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Cyclic RGD-Functionalized pH/ROS Dual-Responsive Nanoparticle for Targeted Breast Cancer Therapy

Yao, Pu, Wang, Xiaowen, Wang, Qianmei, Dai, Qing, Peng, Yu, Yuan, Qian, Mou, Nan, Lv, Shan, Weng, Bangbi, Wang, Yu, Sun, Fengjun·2023·Pharmaceutics
DOI 10.3390/pharmaceutics15071827PMC PMC10386338
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Abstract

Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. Herein, we report a docetaxel (DTX)-loaded pH/ROS-responsive NP that could achieve active targeting of cancer cells and selective and complete drug release for effective drug delivery. The pH/ROS-responsive NPs were fabricated using nanocarriers that consist of an ROS-responsive moiety (4-hydroxymethylphenylboronic acid pinacol ester, HPAP), cinnamaldehyde (CA, an aldehyde organic compound with anticancer activities) and cyclodextrin (α-CD). The NPs were loaded with DTX, modified with a tumor-penetration peptide (circular RGD, cRGD) and named DTX/RGD NPs. The cRGD could promote DTX/RGD NPs penetration into deep tumor tissue and specifically target cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, the pH-responsive acetal was cleaved to release CA in the lysosomal acidic environment. Meanwhile, the high ROS in tumor cells induced the disassembly of NPs with complete release of DTX. In vitro cellular assays verified that DTX/RGD NPs could be effectively internalized by 4T1 cells, obviously inducing apoptosis, blocking the cell cycle of 4T1 cells and consequently, killing tumor cells. In vivo animal experiments demonstrated that the NPs could target to the tumor sites and significantly inhibit the tumor growth in 4T1 breast cancer mice. Both in vitro and in vivo investigations demonstrated that DTX/RGD NPs could significantly improve the antitumor effect compared to free DTX. Thus, the DTX/RGD NPs provide a promising strategy for enhancing drug delivery and cancer therapy.

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Crossref · 10.3390/pharmaceutics15071827

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Figure 1 Fabrication of DTX-loaded pH/ROS dual-responsive NPs for targeted breast cancer therapy.
Figure 1 Fabrication of DTX-loaded pH/ROS dual-responsive NPs for targeted breast cancer therapy.CC BY · PubMed Central
Figure 2 Characterization of DTX/RGD NPs. (A) The size distribution of NPs determined with DLS. (B) The morphology of NPs observed with TEM. Scale bar represents 0.5 μm. (C) The hemolytic activity of NPs at various concentrations. (D) The in vitro drug-release behavior of DTX from NPs in various release media within 48 h. Each value represents the mean ± SD (n = 3).
Figure 2 Characterization of DTX/RGD NPs. (A) The size distribution of NPs determined with DLS. (B) The morphology of NPs observed with TEM. Scale bar represents 0.5 μm. (C) The hemolytic activity of NPs at various concentrations. (D) The in vitro drug-release behavior of DTX from NPs in various release media within 48 h. Each value represents the mean ± SD (n = 3).CC BY · PubMed Central
Figure 3 Cellular uptake of Cy5-labeled NPs in 4T1 cells and fluorescence distribution of Cy5-labeled NPs in 4T1 tumor spheroids. (A) The CLSM images of cellular uptake of Cy5-labeled NPs in 4T1 cells after 4 h treatment. Cell nuclei were stained with DAPI (blue), FITC-phalloidin for cytoskeleton staining (green) and Cy5-labeled NPs (red). Scale bar represents 20 μm. (B) Fluorescence distribution of Cy5-labeled NPs (red) in 4T1 tumor spheroids after 4 h treatment. Cell nuclei were stained with DAPI (blue) and Cy5-labeled NPs (red). Scale bar represents 50 μm.
Figure 3 Cellular uptake of Cy5-labeled NPs in 4T1 cells and fluorescence distribution of Cy5-labeled NPs in 4T1 tumor spheroids. (A) The CLSM images of cellular uptake of Cy5-labeled NPs in 4T1 cells after 4 h treatment. Cell nuclei were stained with DAPI (blue), FITC-phalloidin for cytoskeleton staining (green) and Cy5-labeled NPs (red). Scale bar represents 20 μm. (B) Fluorescence distribution of Cy5-labeled NPs (red) in 4T1 tumor spheroids after 4 h treatment. Cell nuclei were stained with DAPI (blue) and Cy5-labeled NPs (red). Scale bar represents 50 μm.CC BY · PubMed Central
Figure 4 The in vitro antitumor activities of NPs against 4T1 cells. (A) Cell viabilities of 4T1 cells after treatment with blank NPs, DTX and DTX-loaded NPs at various drug concentration for 24 h. (B) Cell viabilities of 4T1 cells after treatment with blank NPs, DTX and DTX-loaded NPs at various drug concentrations for 48 h. (C) Quantitative analysis of cell-cycle profiles of 4T1 cells following treatment with blank NPs, DTX and DTX-loaded NPs for 48 h. (D) The apoptotic percentages of 4T1 cells following treatment with blank NPs, DTX and DTX-loaded NPs for 48 h. Each value represents the mean ± SD (n = 3). *, statistically different at p < 0.05; **, statistically different at p < 0.01; ***, statistically different at p < 0.001, compared with DTX/RGD NPs.
Figure 4 The in vitro antitumor activities of NPs against 4T1 cells. (A) Cell viabilities of 4T1 cells after treatment with blank NPs, DTX and DTX-loaded NPs at various drug concentration for 24 h. (B) Cell viabilities of 4T1 cells after treatment with blank NPs, DTX and DTX-loaded NPs at various drug concentrations for 48 h. (C) Quantitative analysis of cell-cycle profiles of 4T1 cells following treatment with blank NPs, DTX and DTX-loaded NPs for 48 h. (D) The apoptotic percentages of 4T1 cells following treatment with blank NPs, DTX and DTX-loaded NPs for 48 h. Each value represents the mean ± SD (n = 3). *, statistically different at p < 0.05; **, statistically different at p < 0.01; ***, statistically different at p < 0.001, compared with DTX/RGD NPs.CC BY · PubMed Central
Figure 5 In vivo biodistribution of free Cy5, Cy5-labeled NPs and Cy5-labeled RGD NPs in 4T1 tumor-bearing mice. (A) In vivo fluorescence images of mice 2 h, 8 h, 24 h and 48 h after administration. Normal mice were injected with saline. (B) Ex vivo fluorescence image of the excised major tissues and tumors at 48 h post-injection. (C) Semi-quantitative analysis of fluorescence intensity in tumor tissues at the indicated time points. (D) Semi-quantitative analysis of fluorescence intensity of tumors excised from mice. *, statistically different at p < 0.05; **, statistically different at p < 0.01; ***, statistically different at p < 0.001, compared with Cy5-labeled RGD NPs.
Figure 5 In vivo biodistribution of free Cy5, Cy5-labeled NPs and Cy5-labeled RGD NPs in 4T1 tumor-bearing mice. (A) In vivo fluorescence images of mice 2 h, 8 h, 24 h and 48 h after administration. Normal mice were injected with saline. (B) Ex vivo fluorescence image of the excised major tissues and tumors at 48 h post-injection. (C) Semi-quantitative analysis of fluorescence intensity in tumor tissues at the indicated time points. (D) Semi-quantitative analysis of fluorescence intensity of tumors excised from mice. *, statistically different at p < 0.05; **, statistically different at p < 0.01; ***, statistically different at p < 0.001, compared with Cy5-labeled RGD NPs.CC BY · PubMed Central
Figure 6 In vivo antitumor efficacy evaluation of blank NPs, DTX and various DTX-loaded NPs in 4T1 tumor-bearing mice. (A) The administration time after tumor inoculation. Mice received 5 mg/kg of DTX or 5 mg/kg of various DTX-loaded NPs via vein every four days for five times. (B) The body weight changes of mice following different treatment (n = 6). (C) Representative photographs of tumor tissues of mice following different treatment. (D) The tumor growth curves of mice following different treatment (n = 6). (E) Individual tumor volumes of mice following different treatments. The ratio refers to the proportion of mice with tumors that exceed 600 mm3 on day 20. (F) The tumor weight of mice following different treatments. (G) The DTX concentration in tumor tissues of mice following different treatments (n = 3). (H) The photo images of collected lungs in the mice following different treatments on day 20. *, statistically different at p < 0.05; **, statistically different at p < 0.01; ***, statistically different at p < 0.001, compared with DTX/RGD NPs.
Figure 6 In vivo antitumor efficacy evaluation of blank NPs, DTX and various DTX-loaded NPs in 4T1 tumor-bearing mice. (A) The administration time after tumor inoculation. Mice received 5 mg/kg of DTX or 5 mg/kg of various DTX-loaded NPs via vein every four days for five times. (B) The body weight changes of mice following different treatment (n = 6). (C) Representative photographs of tumor tissues of mice following different treatment. (D) The tumor growth curves of mice following different treatment (n = 6). (E) Individual tumor volumes of mice following different treatments. The ratio refers to the proportion of mice with tumors that exceed 600 mm3 on day 20. (F) The tumor weight of mice following different treatments. (G) The DTX concentration in tumor tissues of mice following different treatments (n = 3). (H) The photo images of collected lungs in the mice following different treatments on day 20. *, statistically different at p < 0.05; **, statistically different at p < 0.01; ***, statistically different at p < 0.001, compared with DTX/RGD NPs.CC BY · PubMed Central

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Metadata

Authors
Yao, P., Wang, X., Wang, Q., Dai, Q., Peng, Y., Yuan, Q., Mou, N., Lv, S., Weng, B., Wang, Y., & Sun, F.
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2023-06-26
Volume
15
Issue
7
Pages
1827
ISSN
1999-4923
DOI
10.3390/pharmaceutics15071827
PMC
PMC10386338
Cited by
22
References
1
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Natural Science Foundation of China (82102448, cstc2015zdcy-ztzx120005)
  • Special Project of Common Key Technology Innovation for Key Industries in Chongqing (82102448, cstc2015zdcy-ztzx120005)

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