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Chemotherapeutic potency stimulated by SNAI1-knockdown based on multifaceted nanomedicine
Hongyan Cui1, Yue Wang2, Lili Chen3
1State Key Laboratory of Fine Chemicals, Dalian University of Technology, No. 2 Linggong Road, Dalian 116024, China; School of Bioengineering, Dalian University of Technology, No. 2 Linggong Road, Dalian 116024, China.
Abstract:
Molecular insights into tumorigenesis have uncovered intimate correlation of SNAI1 with tumor malignancy. Herein, to explore merits of SNAI1-knockdown in tumor therapy, we harnessed RNA interference tool (shSNAI1), together with chemotherapeutic doxorubicin. Owing to abundant hydroxyl groups, pullulan was attempted to be covalently conjugated with a multiple of functional moieties, including positively-charged oligoethylenimine components for electrostatic entrapment of polyanionic shSNAI1 and hydrophobic components for entrapment of lipophilic doxorubicin. Notably, the aforementioned covalent conjugations were tailored to be detachable in response to intracellular reducing microenvironment owing to redox disulfide linkage, thereby accounting for selective intracellular liberation of the therapeutic payloads. Moreover, the surface of nanomedicine was modified with hyaluronic acid, endowing not only excellent biocompatibilities but active tumor-targeting function due to its receptors (CD44) overexpressed on tumor cells. Subsequent investigations approved appreciably targeted co-delivery of shSNAI1 and doxorubicin into solid lung tumors via systemic administration and demonstrated critical contribution of SNAI1-knockdown in amplifying chemotherapeutic potencies.
Insights
This study developed a novel nanomedicine for lung cancer therapy. It effectively co-delivers shSNAI1 and doxorubicin to tumors, enhancing chemotherapy efficacy by targeting SNAI1.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- SNAI1 is closely linked to tumor malignancy.
- RNA interference (RNAi) offers therapeutic potential.
- Chemotherapy resistance remains a challenge in cancer treatment.
Purpose of the Study:
- To investigate the therapeutic benefits of SNAI1-knockdown in combination with doxorubicin for lung cancer.
- To develop a targeted nanodelivery system for co-delivering shSNAI1 and doxorubicin.
Main Methods:
- Covalent conjugation of pullulan with oligoethylenimine and hydrophobic components to encapsulate shSNAI1 and doxorubicin.
- Incorporation of redox-sensitive disulfide linkages for controlled intracellular drug release.
- Surface modification with hyaluronic acid for active tumor targeting via CD44 receptors.
- Systemic administration and evaluation of targeted co-delivery in solid lung tumors.
Main Results:
- Successful development of a stimuli-responsive nanomedicine capable of co-delivering shSNAI1 and doxorubicin.
- Demonstrated targeted delivery of the nanomedicine to lung tumors.
- SNAI1-knockdown significantly potentiated the chemotherapeutic effects of doxorubicin.
Conclusions:
- The developed nanomedicine enables targeted co-delivery of shSNAI1 and doxorubicin, enhancing lung cancer therapy.
- SNAI1-knockdown is a promising strategy to overcome chemotherapy resistance.
- This approach holds potential for improving solid tumor treatment outcomes.
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