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Fibroblast Growth Factor Receptor 1-Specific Dehydrogelation to Release Its Inhibitor for Enhanced Lung Tumor Therapy
Runqun Tang1, Ziyi Zhang1, Xiaoyang Liu1
1State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 211189, China.
Abstract:
Fibroblast growth factor receptor 1 (FGFR1) is emerging as a promising molecular target of lung cancer, and various FGFR1 inhibitors have exhibited significant therapeutic effects on lung cancer in preclinical research. Due to their low targeting ability or bioavailability, direct administration of these inhibitors may cause side effects. Herein, a hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH (Nap-Y), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib (Nin) to form a peptide hydrogel Gel Y/Nin for localized administration and FGFR1-triggered release of Nin. Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, Nap-Y in Gel Y/Nin is converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H2PO3)-OH (Nap-Yp), leading to dehydrogelation of the gel and subsequent Nin release. In vitro experiments demonstrate that the release of Nin in a sustained manner from Gel Y/Nin significantly suppresses the survival, migration, and invasion of A549 cells by inhibiting FGFR1 expression and its phosphorylation function on downstream signaling molecules. Nude mouse studies show that Gel Y/Nin exhibits enhanced therapeutic efficacy on lung tumor than free Nin. We anticipate that Gel Y/Nin will be utilized for lung cancer treatment in clinical settings in the near future.
Insights
A novel peptide hydrogel (Gel Y/Nin) delivers nintedanib (Nin) locally for lung cancer treatment. This hydrogel releases Nin upon FGFR1 phosphorylation, enhancing efficacy and reducing side effects.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Pharmacology
Background:
- Fibroblast growth factor receptor 1 (FGFR1) is a key target in lung cancer therapy.
- Current FGFR1 inhibitors face challenges with targeting and bioavailability, leading to potential side effects.
- Localized drug delivery systems are needed to improve therapeutic outcomes for lung cancer.
Purpose of the Study:
- To design and develop a peptide hydrogel (Gel Y/Nin) for localized delivery of the FGFR1 inhibitor nintedanib (Nin).
- To achieve FGFR1-triggered release of Nin from the hydrogel for enhanced lung cancer treatment.
- To evaluate the efficacy of Gel Y/Nin in preclinical lung cancer models.
Main Methods:
- Rational design of a hydrogelator (Nap-Y) to coassemble with nintedanib (Nin).
- Formation of a peptide hydrogel (Gel Y/Nin) for localized administration.
- Investigation of FGFR1-triggered dehydrogelation and drug release mechanism.
- In vitro assessment of Gel Y/Nin on A549 lung cancer cells (survival, migration, invasion).
- In vivo evaluation of Gel Y/Nin efficacy in nude mouse lung tumor models.
Main Results:
- Gel Y/Nin demonstrated sustained release of Nin triggered by FGFR1 phosphorylation.
- In vitro studies showed significant suppression of A549 cell survival, migration, and invasion.
- FGFR1 expression and downstream signaling were inhibited by Gel Y/Nin treatment.
- Nude mouse studies revealed enhanced therapeutic efficacy of Gel Y/Nin compared to free Nin.
Conclusions:
- The developed Gel Y/Nin hydrogel enables localized and targeted delivery of nintedanib for lung cancer.
- FGFR1-triggered release mechanism enhances drug efficacy and potentially reduces systemic side effects.
- Gel Y/Nin shows promise as a future clinical treatment for lung cancer.
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