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, 10 (3), 146

Applying an Innovative Biodegradable Self-Assembly Nanomicelles to Deliver α-Mangostin for Improving Anti-Melanoma Activity

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Applying an Innovative Biodegradable Self-Assembly Nanomicelles to Deliver α-Mangostin for Improving Anti-Melanoma Activity

Shuping Yang et al. Cell Death Dis.

Abstract

α-Mangostin (αM), a traditional natural product with promising application of treating a series of diseases, was limited use in clinical due to its hydrophobicity. Herein, MPEG-PCL nanomicelles were used to embed the αM for resolving hydrophobicity and improving the anti-melanoma effect of the αM. The anti-melanoma activity and potential mechanisms of biodegradable αM/MPEG-PCL nanomicelles were investigated. The αM/MPEG-PCL nanomicelles possessed a stronger effect on anti-melanoma compared to the free αM both in vitro and in vivo with a low cytotoxicity in non-tumor cell lines. In the research of mechanisms, the αM/MPEG-PCL nanomicelles inhibited the proliferation of melanoma cell, induced apoptosis via both apoptosis pathways of intrinsic and exogenous in vitro, as well as suppressed tumor growth and restrained angiogenesis in vivo, which implied that the αM/MPEG-PCL nanomicelles have potential application as a novel chemotherapeutic agent in melanoma therapy.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. The chemical information of the αM and preparation of the αM/MPEG-PCL micelles.
a The chemical structure of the αM. b 1HNMR of the αM. c Preparation scheme of the αM/MPEG-PCL nanomicelles. The free αM and the MPEG-PCL self-assembled into the αM/MPEG-PCL nanomicelles
Fig. 2
Fig. 2. Interaction modes between polymer and compound revealed by Langevin dynamics simulation in an aqueous environment.
a The initial conformation of the polymer MPEG-PCL complexed with the αM; Conformations b, c, d, e, and f are corresponding to snapshots of the complex collected at 9.985 ps, 15.995 ps, 20.020 ps, 29.945 ps, and 100 ps, respectively. The polymer MPEG-PCL is represented with thick stick, whereas the αM is depicted with ball and stick style and its carbon atoms are colored with green. Two terminal heavy atoms in the polymer MPEG-PCL is highlighted using a “ball” style, and the head heavy atom in the αM are highlighted using CPK style
Fig. 3
Fig. 3. Interaction modes between polymer and compound revealed by Langevin dynamics simulation in water and tumor environment.
The demonstration style is the same as in Fig. 2. a The conformation of the polymer MPEG-PCL complexed with the αM after being simulated in water environment for 200 ps; b The conformation of the polymer MPEG-PCL complexed with the αM after being simulated in water environment for 100 ps and then in tumor environment for 100 ps; c and d are corresponding to a and b, but the binding site is highlighted with solid surface and colored light yellow
Fig. 4
Fig. 4. Characterization of the αM/MPEG-PCL nanomicelles.
a Particle size distribution extent of the αM/MPEG-PCL nanomicelles. b Zeta potential spectrum of the αM/MPEG-PCL nanomicelles. c The image of transmission electron micrograph (TEM) of the αM/MPEG-PCL nanomicelles. d In vitro release assay of the free αM and the αM/MPEG-PCL nanomicelles in PBS containing Tween 80 (0.5%, w/w) at 37 °C. e In vivo pharmacokinetics study of the free αM and the αM/MPEG-PCL nanomicelles
Fig. 5
Fig. 5. Effects of the free αM and the αM/MPEG-PCL nanomicelles on the cell proliferation.
Cell viability was measured with MTT assay. a Cell viability of melanoma cells treated with various concentrations of the free αM and the αM/MPEG-PCL nanomicelles for 24 h, 48 h, and 72 h. Values represent mean ± SD (n = 3, in triplicate, *P < 0.05; **P < 0.01; ***P < 0.001 compared to control). b The effects of the free αM and the αM/MPEG-PCL nanomicelles on colony formation in melanoma cells and the statistic assay of colony formation experiments. Data are expressed as mean ± SD (from three independent experiments), *P < 0.05; **P < 0.01; ***P < 0.001 compared to vehicle (0 μM group). c Non-tumor cell lines (LO2, Vero, and HEK293T) were incubated with a series of concentrations of the αM/MPEG-PCL nanomicelles for 48 h. Values represent mean ± SD (n = 3, in triplicate, *P < 0.05; **P < 0.01; ***P < 0.001 compared to control)
Fig. 6
Fig. 6. Apoptosis-induced effect and cellular uptake in A375 cells by the free αM and the αM/MPEG-PCL nanomicelles, as well as the mechanisms of the αM/MPEG-PCL nanomicelles anti-melanoma in vitro.
a PI and Annexin V dual-labeling technique analyzed the apoptotic effect in A375 cells, the αM/MPEG-PCL nanomicelles showed higher cell apoptosis rates than the free αM. b A375 cells uptake drug assay. The αM/MPEG-PCL nanomicelles group’s cells uptake almost twice as much as the free αM group. c The variation in the mitochondrial membrane potential (Ψm) in melanoma cells by the αM/MPEG-PCL. d Upregulation of Bax (pro-apoptosis protein) and downregulation of Bcl-2 (anti-apoptosis protein) in A375 cells treated the αM/MPEG-PCL. e The variation of caspase-3 and caspase-9 protein level were determined via western Blot in A375 cells. The results showed that the αM/MPEG-PCL could induce A375 cells apoptosis by activating caspase-3 and caspase-9. f The caspase-8 protein level associated with the exogenous apoptosis pathways were altered by the αM/MPEG-PCL micelles in A375 cells. β-actin was used as an internal standard in d, e, and f
Fig. 7
Fig. 7. Anti-tumor effect of the αM/MPEG-PCL nanomicelles in vivo.
a Nude mice were inoculated with A375 cells. After 7 days, the mice were randomly assigned to four groups treated, respectively, with the normal saline (NS), the empty MPEG-PCL nanomicelles (MPEG-PCL), the free αM or the αM/MPEG-PCL. Tumor development curve were measured on the indicated days. b The body weight in each treatment group on the indicated days. c The numerical statement of tumor weight in different groups on day 21. d Representative pictures of subcutaneous tumors in each treatment group on day 21. *P < 0.05; **P < 0.01; ***P < 0.001 compared to vehicle (NS group)
Fig. 8
Fig. 8. Immunohistochemistry staining of tumor sections for the research of mechanisms of anti-melanoma in vivo.
a CD31 immunofluorescence staining assay. Tumor tissues sections from four groups treated with the normal saline (NS), the empty MEPG-PCL nanomicelles (MPEG-PCL), the free αM (αM), and the αM/MPEG-PCL nanomicelles (αM/MPEG-PCL) were subjected to immunohistochemistry to analyze anti-angiogenesis effect. b PCNA immunohistochemical staining analysis. Tumor sections from four groups (NS, MPEG-PCL, αM, αM/MPEG-PCL) were analyzed to PCNA immunohistochemical to detect tumor cell proliferation. c TUNEL assay. The apoptosis of A375 tumor sections was measured via TUNEL staining. The group treated with the αM/MPEG-PCL nanomicelles showed the most apoptotic cells, which demonstrated that the MPEG-PCL nanomicelles could improve the anti-tumor activity of the αM

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