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Magnesium Peroxide-Incorporated in situ Forming Gelatin Hydrogel with Sustained Release of Nitric Oxide for Cancer Therapy

초록/요약

Cancer poses a major global health burden, cases predicted to increase to 28.4 million per year by 2040. While conventional treatments like surgery, chemotherapy, and radiation have led to gradual improvements, they have significant limitations. Nitric oxide (NO) delivered under control has the potential to completely transform cancer treatment but faces challenges regarding stability of traditional NO donors, ability to target tumor sites, and biocompatibility. Hydrogels offer unique advantages that could address these hurdles through their biocompatibility, controllable degradation, and capacity for localized drug loading and release. Specifically, hydrogels have potential to enhance efficacy of standard interventions like chemotherapy, radiotherapy, immunotherapy, magnetic hyperthermia, and photothermal/photodynamic therapy. They can also improve drug penetration into tumors, retention at tumor sites, and reduce side effects, thereby improving patient tolerance. Furthermore, in situ forming hydrogels enable minimally invasive administration, precise delivery to target sites, and enhanced patient convenience. Magnesium peroxide (MgO2) allows controlled NO release from hydrogels, increasing bioavailability at tumors and easing administration demands. This study aims to create an in situ hydrogel that can release NO for cancer treatment. A gelatin-hydroxyphenyl propionic acid (GH) polymer precursor was synthesized using EDC/NHS chemistry. The hydrogel, incorporating MgO2, was formed through HRP enzyme-catalyzed crosslinking, minimizing cytotoxicity. Key physicochemical properties were characterized, including gelation time, mechanical strength, degradability, porosity, and swelling. The hydrogel was also investigated for the release of molecules like H2O2, Mg2+ ions, and NO. The cytotoxicity against various cancer cell lines and biocompatibility with normal cells were evaluated based on the amount of NO released. As a result, by adjusting HRP and Mg2+ concentration, the hydrogels' physicochemical characteristics, such as gelation time, mechanical strength, microstructure, swelling ratio, and degradation rate, could be controlled. The amount of NO released over a 24-hour period, ranging from 23.84 to 37.99 µM depending on MgO2 loading, resulted in selective cytotoxicity towards various cancer cell lines including cervical cancer, breast cancer, prostate cancer, lung cancer, and colon cancer while sparing normal cells. In summary, this in situ NO-releasing GH/Mg hydrogel is expected to be a promising material for effective cancer therapy. Keywords: gelatin; in situ forming hydrogel; nitric oxide; cancer therapy.

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목차

I. INTRODUCTION 1
1. Cancer Therapy 1
1.1 Overview of cancer as a global health challenge 1
1.2 Conventional cancer therapies 2
1.2.1 Surgery 2
1.2.2 Radiation therapy 2
1.2.3 Systemic chemotherapy 2
1.2.4 Limitations of conventional treatment methods 3
2. Importance of Controlled Nitric Oxide Release 4
2.1 Role of NO in cancer treatment 5
2.2 Significance of sustained NO delivery 5
2.3 Challenges in achieving controlled NO release 6
2.4 NO-releasing systems for cancer therapy and their limitations . 7
3. The Promise of Hydrogel-Based Therapeutics 7
3.1 Applications of hydrogels for various cancer treatment approaches 7
3.2 Advantages of in situ forming hydrogels 8
3.3 Integration of magnesium peroxide for controlled NO release 9
4. Objectives 10
II.EXPERIMENTAL SECTION 11
1. Materials 11
2. Synthesis and Characterization of Gelatin-Hydroxyphenyl Propionic Acid (GH) Conjugated 11
3. Preparation and Characterization of The Magnesium-Incorporated Gelatin-Based Hydrogels(GH/Mg Hydrogels) 12
3.1 Formation and gelation time of GH and GH/Mg hydrogels 12
3.2 Mechanical strength and morphological study of hydrogels 13
3.3 In vitro swelling behavior and proteolytic degradation 13
4. Determination of Hydrogen Peroxide by Quantitative Peroxide Assay 14
5. Determination of Mg Ion Released Amount from GH/Mg Hydrogels 15
6. Determination of Nitric Oxide Amount by The Griess Assay 15
7. Cytotoxicity Evaluation 16
8. Statistical Analysis 17
III.RESULTS AND DISCUSSION 18
1. Synthesis and Characterization of GH Polymer 18
2. GH/Mg Hydrogel Formation and Gelation Time 19
3. Effects of MgO2 on The Mechanical Strength, Degradation Rate, Porous Structure, and Swelling Ratio 21
3.1 Mechanical strength 21
3.2 Degradation rate 22
3.3 Swelling ratio and porous structure 24
4. In Vitro Release of Mg Ion and NO 25
5. In Vitro Cytotoxicity of GH/Mg Hydrogels 27
IV.CONCLUSIONS 29
V.REFERENCES 30

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