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CXCR4-Targeted and Redox Responsive Dextrin Nanogel for Metastatic Breast Cancer Therapy
Feiran Zhang1, Siman Gong1, Jun Wu2
1State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
Abstract:
The unsatisfied results of cancer therapy are caused by many issues and metastasis of cancer cells is one of the major challenge. It has been reported that inhibiting the SDF1/CXCR4 interaction can significantly reduce the metastasis of breast cancer cells to regional lymph nodes and lung. Herein, a nanogel system equipped with the FDA-approved CXCR4 antagonist AMD3100 was developed and evaluated for its combined antimetastatic and tumor targeting effects. Briefly, a bioreducible cross-linked dextrin nanogel (DNG) coated with AMD3100 was designed to possess multiple functions, including CXCR4 chemokine targeting, inhibition of tumor metastasis, and reduction-responsive intracellular release of doxorubicin (DOX) to reduce the cells proliferation. The in vitro results confirmed that the DOX-loaded AMD3100-coated dextrin nanogel (DOX-AMD-DNG) was more effectively taken up by 4T1 breast cancer cells than DOX-DNG and was significantly more cytotoxic to 4T1 cells than DOX-DNG. In biodistribution studies, the stronger fluorescence intensity of Cy7-AMD-DNG than Cy7-DNG further confirmed that AMD3100 mediated tumor targeting in vivo. AMD3100-coated DOX-DNG also exhibited a distinct antimetastatic effect and CXCR4 antagonistic activity by inhibiting CXCR4-mediated cell invasion in 4T1 and U2OS cells. Moreover, DOX-AMD-DNG displayed superior anticancer activity and antimetastatic effects in orthotopic breast cancer-bearing Balb/C mice. In summary, the multifunctional DOX-AMD-DNG can effectively target the tumor site and dually impede cancer progression and metastasis.
Insights
A novel nanogel system, loaded with doxorubicin and coated with AMD3100, effectively targets breast cancer cells. This system inhibits cancer metastasis and proliferation by blocking the SDF1/CXCR4 interaction, showing superior anticancer and antimetastatic effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Cancer metastasis remains a major challenge in therapy, with the SDF1/CXCR4 pathway significantly contributing to breast cancer spread.
- Targeting the SDF1/CXCR4 interaction offers a promising strategy to inhibit cancer metastasis.
Purpose of the Study:
- To develop and evaluate a multifunctional nanogel system for combined antimetastatic and tumor-targeting effects in breast cancer.
- To investigate the efficacy of a nanogel system incorporating the CXCR4 antagonist AMD3100 and doxorubicin.
Main Methods:
- A bioreducible cross-linked dextrin nanogel (DNG) was engineered and coated with AMD3100.
- Doxorubicin (DOX) was loaded into the nanogel, creating DOX-AMD-DNG, and its in vitro and in vivo performance was assessed.
- Studies included cellular uptake, cytotoxicity assays, biodistribution, and evaluation in orthotopic breast cancer mouse models.
Main Results:
- DOX-AMD-DNG demonstrated enhanced uptake and cytotoxicity in 4T1 breast cancer cells compared to DOX-DNG.
- In vivo studies confirmed AMD3100-mediated tumor targeting and significant antimetastatic effects.
- The nanogel system effectively inhibited CXCR4-mediated cell invasion and showed superior anticancer activity in mice.
Conclusions:
- The multifunctional DOX-AMD-DNG system effectively targets tumor sites, impeding both cancer progression and metastasis.
- This nanogel platform holds potential for enhanced breast cancer therapy by combining targeted drug delivery with antimetastatic strategies.
