NIR-responsive cetuximab-functionalized chitosan-polydopamine hydrogel Co- delivering Ca²⁺ and gefitinib for EGFR-targeted esophageal cancer therapy via Ca²⁺- mediated cytotoxicity and potential immunomodulatory effects.
7 affiliations
- 1Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
- 2Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
- 3Department of Nursing Care, Sichuan Clinical Research Center for Cancer,Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
- 4Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China. [email protected].
- 5Department of Medical Oncology, Sichuan Cancer Hospital, Medical School of University of Electronic Science and Technology of China, No.55, Section 4, South Renmin Road, Chengdu, 610041, China. [email protected].
- 6Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China. [email protected].
- 7Department of Medical Oncology, Sichuan Cancer Hospital, Medical School of University of Electronic Science and Technology of China, No.55, Section 4, South Renmin Road, Chengdu, 610041, China. [email protected].
Abstract
The current study presents the development of a Cetuximab (CTX)-functionalized chitosan-polydopamine (CS-PDA) hydrogel co-delivering calcium ions (Ca2 +) and Gefitinib (GFT) for EGFR-targeted therapy against esophageal cancer through the induction of Ca²⁺ mediated cell death and potential immune modulatory effects. FTIR analysis confirmed the functional groups present in the fabricated hydrogel, while UV-Vis spectroscopy verified successful drug incorporation, and SEM analysis revealed a porous morphology suitable for efficient drug encapsulation. The hydrogel shows high drug loading efficiencies of 78.5 ± 2.3% for Ca2 + and 81.6 ± 3.1% for GFT, with pH-responsive drug release reaching up to 70% under acidic conditions. NIR-activated CTX-CS-pDA@Ca2 +/GFT hydrogel showed superior cytotoxicity in KYSE-140 cells, with significantly lower IC₅₀ values than free GFT. Further, JC-1 and AO/EB staining confirmed mitochondrial depolarization and apoptosis induction, while flow cytometry demonstrated that CTX-CS-pDA@Ca2 +/GFT + NIR markedly induced apoptosis in KYSE-140 cells by combining EGFR inhibition, Ca2 + -mediated stress, and NIR-enhanced ROS generation, resulting in reduced cell viability and increased apoptotic populations. Calcium imaging further validated intracellular Ca2 + accumulation indicated enhanced Ca²⁺mediated cellular stress in treated cells. In vivo evaluation in a xenograft mouse model revealed tumor inhibition rates of 42%, 24%, 60%, 78%, and 92% for GFT, CS-pDA, CS-pDA@Ca2 +/GFT, CTX-CS-pDA@Ca2 +/GFT, and CTX-CS-pDA@Ca2 +/GFT + NIR, respectively. The NIR-activated CTX-CS-pDA@Ca2 +/GFT formulation achieved the most pronounced tumor regression with negligible impact on body weight, confirming its superior therapeutic efficacy and biosafety. Biochemical analyses of serum ALP, SGOT, urea, and creatinine levels confirmed the biocompatibility and safety of the fabricated hydrogel. Histopathological examination of excised tumor tissues supported the induction of apoptosis and tissue necrosis in treated groups. Furthermore, qRT-PCR and Western blot analyses demonstrated upregulation of Bax and cleaved caspase-3 and downregulation of Bcl-2 and EGFR/p-AKT signaling, supporting the dual mechanism of action. Besides, CTX-CS-pDA@Ca2 +/GFT + NIR significantly upregulated pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ), indicating potential immunomodulatory activity associated with cytokine expression changes driven by targeted delivery, Ca2 + -mediated stress, and NIR-triggered activation. Overall, this multifunctional hydrogel demonstrates strong potential as a localized and targeted therapeutic strategy for EGFR-overexpressing esophageal cancer through synergistic EGFR inhibition, Ca2 + -mediated cytotoxicity, and potential immunomodulatory effects.
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BibTeX
@article{chen2026nirresponsive,
title = {{NIR-responsive cetuximab-functionalized chitosan-polydopamine hydrogel Co- delivering Ca²⁺ and gefitinib for EGFR-targeted esophageal cancer therapy via Ca²⁺- mediated cytotoxicity and potential immunomodulatory effects.}},
author = {Jing Chen and Shirong Wu and Yu Zhang and Ya Zhao and Mengqi Xiang and Liqiong Hao},
journal = {Journal of biological engineering},
year = {2026},
month = jul,
doi = {10.1186/s13036-026-00726-w},
url = {https://europepmc.org/article/MED/42894237},
note = {CC BY},
}
RIS
TY - JOUR
TI - NIR-responsive cetuximab-functionalized chitosan-polydopamine hydrogel Co- delivering Ca²⁺ and gefitinib for EGFR-targeted esophageal cancer therapy via Ca²⁺- mediated cytotoxicity and potential immunomodulatory effects.
AU - Jing Chen
AU - Shirong Wu
AU - Yu Zhang
AU - Ya Zhao
AU - Mengqi Xiang
AU - Liqiong Hao
PY - 2026
DA - 2026/07/01
JO - Journal of biological engineering
DO - 10.1186/s13036-026-00726-w
UR - https://europepmc.org/article/MED/42894237
AB - The current study presents the development of a Cetuximab (CTX)-functionalized chitosan-polydopamine (CS-PDA) hydrogel co-delivering calcium ions (Ca2 +) and Gefitinib (GFT) for EGFR-targeted therapy against esophageal cancer through the induction of Ca²⁺ mediated cell death and potential immune modulatory effects. FTIR analysis confirmed the functional groups present in the fabricated hydrogel, while UV-Vis spectroscopy verified successful drug incorporation, and SEM analysis revealed a porous morphology suitable for efficient drug encapsulation. The hydrogel shows high drug loading efficiencies of 78.5 ± 2.3% for Ca2 + and 81.6 ± 3.1% for GFT, with pH-responsive drug release reaching up to 70% under acidic conditions. NIR-activated CTX-CS-pDA@Ca2 +/GFT hydrogel showed superior cytotoxicity in KYSE-140 cells, with significantly lower IC₅₀ values than free GFT. Further, JC-1 and AO/EB staining confirmed mitochondrial depolarization and apoptosis induction, while flow cytometry demonstrated that CTX-CS-pDA@Ca2 +/GFT + NIR markedly induced apoptosis in KYSE-140 cells by combining EGFR inhibition, Ca2 + -mediated stress, and NIR-enhanced ROS generation, resulting in reduced cell viability and increased apoptotic populations. Calcium imaging further validated intracellular Ca2 + accumulation indicated enhanced Ca²⁺mediated cellular stress in treated cells. In vivo evaluation in a xenograft mouse model revealed tumor inhibition rates of 42%, 24%, 60%, 78%, and 92% for GFT, CS-pDA, CS-pDA@Ca2 +/GFT, CTX-CS-pDA@Ca2 +/GFT, and CTX-CS-pDA@Ca2 +/GFT + NIR, respectively. The NIR-activated CTX-CS-pDA@Ca2 +/GFT formulation achieved the most pronounced tumor regression with negligible impact on body weight, confirming its superior therapeutic efficacy and biosafety. Biochemical analyses of serum ALP, SGOT, urea, and creatinine levels confirmed the biocompatibility and safety of the fabricated hydrogel. Histopathological examination of excised tumor tissues supported the induction of apoptosis and tissue necrosis in treated groups. Furthermore, qRT-PCR and Western blot analyses demonstrated upregulation of Bax and cleaved caspase-3 and downregulation of Bcl-2 and EGFR/p-AKT signaling, supporting the dual mechanism of action. Besides, CTX-CS-pDA@Ca2 +/GFT + NIR significantly upregulated pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ), indicating potential immunomodulatory activity associated with cytokine expression changes driven by targeted delivery, Ca2 + -mediated stress, and NIR-triggered activation. Overall, this multifunctional hydrogel demonstrates strong potential as a localized and targeted therapeutic strategy for EGFR-overexpressing esophageal cancer through synergistic EGFR inhibition, Ca2 + -mediated cytotoxicity, and potential immunomodulatory effects.
SN - 1754-1611
ER -