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Published on: May 2, 2019
STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy
Le Sun1, Jishang Sun1, Cuiyao Li1
1College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China.
Abstract:
Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.
Insights
This study developed dual-loaded nanoparticles to combat chemotherapy resistance in non-small cell lung cancer (NSCLC). The nanoparticles target STAT3, reversing drug resistance and enhancing treatment efficacy for personalized NSCLC therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Non-small cell lung cancer (NSCLC) presents significant challenges due to high incidence, low survival rates, and acquired chemotherapy resistance.
- Abnormal activation of Signal Transducer and Activator of Transcription 3 (STAT3) is a key mechanism contributing to secondary drug resistance in NSCLC chemotherapy.
Purpose of the Study:
- To develop a novel dual-delivery system for precision targeted therapy in NSCLC.
- To investigate the synergistic effect of doxorubicin (DOX) and STAT3-targeting shRNA delivered via multifunctional nanoparticles.
- To overcome chemotherapy resistance and improve treatment outcomes in NSCLC.
Main Methods:
- Construction of a STAT3-targeting recombinant plasmid (pGPU6/GFP/Neo STAT3-shRNA).
- Synthesis of multifunctional micelles (VES-CTS-mPEG-His) by modifying chitosan blocks.
- Formation of dual-loaded nanoparticles (DOX/VCPH/pDNA) encapsulating DOX and pDNA for co-delivery.
Main Results:
- The DOX/VCPH/pDNA nanoparticles demonstrated co-delivery and synergistic effects, up-regulating PTEN and down-regulating CD31 expression.
- These nanoparticles induced apoptosis in tumor cells and significantly reduced STAT3 protein expression.
- The treatment effectively reversed chemotherapy drug resistance in NSCLC models.
Conclusions:
- The developed DOX/VCPH/pDNA nanoparticles offer a promising strategy for precision personalized treatment of NSCLC.
- This approach effectively reverses chemotherapy resistance in NSCLC, providing new therapeutic avenues.
- The study highlights the potential of dual-drug delivery systems in overcoming drug resistance in challenging cancers.
