fig. 1) has been synthesized by conjugating PTX and vitamin E (VE) together via an ester bond, and it has been encapsulated in the VE/VE2-PEG2000/water nanoemulsions (NES) because PTX-VE, VE, and VE2-PEG2000 were molecularly matched. Based on this, we have codelivered PTX and 5-fluoroucacil in a same nanoparticle by their conjugation with the VE29. What is more, using the same strategy, theranostic (PTX, and sulforhodamine B) has been also achieved30. However, PTX-VE did not release active PTX in vitro within 48 h, resulted in negotiated cytotoxicity. Thus, the aim of this paper was to find out a substitute for PTX-VE. We initially demonstrated that its hydrolysis was impeded by steric hindrance and improved by sufficient polarity, by grafting different groups onto PTX. Then, we proposed and synthesized PTX-S-S-VE, PTX conjugated with VE via a disulfide bond, a redox sensitive bridge (Fig. 2). This bridge would be broken in tumor cells because of the sufficient glutathione (GSH) concentration (2–8 mM)31, to promote the hydrolysis. In addition, the PTX-S-S-VE can also be encapsulated and assembled as PTX-S-S-VE/VE/VE2-PEG2000/water NES for administration because of favourable hydrophobic interactions between the prodrug and the nanocarrier. The tissue distribution, in vivo antitumor activity and hemolytic activity were evaluated for PTX-S-S-VE/VE/VE2-PEG2000/water NES, with PTX-VE/VE/VE2-PEG2000/water NES and Taxol® as reference formulations.

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