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. 2018 Mar 9:13:1443-1456.
doi: 10.2147/IJN.S147759. eCollection 2018.

Co-delivery of Aurora-A inhibitor XY-4 and Bcl-xl siRNA enhances antitumor efficacy for melanoma therapy

Xingmei Duan #  1   2 , Minjie Mu #  3 , Junfeng Yan  1 , Lan Bai  1 , Lei Zhong  1 , Yuxuan Zhu  1 , Haixia Pan  1 , Mei Zhang  3 , Jianyou Shi  1   3
Affiliations

Co-delivery of Aurora-A inhibitor XY-4 and Bcl-xl siRNA enhances antitumor efficacy for melanoma therapy

Xingmei Duan et al. Int J Nanomedicine. .

Abstract

Background: The newly synthesized Aurora-A kinase inhibitor XY-4 is a potential anti-cancer agent, but its hydrophobicity and limited efficiency restrict further application. Nanotechnology based combined therapy provides an optimized strategy for solving these issues.

Methods: In this study, the newly synthesized Aurora-A kinase inhibitor XY-4 and Bcl-xl _targeted siRNA were co-delivered by cationic liposomes, creating an injectable co-delivery formulation. The anti-cancer ability and mechanisms of XY-4/Bcl-xl siRNA co-loaded cationic liposomes were studied both in vitro and in vivo.

Results: The prepared liposomes had a mean particle size of 91.3±4.5 nm with a zeta potential of 38.5±0.5 mV and were monodispersed (Polydispersity index =0.183) in water solution, with high drug loading capacity and stability. Intriguingly, the positive charges of co-delivery liposomes not only facilitated gene delivery, but also obviously enhanced drug uptake. The XY-4/Bcl-xl siRNA co-loaded cationic liposomes demonstrated enhanced anti-cancer effects on B16 melanoma cells in vitro by activation mitochondrial apoptosis pathway. Moreover, intratumoral injection of this co-delivery formulation efficiently inhibited the growth of a B16 melanoma xenograft model in vivo.

Conclusion: By co-delivering Aurora-A kinase inhibitor XY-4 and Bcl-xl _targeting siRNA in a nanoformulation, our study supplied a potential combination strategy for melanoma therapy.

Keywords: Aurora-A kinase inhibitor; RNA interference; apoptosis; co-delivery; liposome; melanoma.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Molecular structures of Aurora-A kinase inhibitor XY-4.
Figure 2
Figure 2
Scheme of XY-4/Bcl-xl siRNA co-loaded cationic liposome.
Figure 3
Figure 3
Characterization of XY-4/Bcl-xl siRNA co-loaded cationic liposomes. (A) Size distribution; (B) zeta potential; (C) siRNA retarding assay.
Figure 4
Figure 4
In vitro drug release behaviors of XY-4/Bcl-xl siRNA co-loaded cationic liposomes (siBcl-xl-CLP).
Figure 5
Figure 5
Transfection efficiency of prepared cationic liposomes. (A) Transfection efficiency of cationic liposomes (CLP) and PEI25K (PEI), counted by flow cytometry; (B) picture of transfected B16 cells in normal light under microscope; (C) picture of transfected B16 cells in fluorescent light under microscope 100×, scale bar represents 100 µm (the same field of vision as B).
Figure 6
Figure 6
Enhanced cell uptake by B16 melanoma cells; hydrophobic coumarin-6 was used as the fluorescence (fluor) probe. The fluorescence was observed under microscope (100×).
Figure 7
Figure 7
Inhibition of cell cycle progression by XY-4 on B16 cells. (A) cell cycle distribution of XY-4 treated cells and control group by flow cytometry; (B) statistical analysis of cycle distribution in G1, S and G2/M phase based on flow cytometry results. Cell cycle of XY-4 treated cell was obviously distributed from G1 and S phase into G2/M phase, (**p<0.05).
Figure 8
Figure 8
(A) Anti-cancer abilities of free XY-4 on B16 cells; (B) mRNA level of Bcl-xl was obviously reduced by both two concentration of cationic liposome delivered Bcl-xl siRNA (**p<0.05).
Figure 9
Figure 9
Anti-cancer effect of free Bcl-xl siRNA (siBcl-xl-CLP) and XY-4 combination. The results of the 400:1 and 800:1 combination groups (mol/mol) demonstrated obvious anti-cancer effects.
Figure 10
Figure 10
Anti-cancer abilities of different formulations containing XY-4 or/and Bcl-xl siRNA against B16 cells after treatment for 72 h (CLP= cationic liposome).
Figure 11
Figure 11
XY-4/Bcl-xl siRNA co-loaded cationic liposomes (XY-4/siBcl-xl-CLP) induced apoptosis in B16 melanoma cells. (A) Cell apoptosis detected by flow cytometry; (B) cell apoptosis rates of cells from each group. XY-4/siBcl-xl-CLP group demonstrated strong apoptosis compare into Control group (**p<0.05).
Figure 12
Figure 12
XY-4/Bcl-xl siRNA co-loaded cationic liposomes (XY-4/siBcl-xl-CLP) demonstrated stronger effect on activating the mitochondrial based apoptosis signaling pathway than the single drug formulation.
Figure 13
Figure 13
Anticancer effects and safety of XY-4/Bcl-xl siRNA co-loaded cationic liposomes on B16 mouse melanoma xenograft model. (A) Tumor development curve, calculated by tumor volume (CLP= cation liposome); (B) average weight of tumors in each group. Compared with other treatment groups, the co-delivery formulation group achieved a statistically significant reduction in tumor weight (***P<0.001); (C) Bcl-xl mRNA levels in tumors from each group. The co-delivery formulation group achieved a statistically significant reduction in mRNA levels (*P<0.1); (D) histological analysis of mouse tissues; (E) TdT-mediated dUTP nick-end labeling (TUNEL) staining of B16 mouse melanoma xenograft.
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