Glutamine modified lipid nanoparticles loaded with GPX4 siRNA for cervical cancer targeting
Yuxin Chen1, Lanjie Zhong2, Jianqiang Chen3
1Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, PR China; College of Pharmacy, Chongqing Medical University, Yixueyuan Road, Yuzhong District, Chongqing, 400016, PR China.
Abstract:
Despite significant efforts to develop nanocarriers for siRNA delivery, clinical application in cancer therapy has been hindered by inadequate tumor-targeting specificity, with cervical cancer particularly affected by poor tumor-specific targeting. Our previous work identified aberrant glutamine metabolism and ASCT2 overexpression in cervical cancer, providing a rationale for designing glutamine-ASCT2 interaction-based delivery systems. Based on this, we developed a self-fabricated microfluidic device for the preparation of lipid nanoparticles (LNP) and constructed a glutamine-modified lipid nanoparticle (GLN-LNP) for targeted siRNA delivery to cervical cancer. GLN-LNP exhibited significantly enhanced cellular uptake in both 2D cell monolayers and 3D tumor spheroid models. The competitive inhibition of uptake by free glutamine and the significant inhibition by an ASCT2-specific inhibitor V-9302 further confirm the critical role of the glutamine-ASCT2 interaction in facilitating LNP transport. GLN-LNP significantly decreased GPX4 expression in vitro at both transcriptional and translational level. In vivo results illustrated GLN-LNP had enhanced tumor accumulation capability compared to PEG-LNP, which has no glutamine modification. Additionally, GLN-LPN induced obvious in vivo GPX4 knockdown. These findings demonstrate GLN-LNP as a promising preclinical delivery system for cervical cancer, highlighting their potential to advance the clinical development of siRNA-based therapeutic.
Insights
Researchers developed glutamine-modified lipid nanoparticles (GLN-LNP) for targeted siRNA delivery in cervical cancer. GLN-LNPs show enhanced tumor uptake and GPX4 knockdown, offering a promising preclinical therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Clinical siRNA cancer therapy is limited by poor tumor targeting, especially in cervical cancer.
- Cervical cancer exhibits aberrant glutamine metabolism and ASCT2 overexpression, suggesting a therapeutic target.
- Targeted delivery systems are crucial for overcoming current limitations in siRNA-based cancer treatments.
Purpose of the Study:
- To develop a novel glutamine-modified lipid nanoparticle (GLN-LNP) for targeted siRNA delivery to cervical cancer.
- To investigate the uptake mechanism and efficacy of GLN-LNP in vitro and in vivo.
- To evaluate the potential of GLN-LNP as a preclinical therapeutic delivery system for cervical cancer.
Main Methods:
- Fabrication of GLN-LNP using a self-fabricated microfluidic device.
- Assessment of cellular uptake in 2D monolayers and 3D spheroids, including competitive inhibition studies with glutamine and ASCT2 inhibitor V-9302.
- In vitro and in vivo evaluation of GPX4 expression knockdown.
- Comparison of tumor accumulation of GLN-LNP and PEG-LNP in vivo.
Main Results:
- GLN-LNP demonstrated significantly enhanced cellular uptake in cervical cancer models.
- Uptake mechanism confirmed to be dependent on the glutamine-ASCT2 interaction.
- GLN-LNP effectively reduced GPX4 expression both in vitro and in vivo.
- GLN-LNP exhibited superior tumor accumulation compared to non-modified PEG-LNP in vivo.
Conclusions:
- GLN-LNP represents a novel and effective targeted delivery system for siRNA in cervical cancer.
- The glutamine-ASCT2 interaction is a viable strategy for enhancing nanoparticle delivery to cervical tumors.
- GLN-LNP shows significant preclinical promise for advancing siRNA-based cervical cancer therapeutics.
