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CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
Jiyang Xue1, Ruixiang Li2, Dingding Gao2
1Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People's Republic of China.
Introduction:
Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes.
Methods:
AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied.
Results:
AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial-mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway.
Conclusion:
The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.
Insights
This study developed dual-functional nanoparticles (AMD-NP-PTX) that target ovarian cancer cells by binding to CXCR4. These nanoparticles enhance chemotherapy effectiveness and reduce side effects, offering a promising new treatment strategy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Ovarian cancer chemotherapy faces challenges with drug resistance and systemic toxicity.
- Existing targeted delivery systems often show limited therapeutic success despite improved targeting.
- Chemokine receptor 4 (CXCR4) is highly expressed on ovarian cancer cells, presenting a therapeutic target.
Purpose of the Study:
- To design and synthesize a dual-functional nanoparticle system for ovarian cancer therapy.
- To utilize AMD3100 as a targeting ligand for CXCR4-expressing ovarian cancer cells.
- To enhance the efficacy and safety of paclitaxel (PTX) chemotherapy through targeted delivery and pathway inhibition.
Main Methods:
- Synthesis and characterization of paclitaxel-loaded PEGylation bovine serum albumin nanoparticles modified with AMD3100 (AMD-NP-PTX).
- In vitro and in vivo evaluation of nanoparticle targeting efficiency and cellular uptake.
- Assessment of the anticancer effects of AMD-NP-PTX on ovarian cancer cells and tumor-bearing mice, including mechanism studies.
Main Results:
- AMD-NP-PTX nanoparticles were successfully synthesized and characterized.
- AMD3100 modification significantly enhanced nanoparticle uptake by ovarian cancer cells in vitro and in vivo.
- AMD-NP-PTX demonstrated superior inhibition of tumor growth and metastasis with an improved safety profile compared to control groups.
Conclusions:
- The developed AMD-NP-PTX system shows significant potential for targeted ovarian cancer therapy.
- This dual-functional nanoparticle approach offers a novel strategy to overcome chemotherapy resistance and reduce side effects.
- Targeting the CXCL12/CXCR4 axis with AMD-NP-PTX effectively inhibits tumor progression and associated signaling pathways.
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