Intravenous delivery of STING agonists using acid-sensitive polycationic polymer-modified lipid nanoparticles for enhanced tumor immunotherapy.
10.1016/j.apsb.2024.06.004
- Author:
Ying HE
1
;
Ke ZHENG
2
;
Xifeng QIN
1
;
Siyu WANG
1
;
Xuejing LI
1
;
Huiwen LIU
3
;
Mingyang LIU
1
;
Ruizhe XU
1
;
Shaojun PENG
4
;
Zhiqing PANG
1
Author Information
1. School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China.
2. School of Materials Science and Engineering, Dongguan University of Technology, Dongguan 523808, China.
3. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China.
4. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, China.
- Publication Type:Journal Article
- Keywords:
ADU-S100;
CT26 colon cells;
Cancer nanotechnology;
Cyclic dinucleotides;
Intravenous delivery;
Lipid nanoparticles (LNP);
Polycationic polymer;
The stimulator of interferon genes (STING) pathway
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1211-1229
- CountryChina
- Language:English
-
Abstract:
Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.
