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Folic Acid-Modified Ginger-Derived Exosome-Like Nanoparticles Co-Delivering Sunitinib Suppress Renal Cell Carcinoma
Haoyu Xu1,2, Daixing Hu3, Shixue Liu1,4
1Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Abstract:
Renal cell carcinoma (RCC) is a malignant tumor with highly recurrent and metastatic capability. The current therapies for RCC are limited by drug resistance and toxic side effects. This study introduces an innovative approach that combines ginger-derived exosome-like nanoparticles (GELNs) with sunitinib (Su) and folic acid-polyethylene glycol (FA-PEG, FPD) in an active-passive targeting strategy to explore its multi-mechanism and synergistic therapeutic effects on RCC. GELNs are extracted via differential centrifugation combined with sucrose gradient ultracentrifugation. Metabolomics and network pharmacology predicted that GELNs may exert their anticancer efficacy via the PI3K-Akt signaling pathway, which is subsequently validated through in vitro experiments. By loading Su and modifying it with FPD, FPD-GELNs/Su is constructed. The FPD modification significantly enhanced tumor targeting and amplified the Su sensitivity by reducing ABCB1/P-gp expression induced by GELNs. In vivo experiments revealed that FPD-GELNs/Su promoted M1 macrophage polarization and increased immune T-cell infiltration by remodeling the tumor microenvironment, leading to significant inhibition of tumor growth and lung metastasis without causing notable liver or kidney toxicity. This study integrates network pharmacology with targeted delivery strategies, elucidating the mechanisms by which FPD-GELNs/Su inhibits RCC progression through multiple pathways, providing new insights for the development of precise and low-toxicity nano-therapies.
Insights
Ginger-derived nanoparticles combined with sunitinib offer a novel, low-toxicity therapy for renal cell carcinoma (RCC). This targeted approach enhances drug efficacy and reduces side effects by remodeling the tumor microenvironment.
Area of Science:
- Oncology
- Nanomedicine
- Pharmacology
Background:
- Renal cell carcinoma (RCC) presents significant therapeutic challenges due to drug resistance and severe side effects of current treatments.
- Developing novel, targeted therapies with reduced toxicity is crucial for improving RCC patient outcomes.
Purpose of the Study:
- To investigate the synergistic therapeutic effects of ginger-derived exosome-like nanoparticles (GELNs) combined with sunitinib (Su) and FA-PEG (FPD) for RCC treatment.
- To elucidate the multi-mechanism action and targeted delivery strategy of the FPD-GELNs/Su nanoplatform.
Main Methods:
- GELNs were extracted and characterized; metabolomics and network pharmacology predicted anticancer mechanisms via the PI3K-Akt pathway.
- A targeted nanoplatform, FPD-GELNs/Su, was constructed by loading sunitinib onto FPD-modified GELNs.
- In vitro and in vivo studies evaluated the efficacy, targeting ability, drug sensitivity enhancement, and immunomodulatory effects of FPD-GELNs/Su on RCC.
Main Results:
- GELNs demonstrated anticancer efficacy potentially through the PI3K-Akt pathway.
- FPD modification enhanced tumor targeting and sunitinib sensitivity by reducing ABCB1/P-gp expression.
- FPD-GELNs/Su significantly inhibited RCC tumor growth and lung metastasis by promoting M1 macrophage polarization and T-cell infiltration, with minimal liver/kidney toxicity.
Conclusions:
- The FPD-GELNs/Su nanoplatform exhibits potent anti-RCC activity through multi-mechanism pathways, including immunomodulation and targeted drug delivery.
- This study provides a promising strategy for developing precise, low-toxicity nano-therapies for renal cell carcinoma.
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