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In Situ Crosslinked Micelle/Hydrogel Composites for Local and Sustained Delivery of Hydrophobic Anticancer Drugs

초록/요약

Conventional cancer treatments containing surgery, radiation therapy, and systemic chemotherapy have been performed for the past several decades. However, surgical limitations, undesired side effects on normal cells, and poor water solubility of strong anti-cancer drugs remain challenges. As an alternative method, localized chemotherapy which delivers anti-cancer drugs directly to the target site has gained attention due to the improved drug efficacy and minimized systemic side effects. Furthermore, prolonged release of the chemotherapeutic is also important for the treatment of large tumors and the avoidance of tumor recurrence. Although nanocarriers and in situ forming hydrogels have been widely studied for the localized delivery systems of hydrophobic anti-cancer drugs, they are not sufficient ways to treat cancer due to the low physical stability of particles and hydrophilic nature of the hydrogels. Therefore, the design and formation of a drug carrier with the desired function by combining these two types of materials are drawing attention. Among various particles, Kim and colleagues developed the HRP/H2O2 mediated shell-crosslinked Tetronic-tyramine (Tet-TA) micelles for the enhanced stability (> 4 weeks) and prolonged release of the hydrophobic drugs (~80% cumulative release in 4 days). In this study, we prepared the in situ crosslinked Tet-TA micelle/gelatin hydrogel composites via HRP/H2O2 ¬mediated cross-linking for the sustained delivery of hydrophobic anticancer drugs. Biocompatible-polymers, gelatin, and Tet were modified with phenol moieties and characterized by 1H NMR and UV spectrometer. Paclitaxel (PTX), a hydrophobic anticancer drug, was successfully encapsulated (loading efficiency= 59.9%) in the Tet-TA micelles. PTX-loaded micelle/hydrogel composites were simply formed via enzymatic crosslinking between phenolic groups of gelatin derivatives and Tet-TA. The gelation time varied from 13 to 209 s and could be simply controlled by changing HRP concentrations. The PTX-loaded micelles were enzymatically crosslinked to the hydrogel network restricting the aggregation of the micelles in the composites, increasing the mechanical strength of hydrogels (6636→7351 Pa). The relatively low swelling ratio of the crosslinked micelle/hydrogel composites also indicated the slightly increased crosslinking density. PTX was released from the crosslinked micelle/hydrogel composites in a sustained manner (~47%) for 28 days in vitro. In vitro cytotoxicity test proved the excellent cytocompatibility of the composite systems and improved drug efficacy against cancer cells. In conclusion, we can suggest the in situ crosslinked micelle/hydrogel composite system as a promising local hydrophobic anti-cancer drug carrier for improved cancer treatment.

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목차

I. INTRODUCTION 1
1. Cancer 1
2. Conventional cancer treatment methods 2
2.1. Surgery 2
2.2. Radiation therapy 2
2.3. Systemic chemotherapy 3
3. Localized (Regional) chemotherapy 4
4. Polymeric biomaterials for local chemotherapy 5
4.1. Implant solid types 7
4.2. Particle type carriers 8
4.2.1. Polymeric micro/nanospheres and capsules 8
4.2.2. Polymeric micelles and liposomes 9
4.2.2.1. Tetronic-based micelles 10
4.2.2.2. Crosslinked micelles 11
4.3. In situ forming hydrogels 12
4.3.1. Enzyme-mediated hydrogels 14
4.3.1.1. Horseradish peroxidase (HRP)/H2O2-mediated hydrogels 15
4.4. Composites 16
5. Objectives 17
II. MATERIALS & METHODS 19
1. Materials 19
2. Polymer synthesis and characterization 20
2.1. Synthesis of gelatin-hydroxyphenyl propionic acid (GHPA) 20
2.2. Synthesis of Tetronic-tyramine (Tet-TA) 20
2.3. Chemical structure analysis by 1H NMR 21
2.4. Phenol contents measurement 22
3. Micelle formation and characterizations 22
3.1. Preparation of Tet, Tet-TA micelles 22
3.2. Preparation of PTX-loaded Tet, Tet-TA micelles 23
3.3. Size distribution and morphology 23
3.4. Drug loading amount and drug loading efficiency 24
4. PTX-loaded micelle/hydrogel composite formation and characterizations 24
4.1. Formation of PTX-loaded Micelle/hydrogel composites 24
4.2. Gelation time measurement 25
4.3. Surface morphology and microporous structure 26
4.4. Mechanical strength (elastic modulus, G’) 26
4.5. In vitro swelling behavior 27
5. In vitro PTX release test 27
6. In vitro cytotoxicity test 28
6.1. in vitro cytotoxicity 28
6.2. in vitro drug efficacy 29
III. RESULTS & DISCUSSION 30
1. Polymer synthesis and characterization 30
2. PTX-loaded micelle formation and characterizations 33
2.1. Micelle size and morphology before and after drug loading 33
2.2. Drug loading amount and drug loading efficiency 36
3. PTX-loaded micelle/hydrogel composite formation and characterizations 37
3.1. Micelle/hydrogel composite formation and their gelation times 37
3.2. Microporous structures 40
3.3. Mechanical strength 41
3.4. Swelling behavior 42
4. In vitro PTX release profile 43
5. In vitro cytotoxicity test 46
5.1. Cytotoxicity studies of blank micelle/hydrogel composites 46
5.2. In vitro drug efficacy of PTX-loaded hydrogels 48
IV. CONCLUSION 49
V. REFERENCE 50

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