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. 2022 Sep;10(18):971.
doi: 10.21037/atm-22-3646.

Biomimetic cytomembrane-coated ZIF-8-loaded DMDD nanoparticle and sonodynamic co-therapy for cancer

Shuqi Zhao #  1 , Meifeng Chen #  1 , Zhu Yu  2 , Thi Thai Hoa Pham  3 , Shutian Mo  1 , Yongfei He  1 , Tianyi Liang  1 , Wenlong Cao  2 , Chuangye Han  1   4
Affiliations

Biomimetic cytomembrane-coated ZIF-8-loaded DMDD nanoparticle and sonodynamic co-therapy for cancer

Shuqi Zhao et al. Ann Transl Med. 2022 Sep.

Abstract

Background: Breast cancer (BC) is the most common type of cancer affecting females. It is also a leading cause of cancer-related death in women worldwide.

Methods: Sonodynamic therapy (SDT) is an emerging therapeutic strategy for cancer treatment. SDT ensures non-invasive penetration of deep tumors and results in activation of non-toxic sonosensitizers administered in deep tumor sites to become cytotoxic. It has been reported that 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) has a significant anti-tumor effect against various cancer types including BC. However, DMDD is hydrophobic. Therefore, a one-step encapsulation method was used in the current study to construct zeolitic imidazole frameworks-8 (ZIF-8) loaded with DMDD and sonosensitizer chlorin e6 (Ce6). ZIF-8 was further modified by coating it with a biomimetic cell membrane to improve targeted delivery.

Results: In vitro and in vivo results indicated that the nanomedicines had great biocompatibility properties and targeting ability. The nanocomposite exhibited a higher release rate under an acidic tumor microenvironment. The tumor killing effect of reactive oxygen species (ROS) generated from Ce6 and inhibition of tumor growth was enhanced after ultrasound (US) treatment, which might be caused by the increase in apoptosis rate.

Conclusions: These findings show that the combination of nanomedicine and SDT provides a potential therapeutic method for BC.

Keywords: 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD); Breast cancer (BC); ZIF-8 nanoparticles; metal-organic framework; sonodynamic therapy.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3646/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Schematic illustration of the synthesis process of the ZDC@M nanoparticles and pH-sensitive ultrasound triggered SDT combined with DMDD therapy. ZDC@M, ZIF-8@ DMDD/Ce6@ cytomembrane; ZIF-8, zeolitic imidazole frameworks-8; SDT, sonodynamic therapy; DMDD, 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.
Figure 2
Figure 2
The morphology and structure of nanomedicines. TEM images of ZIF-8 (A), ZDC (B), and ZDC@M (C). Hydrated nanoparticle size distribution of ZIF-8 (D), ZDC (E), and ZDC@M (F). Zeta potential of different nanoparticles (G). Ultraviolet-visible absorption spectra of Ce6, DMDD, and ZDC (H). Reactive oxygen species (ROS) production by ZDC under different conditions (I). Hemolysis rate at different concentrations of the nanoparticles (J). Ce6 (K) and DMDD (L) release curves of ZDC@M triggered by different pHs. TEM, transmission electron microscopy; ZIF-8, zeolitic imidazole frameworks-8; ZDC@M, ZIF-8@ DMDD/Ce6@ cytomembrane; SDT, sonodynamic therapy; DMDD, 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; ns, no significant; PBS, phosphate buffer solution.
Figure 3
Figure 3
In vitro cellular uptake and ROS generation. Fluorescence imaging (600×) (A) and flow cytometry (quantitative detection of intracellular Ce6 fluorescence) (B) of 4T1 cells incubated with different nanoparticles at pH 7.4 and 5.5, respectively. ROS production was detected by fluorescence of DCFH-DA in 4T1 cells (E) (100×). Quantification of intracellular fluorescence intensity in A (C). Level of 4T1 cells with intracellular fluorescence of B (D). Quantification of intracellular fluorescence intensity in E (F). species. (A) DAPI staining. (E) Fluorescent probe DCFH-DA. **P<0.0001. ZIF-8, zeolitic imidazole frameworks-8; ZDC@M, ZIF-8@ DMDD/Ce6@ cytomembrane; ROS, reactive oxygen species.
Figure 4
Figure 4
In vitro therapeutic effects of nanoparticles. Cell viabilities of 4T1 cells incubated with ZDC at different loading concentrations of DMDD (A). Cell viabilities of 4T1 cells treated with different nanomedicines (B) and (C). Quantification of intracellular fluorescence intensity (D) of Calcein-AM and PI staining fluorescence images (F). The bar chart indicates the population of apoptotic cells (E) in the flow cytometry analysis (G). **P<0.0001. ZDC, ZIF-8@ DMDD/Ce6; DMDD, 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.
Figure 5
Figure 5
In vivo biocompatibility of nanoparticles. Changes in WBC, RBC, Hb, PLT, ALT, AST, ALP, and BUN suggesting ZDC@M had no blood toxicity effects and had no hepatotoxicity and nephrotoxicity effects in vivo (A). H&E staining of nude mouse organs on day 10 and day 30 after 3 injections of ZDC@M (B) (100×) showed no obvious damage and pathological changes in the heart, liver, spleen, lungs, and kidneys of the 2 experimental groups compared with the CON group. WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin; PLT, platelet; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; BUN, blood urea nitrogen; ZDC@M, ZIF-8@ DMDD/Ce6@ cytomembrane; ns, no significant.
Figure 6
Figure 6
In vivo therapeutic effect of nanoparticles. Tumor size (A), body weight change (B), tumor volume change (C), and tumor inhibition rate (D) of 4T1 tumor-bearing nude mice under different treatments. H&E staining of tumor after different treatments (100×) (E). n=5. **P<0.0001.
Figure 7
Figure 7
The ZDC@M+ ultrasound (US) induces morphological and molecular markers of apoptosis. Cleaved caspase-3, Bax, and Bcl-2 protein level (A). The bar chart indicates the relative density of cleaved caspase-3, Bax, and Bcl-2 to β-actin in A (B). The ratio of Bax/Bcl-2 (C). Immunohistochemistry staining of tumor tissues after different treatments (D). *P<0.05, **P<0.0001. ZDC@M, ZIF-8@ DMDD/Ce6@ cytomembrane.
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