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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

(A) Body weights of tumor-bearing nude mice in all groups (n = 5). (B) Antitumor effect of different formulations through i.v. injection (n = 5). (C) Size of collected tumor in all groups. (D) Representative of tumor-bearing nude mice from each group and its P-gp protein content detected by Western blot. **p < 0.01 compared with the NS group; ##p < 0.01 compared with the Dox group (n = 3).
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f11: (A) Body weights of tumor-bearing nude mice in all groups (n = 5). (B) Antitumor effect of different formulations through i.v. injection (n = 5). (C) Size of collected tumor in all groups. (D) Representative of tumor-bearing nude mice from each group and its P-gp protein content detected by Western blot. **p < 0.01 compared with the NS group; ##p < 0.01 compared with the Dox group (n = 3).

Mentions: Tumor suppression with various formulations administered in vivo was analyzed to evaluate the synergistic antitumor activity of siRNA–Dox-micelle. As shown in Fig. 11B, simultaneous delivery of siRNA and Dox by siRNA–Dox-micelle exhibited the strongest anti-tumor activity among the formulations. Furthermore, the synergistic antitumor activity of siRNA–Dox-micelle was demonstrated compared with siRNA-micelle and Dox-micelle treatments2837. The delivery of Dox by Dox-micelle did not significantly increase tumor suppression compared with Dox only treatment, but significantly improved the survival quality of tumor-bearing mice, as the mice weight significantly decreased after Dox injection (Fig. 11A), indicating the safety of the micelle material. The size of the collected tumor was in accordance with the above results, and further confirmed the synergistic antitumor activity of siRNA–Dox-micelle (Fig. 11C). Analysis of P-gp expression in each treatment showed a consistent knockdown efficiency (Fig. 11D). The delivery of siRNA by siRNA-micelle could significantly downregulate P-gp expression for MDR reversal in vivo. The combination of Dox and siRNA-P-gp could enhance the chemotherapeutics and exert better tumor suppressive effects.


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)

(A) Body weights of tumor-bearing nude mice in all groups (n = 5). (B) Antitumor effect of different formulations through i.v. injection (n = 5). (C) Size of collected tumor in all groups. (D) Representative of tumor-bearing nude mice from each group and its P-gp protein content detected by Western blot. **p < 0.01 compared with the NS group; ##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

f11: (A) Body weights of tumor-bearing nude mice in all groups (n = 5). (B) Antitumor effect of different formulations through i.v. injection (n = 5). (C) Size of collected tumor in all groups. (D) Representative of tumor-bearing nude mice from each group and its P-gp protein content detected by Western blot. **p < 0.01 compared with the NS group; ##p < 0.01 compared with the Dox group (n = 3).
Mentions: Tumor suppression with various formulations administered in vivo was analyzed to evaluate the synergistic antitumor activity of siRNA–Dox-micelle. As shown in Fig. 11B, simultaneous delivery of siRNA and Dox by siRNA–Dox-micelle exhibited the strongest anti-tumor activity among the formulations. Furthermore, the synergistic antitumor activity of siRNA–Dox-micelle was demonstrated compared with siRNA-micelle and Dox-micelle treatments2837. The delivery of Dox by Dox-micelle did not significantly increase tumor suppression compared with Dox only treatment, but significantly improved the survival quality of tumor-bearing mice, as the mice weight significantly decreased after Dox injection (Fig. 11A), indicating the safety of the micelle material. The size of the collected tumor was in accordance with the above results, and further confirmed the synergistic antitumor activity of siRNA–Dox-micelle (Fig. 11C). Analysis of P-gp expression in each treatment showed a consistent knockdown efficiency (Fig. 11D). The delivery of siRNA by siRNA-micelle could significantly downregulate P-gp expression for MDR reversal in vivo. The combination of Dox and siRNA-P-gp could enhance the chemotherapeutics and exert better tumor suppressive effects.

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