| Summary: | 碩士 === 國立臺灣大學 === 醫學工程學研究所 === 104 === High-grade gliomas are the most common and aggressive types of primary brain tumor. Surgery remains the first line therapy of gliomas nowadays because of its effectiveness. However, high-grade gliomas have feature of diffuse infiltration that may cause the difficulty and failure of surgical resection, that is, the relapse rate after surgery remains high. Therefore, it is necessary to apply adjuvant chemotherapy to inhibit the cancer recurrence. However, when drugs are given via systemic circulation, Blood-Brain Barrier (BBB) restricts the entry of chemotherapeutic agents from blood side to brain side, and consequently limits the concentration and the effect of drugs. The drugs would also cause damage of normal tissues or organs when circulating. As a result, different route of administration is needed in the treatment of gliomas. Using biodegradable biomaterials as drug carriers for local delivery in brain is a promising therapy lately. For instance, the only drug carriers product approved by FDA in clinic, GLIADELR Wafer, can achieve long-term drug release and maintain the effective drug concentration in the brain tumor site.
This study is willing to develop hydroxyapatite particles as drug carriers carrying honokiol (HAp-honokiol) and provides an alternative option when dealing with gliomas in clinical. The effectivity of the drug adsorption, drug-releasing profile, and tumor cell inhibition effect and its mechanism would be analyzed. And the animal model of C57BL/6 mice glioma would be established in this study.
In this research, the synthesis of hydroxyapatite (HAp) particles is conducted by modified co-precipitation method. The addition of egg white helps the formation of porous structures afterwards. XRD is for observing the crystal phase of the HAp particles and FTIR is used to analyze the modification of stearic acid on the HAp particles. The drug loading capacity is then evaluated by TGA. And the drug releasing profiles in neutral and acid environment are conducted by UV-Vis. ALTS1C1 is the glioma cell model in this experiment. Cell viability tests, toxicity tests, and immunostaining are used to analyzed the inhibition effect and apoptosis pathway by HAp-honokiol. Finally, the intercerebral injection of ALTS1C1 to establish the mice glioma model is conducted by the stereotactic apparatus.
The results show promisingly high adsorption rate of HAp-honokiol, that 100 μg sample contains 15 μg of honokiol. Through the drug releasing experiments, honokiol would be rapidly released within 48 hours in acid environment, while the accumulative concentration of releasing honokiol reach the plateau of 65 % and stop rising. And the in vitro studies show well inhibiting effect of tumor growth and induction of cell apoptosis of HAp-honokio. The apoptosis pathway of ALTS1C1 by honokiol is also confirmed through Annexin V-PI double staining and western blot.
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