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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

Subcellular localization of Dox-micelle, siRNA-micelle, and Dox–siRNA-micelle in HepG2/ADM cells evaluated by CLSM after incubation for 1 h.
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f3: Subcellular localization of Dox-micelle, siRNA-micelle, and Dox–siRNA-micelle in HepG2/ADM cells evaluated by CLSM after incubation for 1 h.

Mentions: Cellular uptake and intracellular distribution of Dox–siRNA-micelle in HepG2/ADM cells were measured by CLSM (Fig. 3). The co-localization of Dox and siRNAFAM in the cytoplasm indicated the simultaneous delivery of siRNAFAM and Dox in HepG2/ADM cells after incubation with Dox–siRNAFAM-micelle. The preponderant cellular uptake and intracellular release were further confirmed by a live cell station (Fig. 4). Dox and siRNAFAM were simultaneously delivered by Dox–siRNAFAM-micelle in the cells and then released into the cytoplasm. Dox was transferred to the nucleus and embedded into the DNA bases, whereas siRNA stayed within the cytoplasm to disrupt mRNA transcription and downregulate the expression of the target protein.


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)

Subcellular localization of Dox-micelle, siRNA-micelle, and Dox–siRNA-micelle in HepG2/ADM cells evaluated by CLSM after incubation for 1 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Subcellular localization of Dox-micelle, siRNA-micelle, and Dox–siRNA-micelle in HepG2/ADM cells evaluated by CLSM after incubation for 1 h.
Mentions: Cellular uptake and intracellular distribution of Dox–siRNA-micelle in HepG2/ADM cells were measured by CLSM (Fig. 3). The co-localization of Dox and siRNAFAM in the cytoplasm indicated the simultaneous delivery of siRNAFAM and Dox in HepG2/ADM cells after incubation with Dox–siRNAFAM-micelle. The preponderant cellular uptake and intracellular release were further confirmed by a live cell station (Fig. 4). Dox and siRNAFAM were simultaneously delivered by Dox–siRNAFAM-micelle in the cells and then released into the cytoplasm. Dox was transferred to the nucleus and embedded into the DNA bases, whereas siRNA stayed within the cytoplasm to disrupt mRNA transcription and downregulate the expression of the target protein.

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