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ANTIBODY-TARGETED PHOTODYNAMIC THERAPY USING TRASTUZUMAB-CONJUGATED CHLORIN E6 FOR HER2-POSITIVE GASTROINTESTINAL CANCERS

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ANTIBODY-TARGETED PHOTODYNAMIC THERAPY USING TRASTUZUMAB-CONJUGATED CHLORIN E6 FOR HER2-POSITIVE GASTROINTESTINAL CANCERS

Mamoru Tanaka 1, Makiko Sasaki 1, Yasunari Sasaki 1, Yuki Kojima 1, Taketo Suzuki 2, Hirotada Nishie 2, Takaya Shimura 1, Eiji Kubota 1, Hiromi Kataoka 1

Affiliations

1 Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2 Nagoya City University Midori Municipal Hospital, Nagoya, Japan

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Abstract

Introduction

Photodynamic therapy (PDT) induces tumor cell death through the generation of reactive oxygen species (ROS) following activation of a photosensitizer by light irradiation. Although PDT enables localized tumor destruction with relatively low systemic toxicity, limited tumor selectivity of conventional photosensitizers may result in damage to surrounding normal tissues. Antibody-drug conjugate strategies enable selective delivery of therapeutic agents to tumor cells and may improve tumor specificity in PDT (1). Human epidermal growth factor receptor 2 (HER2) is overexpressed in several gastrointestinal cancers and represents an important therapeutic target (2).

Aims & Methods

We developed a novel HER2-targeted photosensitizer by conjugating glucose-linked chlorin e6 (G-Ce6) with trastuzumab (G-Ce6-trastuzumab) and evaluated its tumor selectivity and photodynamic cytotoxicity. G-Ce6 is a glucose-conjugated chlorin derivative previously reported to show strong photodynamic activity in gastrointestinal cancer cells (3). G-Ce6-trastuzumab was synthesized using sulfo-NHS-mediated conjugation between G-Ce6 and trastuzumab. Cellular uptake, ROS generation, and cytotoxic effects following PDT were evaluated in HER2-high expressing human gastric cancer cells (NCI-N87) and HER2-low expressing gastric cancer cells (MKN-45). Cellular uptake was analyzed by flow cytometry. ROS production following PDT (660 nm irradiation, 16 J/cm²) was measured using the fluorescent probe DCFH-DA. Cytotoxic effects were evaluated using WST-8 assays, and IC50 values were calculated.

Results

Flow cytometric analysis demonstrated that G-Ce6 alone showed comparable cellular uptake in both cell lines. In contrast, G-Ce6-trastuzumab exhibited markedly enhanced uptake in HER2-overexpressing NCI-N87 cells compared with HER2-low MKN-45 cells. Following PDT, ROS generation was significantly increased in NCI-N87 cells treated with G-Ce6-trastuzumab. Cytotoxicity assays demonstrated enhanced antitumor effects of G-Ce6-trastuzumab-mediated PDT in HER2-overexpressing cells. The IC50 value in NCI-N87 cells was significantly lower for G-Ce6-trastuzumab (1.14 ± 0.40 nM) than for G-Ce6 (8.35 ± 2.17 nM), indicating substantially improved therapeutic efficacy (Table). In contrast, the difference between the two agents was less pronounced in HER2-low MKN-45 cells.

Cell line	IC50 G-Ce6 (nM)	IC50 G-Ce6-Trastuzumab (nM)
MKN-45	5.98 ± 1.30	3.16 ± 0.68
NCI-N87	8.35 ± 2.17	1.14 ± 0.40

Conclusion

The novel HER2-targeted photosensitizer G-Ce6-trastuzumab demonstrated enhanced tumor-selective uptake, increased ROS generation, and stronger cytotoxic effects in HER2-overexpressing gastric cancer cells compared with the conventional photosensitizer G-Ce6. Antibody-mediated targeting significantly improved the selectivity and therapeutic efficacy of photodynamic therapy while minimizing potential damage to surrounding normal tissues. These findings suggest that antibody-targeted PDT may represent a promising strategy to enhance tumor specificity in photodynamic therapy. Furthermore, this approach could provide a novel translational platform for precision photodynamic therapy and theranostic applications in HER2-positive gastrointestinal cancers.

References

Beck A, et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017.
Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric cancer (ToGA trial). Lancet. 2010.
Nishie H, et al. Glucose-linked chlorin e6 as a novel photosensitizer for photodynamic therapy in gastrointestinal cancers. Biochem Biophys Res Commun. 2018;496:1204–1209.

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine Stomach & H. Pylori Digestive Oncology Oesophagus

Submission format

Abstract

Session

Evolving molecular paradigms in gastric cancer

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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