Single low-dose INC280-loaded theranostic nanoparticles achieve multirooted delivery for MET-targeted primary and liver metastatic NSCLC
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Published on: August 2, 2022
Yige Sun1,2, Jie Yang1,2, Yingbo Li1,2
1Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028, Heilongjiang, China.
Background:
Non-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC.
Methods:
We developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens.
Results:
INC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens.
Conclusions:
These results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose.
Insights
A novel nanoparticle delivery system for capmatinib (INC280) shows potent anti-cancer effects against non-small cell lung cancer (NSCLC) liver metastasis. This MET-targeted therapy demonstrates improved efficacy and reduced toxicity in preclinical models.
Area of Science:
- Nanotechnology in Cancer Therapy
- Molecular Targeted Therapy
- Medical Imaging and Diagnostics
Background:
- Non-small cell lung cancer (NSCLC) with liver metastases has poor survival rates.
- MET signaling is crucial in advanced NSCLC, making MET inhibitors like capmatinib (INC280) promising.
- Current MET-targeted therapies face challenges with poor solubility and off-tumor effects, limiting efficacy.
Purpose of the Study:
- To develop an improved drug delivery system for capmatinib (INC280) to enhance MET-targeted therapy for NSCLC.
- To evaluate the efficacy and biodistribution of INC280-loaded nanoparticles (INC280-PFCE NPs) in preclinical NSCLC models.
- To assess the clinical translation potential of this novel nanoparticle formulation.
Main Methods:
- Developed INC280-PFCE nanoparticles by encapsulating INC280 into perfluoro-15-crown-5-ether.
- Validated NP biodistribution and anti-MET/antimetastatic effects in orthotopic NSCLC and liver metastasis models.
- Utilized 19F-MRI for real-time visualization of NP retention and release within tumors.
Main Results:
- INC280-PFCE NPs demonstrated significant in vitro antitumor activity.
- Real-time 19F-MRI confirmed sustained NP release and tumor retention in orthotopic NSCLC models.
- A single low-dose intravenous administration of INC280-PFCE NPs effectively suppressed liver metastasis without systemic toxicity, outperforming oral capmatinib.
Conclusions:
- The developed INC280-PFCE nanoparticles exhibit potent anti-MET and antimetastatic efficacy.
- The NPs allow for real-time MRI visualization of tumor targeting and retention.
- This novel nanoparticle formulation shows high biocompatibility and potential for clinical translation in NSCLC treatment.
