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Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy.

Zhang CG, Zhu WJ, Liu Y, Yuan ZQ, Yang SD, Chen WL, Li JZ, Zhou XF, Liu C, Zhang XN - Sci Rep (2016)

Bottom Line: In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle).Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments.The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.

ABSTRACT
Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle). Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox-siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox-siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Cytotoxicity of different Dox formulations in two cell types after incubation for 24 h or 48 h.HepG2 cells (A,B), HepG2/ADM cells (C,D); 24 h (A,C); 48 h (B,D). *p < 0.05, **p < 0.01 compared with the controls; #p < 0.05, ##p < 0.01 compared with the Dox group (n = 3).
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f8: Cytotoxicity of different Dox formulations in two cell types after incubation for 24 h or 48 h.HepG2 cells (A,B), HepG2/ADM cells (C,D); 24 h (A,C); 48 h (B,D). *p < 0.05, **p < 0.01 compared with the controls; #p < 0.05, ##p < 0.01 compared with the Dox group (n = 3).

Mentions: The cytotoxicity of different Dox formulations toward resistant and sensitive cells was determined by MTT assay after incubation for 24 or 48 h. As shown in Fig. 8, blank-micelle hardly decreased the viability of HepG2 and HepG2/ADM cells even at a relatively high concentration. In HepG2 cells, the IC50 value of Dox was lower than that of Dox-micelle at 24 h (Fig. 8A), as Dox was directly located in the nucleus, whereas the release of loaded drug in Dox-micelle required a specific time period. This assumption was verified by the result of cytotoxicity at 48 h in HepG2 cells (Fig. 8B), as the IC50 values of Dox and Dox-micelle were much closer in 48 h than that in 24 h, resulting from more drugs released from Dox-micelle. On the contrary, Dox-micelle induced higher cytotoxicity in HepG2/ADM cells than Dox (Fig. 8C,D), which was due to the fact that P-gp, overexpressed in HepG2/ADM cells, was effluxed of drugs from intracellular to extracellular environments. Moreover, Dox-micelle could bypass the P-gp-mediated drug efflux under the advantages of micelles. Dox–siRNA-micelle led to further increases in cytotoxicity in HepG2/ADM cells, and improved the antitumor activity in HepG2/ADM cells close to that in HepG2 cells, which was associated with the siRNA-mediated decrease in drug efflux. Thus, Dox–siRNA-micelle could improve the therapeutic efficacy by bypassing drug efflux and downregulating the P-gp level.


Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy.

Zhang CG, Zhu WJ, Liu Y, Yuan ZQ, Yang SD, Chen WL, Li JZ, Zhou XF, Liu C, Zhang XN - Sci Rep (2016)

Cytotoxicity of different Dox formulations in two cell types after incubation for 24 h or 48 h.HepG2 cells (A,B), HepG2/ADM cells (C,D); 24 h (A,C); 48 h (B,D). *p < 0.05, **p < 0.01 compared with the controls; #p < 0.05, ##p < 0.01 compared with the Dox group (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814909&req=5

f8: Cytotoxicity of different Dox formulations in two cell types after incubation for 24 h or 48 h.HepG2 cells (A,B), HepG2/ADM cells (C,D); 24 h (A,C); 48 h (B,D). *p < 0.05, **p < 0.01 compared with the controls; #p < 0.05, ##p < 0.01 compared with the Dox group (n = 3).
Mentions: The cytotoxicity of different Dox formulations toward resistant and sensitive cells was determined by MTT assay after incubation for 24 or 48 h. As shown in Fig. 8, blank-micelle hardly decreased the viability of HepG2 and HepG2/ADM cells even at a relatively high concentration. In HepG2 cells, the IC50 value of Dox was lower than that of Dox-micelle at 24 h (Fig. 8A), as Dox was directly located in the nucleus, whereas the release of loaded drug in Dox-micelle required a specific time period. This assumption was verified by the result of cytotoxicity at 48 h in HepG2 cells (Fig. 8B), as the IC50 values of Dox and Dox-micelle were much closer in 48 h than that in 24 h, resulting from more drugs released from Dox-micelle. On the contrary, Dox-micelle induced higher cytotoxicity in HepG2/ADM cells than Dox (Fig. 8C,D), which was due to the fact that P-gp, overexpressed in HepG2/ADM cells, was effluxed of drugs from intracellular to extracellular environments. Moreover, Dox-micelle could bypass the P-gp-mediated drug efflux under the advantages of micelles. Dox–siRNA-micelle led to further increases in cytotoxicity in HepG2/ADM cells, and improved the antitumor activity in HepG2/ADM cells close to that in HepG2 cells, which was associated with the siRNA-mediated decrease in drug efflux. Thus, Dox–siRNA-micelle could improve the therapeutic efficacy by bypassing drug efflux and downregulating the P-gp level.

Bottom Line: In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle).Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments.The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.

ABSTRACT
Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle). Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox-siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox-siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.

No MeSH data available.


Related in: MedlinePlus