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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

TEM micrographs (A), AFM micrographs (B), and particle diameter distribution (C) of siRNA–Dox-micelle. (D) Changes in size and zeta potential of Dox–siRNA-micelle in different pH media after incubation at various times (n = 3).
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f2: TEM micrographs (A), AFM micrographs (B), and particle diameter distribution (C) of siRNA–Dox-micelle. (D) Changes in size and zeta potential of Dox–siRNA-micelle in different pH media after incubation at various times (n = 3).

Mentions: The particle size and zeta potential of micelles measured using Zetasizer Nano ZS were 179 nm and 3.2 mV, respectively, accompanied with a narrow size distribution and good dispersion (Fig. 2C). The size and surface morphology of micelles confirmed by TEM (Fig. 2A) and AFM (Fig. 2B) showed that most of the micelle nanoparticles were compact and spherical, with an average diameter of approximately 170 nm. This size was smaller than the result measured by Zetasizer Nano ZS, which was due to the collapse and shrinking that occurred during sample preparation for detection34.


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)

TEM micrographs (A), AFM micrographs (B), and particle diameter distribution (C) of siRNA–Dox-micelle. (D) Changes in size and zeta potential of Dox–siRNA-micelle in different pH media after incubation at various times (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: TEM micrographs (A), AFM micrographs (B), and particle diameter distribution (C) of siRNA–Dox-micelle. (D) Changes in size and zeta potential of Dox–siRNA-micelle in different pH media after incubation at various times (n = 3).
Mentions: The particle size and zeta potential of micelles measured using Zetasizer Nano ZS were 179 nm and 3.2 mV, respectively, accompanied with a narrow size distribution and good dispersion (Fig. 2C). The size and surface morphology of micelles confirmed by TEM (Fig. 2A) and AFM (Fig. 2B) showed that most of the micelle nanoparticles were compact and spherical, with an average diameter of approximately 170 nm. This size was smaller than the result measured by Zetasizer Nano ZS, which was due to the collapse and shrinking that occurred during sample preparation for detection34.

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