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Published on: January 15, 2015
Calcium Phosphate Nanoparticle Delivery of siTRIB3 Inhibits EMT and Stemness in NSCLC
Yinqiu Wu1,2, Jixin Song1,2, Sheng He3
1School of Basic Medical Sciences & School of Public Health, Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, People's Republic of China.
Background:
TRIB3 is upregulated in non-small cell lung cancer (NSCLC) and associates with worse survival, yet targeted therapeutics remain lacking. Calcium phosphate (CaP) nanoparticles offer biocompatible, serum-stable delivery for siRNA therapy. Here, we developed CaP nanoparticles loading siRNA targeting TRIB3 (NPCaP/siTrib3) and evaluated antitumor efficacy and mechanisms in vitro and in vivo.
Methods:
NPCaP/siTrib3 was synthesized via biomineralization, and RNase resistance was verified by PAGE. Mouse KP-1 NSCLC cells were used for transfection, apoptosis (Annexin V/7-AAD), migration (scratch), invasion (Matrigel Transwell), qRT-PCR, and Western blot of epithelial-mesenchymal transition (EMT) and stemness markers. C57BL/6 subcutaneous tumor models received tail-vein injections for efficacy and biosafety assessment.
Results:
TRIB3 was significantly upregulated in NSCLC tissues compared with normal lung tissues and was associated with poorer overall survival. NPCaP/siTrib3 formed nanosheets with an average size of approximately 159.4 nm and exhibited a more negative zeta potential than bare CaP, indicating successful siRNA loading. The CaP shell effectively protected siTrib3 from RNase degradation. NPCaP/siTrib3 efficiently silenced TRIB3 protein expression in KP-1 cells, with gene knockdown efficacy comparable to Lipo8000 but with lower cytotoxicity. Functionally, NPCaP/siTrib3 significantly promoted apoptosis and inhibited cell migration and invasion. In vivo, intravenously administered NPCaP/siTrib3, which primarily accumulated in tumors through the enhanced permeability and retention (EPR) effect, markedly suppressed tumor growth without affecting body weight. Mechanistically, NPCaP/siTrib3 reversed EMT by upregulating E-cadherin and downregulating N-cadherin and Snail, and reduced cancer stemness by decreasing the expression of Sox2, Nanog, Pou5f1, Klf4, and c-Myc. Biosafety evaluations demonstrated negligible hemolysis, normal serum biochemistry and hematology, and no histopathological damage in major organs.
Conclusion:
NPCaP/siTrib3 is an effective and biocompatible siRNA nanoplatform that suppresses NSCLC progression through dual inhibition of EMT and cancer stemness, supporting TRIB3 as a promising therapeutic target.
Insights
Calcium phosphate nanoparticles effectively deliver siRNA to target TRIB3 in non-small cell lung cancer (NSCLC). This novel therapy suppresses tumor growth by inhibiting epithelial-mesenchymal transition and cancer stemness, offering a promising treatment strategy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- TRIB3 is overexpressed in non-small cell lung cancer (NSCLC), correlating with poor patient survival.
- Existing targeted therapies for TRIB3 in NSCLC are limited.
- Calcium phosphate (CaP) nanoparticles present a viable platform for biocompatible and stable siRNA delivery.
Purpose of the Study:
- To develop and evaluate calcium phosphate nanoparticles loaded with siRNA targeting TRIB3 (NPCaP/siTrib3).
- To assess the in vitro and in vivo antitumor efficacy of NPCaP/siTrib3.
- To elucidate the underlying mechanisms of action, including effects on epithelial-mesenchymal transition (EMT) and cancer stemness.
Main Methods:
- NPCaP/siTrib3 synthesized via biomineralization; siRNA loading and RNase resistance confirmed.
- In vitro studies utilized mouse KP-1 NSCLC cells for assessing gene silencing, cytotoxicity, apoptosis, migration, and invasion.
- In vivo studies involved subcutaneous tumor models in C57BL/6 mice treated via tail-vein injection to evaluate antitumor efficacy and biosafety.
Main Results:
- NPCaP/siTrib3 nanoparticles (approx. 159.4 nm) effectively protected siRNA from degradation and efficiently silenced TRIB3 in NSCLC cells with lower cytotoxicity than controls.
- The treatment promoted apoptosis and inhibited cell migration and invasion in vitro.
- In vivo, NPCaP/siTrib3 suppressed tumor growth via the EPR effect, reversed EMT, reduced cancer stemness markers, and demonstrated excellent biosafety with no significant adverse effects.
Conclusions:
- NPCaP/siTrib3 nanoparticles represent an effective and biocompatible siRNA delivery system for NSCLC.
- This nanoplatform demonstrates significant antitumor activity by simultaneously inhibiting EMT and cancer stemness.
- TRIB3 is validated as a promising therapeutic target for NSCLC treatment using this nanomedicine approach.
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