| Summary: | 碩士 === 國立清華大學 === 生醫工程與環境科學系 === 100 === Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Most GBM patients have poor prognosis even after proper treatment. The major obstacles include less drugs reaching targeted area due to the existence of blood-brain barrier (BBB) and appearance of severe side effects preventing further increase in prescription dosage. Recently many techniques have been proposed to resolve these problems. Among these techniques, focus ultrasound combined with microbubbles provided the potential for elevating amount of drugs delivered into brain tissue. In order to reduce the exposure of normal tissue to drugs, designing a drug carrier or chelating a targeting molecule to drugs is needed.
The aim of this study is to develop the multi-functional phospholipid microbubbles (UD-MB) which loaded with doxorubicin (DOX) and ultrasmall superparamagnetic iron oxide nanoparticle (USPIO). As a drug carrier, UD-MB can reduce DOX toxicity to normal tissue and increase the accumulation of drugs in brain when combined with focus ultrasound insonation. Moreover, loading with USPIO on microbubbles, UD-MB can be transported to the targeting site by magnet and used as MRI contrast agents.
The DOX molecules with positive charge were electrostatically complex to anion phospholipid molecules and surface modified USPIO were trapped onto the inner shell by hydrophobic linkage between phospholipid molecules and USPIO. We also conducted the in-vitro experiments to quantify and qualify the sono-properties and magnetic properties of UD-MB. The cells toxicity of UD-MB was evaluated by using C-6 glioma cells. The degree of BBB opening by UD-MB with focused ultrasound (328 kPa, 1000 cycles, PRF 1 Hz, sonicate for 90 sec) in Sprague–Dawley rats bearing GBM tumors were also evaluated.
The results show the payloads of 675± 62 mg/mL DOX and 707± 57 mg/mL USPIO on the fabricated UD-MB. The ultrasound images can be enhanced by 37 dB and MRI relaxivity was 107.3 s-1mM-1 by using UD-MB. Moreover, intact UD-MB can reduce cells toxicity significantly compared to ionizing DOX. A magnet loacated on the beneath cell culture dish would enhance uptakes of DOX and USPIO by cells. In-vivo experiments demonstrate that UD-MB have the potential to increase the permeability of BBB.
In conclusion, UD-MB can be used as a dual imaging modality contrast agents and a magnetic targeting therapeutic drug for treating GBM. Future works include chelating a targeting molecule on UD-MB and applying the magnet to enhance the accumulation.
Keywords: glioblastoma multiforme (GBM), blood-brain barrier (BBB), microbubbles , focused ultrasound, chemotherapy, superparamagnetic iron oxide nanoparticle (SPIO), targeting therapy
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