Photodynamic Medical Device for Gastrointestinal Cancer Therapy = 위장관암 치료를 위한 광역학 의료기기

다국어 초록 (Multilingual Abstract)

Photodynamic Medical Device for Gastrointestinal Cancer Therapy Gastrointestinal (GI) cancers encompass a heterogeneous group of malignant tumors arising in the digestive tract and associated organs, including the esophagus, stomach, biliary tract, pancreas, small intestine, colon, rectum, and anus. Among these, colorectal, gastric, and esophageal cancers exhibit notably higher incidence and mortality rates in east Asia compared to other regions. Current treatment strategies involve surgical resection followed by chemotherapy and radiotherapy, with increasing adoption of immune checkpoint inhibitors recently. However, surgical interventions are often associated with significant physical burden and functional impairment, while chemotherapy is limited by systemic toxicity, immunosuppression, and the development of drug resistance. Radiotherapy may induce complications such as bleeding, pain, and luminal stricture, and immunotherapy continues to demonstrate relatively low response rates in a substantial subset of patients. Ablation therapy is minimally invasive procedure that offers several advantages in this context. It enables rapid and localized tumor removal while reducing patient burden and avoiding organ failure associated with surgical section. However, because conventional ablation modalities rely on the delivery of thermal, or electrical energy to induce physical tumor destruction, they may cause serious adverse events, including damage to surrounding tissue, or perforation, etc. Photodynamic therapy (PDT) has emerged as a promising alternative modality, utilizing a combination of photosensitizers (PS), light, and oxygen to generate localized reactive oxygen species, leading to tumor cell death. In addition to its direct cytotoxic effects, PDT has reported t induce anti-tumor immune responses. Despite these advantages, its clinical application remains limited due to low tumor selectivity of PS and the associated risk of systemic phototoxicity, which can significantly compromise patients quality of life. Self-expanding metal stents (SEMS) are commonly used medical devices in GI oncology to alleviate luminal obstruction caused by tumor progression, particularly in the esophagus an colon. Because SEMSs directly expand to within tumor obstructed GI tract lumens, it can serve as an optimized platform for localized PS delivery, and catheter-guided light irradiation. To address the limitations of existing treatment modalities, this study explores the development of a PDT-enabled medical device designed for localized treatment of GI cancers. In Chapter 2, a representative 2nd-generation hydrophobic PS, Chlorin e6 (Ce6), was conjugated with methoxy-PEG 5k-NH2 to improve its dispersibility, and subsequently incorporated into a silicone matrix to fabricate a PDT-applicable stent. This system was evaluated for its ability to induce cytotoxic effects in colorectal cancer cells through localized PDT. In Chapter 3, a hydrophilic PS, Aluminum (III) Phthalocyanine chloride tetrasulfonic acid (AlPcS4), characterized for resistant to photobleaching and enhanced thermal stability, was uniformly dispersed within a silicone film to construct a stent platform. This device was further applied to the treatment of esophageal cancer, demonstrating its potential for improved PDT performance. In conclusion, by integrating PDT capability into a SEMS-based platform, this approach aims to enhance site-specific anti-tumor efficacy while minimizing systemic side effects.

2.1 Abstract
Photodynamic therapy (PDT) using photosensitizer (PS)-embedded silicone film-covered self-expandable metallic stents (SEMSs) offers a potential palliative treatment for malignant gastrointestinal obstruction, through precise light delivery and stent-related complications remain challenges. Here, a Chlorin e6 (Ce6)-embedded stent-based catheter was developed to enhance therapeutic efficacy and safety. PDT effectively induced colorectal cancer cell death and achieved dose-dependent tissue ablation, with uniform and sufficient depth at 600 J/cm2 irradiation. In a rat colon model, endoluminal PDT was successfully performed without procedure-related complications, demonstrating localized apoptotic cell death followed by gradual tissue recovery from 2-4 weeks. These findings suggest that Ce6-embedded stent-based PDT is a promising approach for treating malignant colorectal obstruction.

3.1 Abstract
Localized photodynamic therapy (PDT) using a photoactive stent-based catheter enables direct delivery of reactive oxygen species (ROS) to esophageal tumors, but its clinical utility is limited by rapid mucosal recovery. To address this, Aluminum (III) phthalocyanine chloride tetrasulfonic acid (AlPcS4), a photostable and low-photobleaching 2nd-generation photosensitizer, was embedded into a silicone-based stent coating system for repeated PDT. The AlPcS4 concentrations were optimized to achieve Photosensitizer (PS) coating uniformity. After optimization, the AlPcS4 coating stent demonstrated superior photostability and sustained singlet oxygen generation compared to conventional PSs. Repeated PDT enhanced cancer cell death in vitro and significantly suppressed tumor growth in a esophageal cancer xenograft mouse model, with greater efficacy than single treatment. In a porcine esophagus, periodic PDT induced progressive mucosal injury and apoptosis, confirming technical feasibility and sustained therapeutic effects. Overall, this repeatable PDT stent shows strong potential as a minimally invasive and effective treatment strategy for esophageal carcinoma.

목차 (Table of Contents)

• Ⅰ Chapter 1. INTRODUCTION 1
• 1.1 Photodynamic therapy 2
• 1.2 Gastrointestinal cancer 4
• 1.3 PDT-enabling combined medical devices 7
• II MAIN BODY 9
• Chapter 2 . Endoluminal Photodynamic Therapy with a Photoreactive Stent- based Catheter System to Treat Malignant Colorectal Obstruction 9
• 2.1. Abstract 10
• 2.2. Introduction 11
• 2.3. Materials and methods 15
• 2.3.1. Materials 15
• 2.3.2. Preparation and characterization of mPEG5k-Ce 6 16
• 2.3.3. Fabrication and characterization of mPEG5k-Ce6-embedded film/ stent 17
• 2.3.4. Phototoxicity of the mPEG5k-Ce6 stent 18
• 2.3.5. Procedure of localized PDT in the rat colon 18
• 2.3.6. Histological and immunohistochemical staining 20
• 2.3.7. Statistical analysis 21
• 2.4. Result and discussion 22
• 2.4.1. Preparation of mPEG5K-Ce 622
• 2.4.2. Characterization of mPEG5k-Ce6-embedded stent· 25
• 2.4.3. Phototoxicity of the mPEG5k-Ce6 stent in colon cancer cells 28
• 2.4.4. Procedure of localized PDT in the rat colon 30
• 2.4.5. Histological and immunohistochemical staining image of rat colon 33
• 2.5. Conclusion 37
• Chapter 3. Repeatable Photoactive Stent-based Catheter to Enhance Therapeutic Efficacy for Esophageal Carcinoma 39
• 3.1. Abstract 40
• 3.2. Introduction 41
• 3.3. Materials and methods 46
• 3.3.1. Materials 46
• 3.3.2. AlPcS4 dispersion to coating solution optimization 47
• 3.3.3. AlPcS4 film characterization 48
• 3.3.4. Optimal photosensitizer selection for repeated PDT 49
• 3.3.5. In vitro phototoxicity of AlPcSA4 film 50
• 3.3.6. In vivo anticancer effect of repeated PDT with AlPcS4 film 51
• 3.3.7. Effects of repeated PDT with AlPcS4 coating stent in porcine model 52
• 3.3.8. Histological and immunohistochemical staining image of porcine esophagus tissue 54
• 3.3.9. Statistical analysis 55
• 3.4. Result and discussion 56
• 3.4.1. AlPcS4 dispersion to coating solution optimization 56
• 3.4.2. AlPcS4 film characterization· 59
• 3.4.3. Optimal photosensitizer selection for repeated PDT 62
• 3.4.4. In vitro phototoxicity of AlPcSA4 film 65
• 3.4.5. In vivo anticancer effect of repeated PDT with AlPcS4 film 67
• 3.4.6. Effects of repeated PDT with AlPcS4 coating stent in porcine model 70
• 3.4.7. Histological and immunohistochemical staining image of porcine esophagus tissue 72
• 3.5. Conclusion 76
• Ⅳ REFERENCES 78
• Ⅵ 국문 초록 98