- 學位論文
薑黃素奈米粒子和抗癌奈米藥物對腫瘤治療之研究
Investigation of the Therapeutic Efficacy of Curcumin Nanoparticles and Antitumor Nanodrug for Tumors
摘要
背景：薑黃素(Curcumin (Cur))可用來抗氧化、抗發炎及抗癌，但為親脂性分子，生物利用性低。固體脂質奈米粒子(Solid Lipid Nanoparticles (SLNP))可包覆脂溶性藥物，生物相容性高、長期物理化學穩定性佳，是一種有效藥物載體。 目的：本研究利用固體脂質奈米粒子(SLNP)來包覆薑黃素，製成薑黃素固體脂質奈米粒子(Cur SLNP)，結合抗癌奈米藥物(Pegylated Liposomal Doxorubicin (PLD))以達到更有效抑制腫瘤成長並減少副作用。 材料與方法：GEC-Cholesterol和Cholesterol兩種脂質用來組成固體脂質奈米粒子，來包覆薑黃素。使用動態光散射粒徑分析儀來量測粒徑大小與電性，利用全光譜分析儀來量測薑黃素吸光值，以計算包覆率。將製成之薑黃素固體脂質奈米粒子置於不同溫度環境中，以測試其穩定性；置於不同pH值的溶液中以了解薑黃素釋放速度。利用4T1小鼠乳腺癌細胞來進行細胞毒性測試。並利用小鼠來做藥物動力學分析與在組織器官中之累積量。將4T1癌細胞植入BALB/c母鼠背部，腫瘤體積約生長至50 mm3開始進行治療，實驗分為Control、Cur SLNP、PLD (4 mg/kg, 10mg/kg)、PLD (4 mg/kg) + Cur SLNP，於第28天取下腫瘤，秤重並以石蠟切片進行H&E染色。 結果：奈米粒子和薑黃素莫耳數比為3:4時有最高包覆率，約57.8 %。薑黃素固體脂質奈米粒子在低溫環境中較為穩定；在酸性環境中釋放速度較快。細胞毒性測試結果顯示，薑黃素固體脂質奈米粒子在較低的濃度下仍能抑制癌細胞的生長。藥物動力學分析結果顯示，固體脂質奈米粒子能延長薑黃素在血液中循環時間。PLD (4 mg/kg) + Cur SLNP對腫瘤成長的抑制效果和PLD (10 mg/kg)相近，H&E染色亦具有相同結果。 結論：薑黃素固體脂質奈米粒子於低溫時較為穩定，其在較低的濃度下仍能抑制癌細胞的生長；固體脂質奈米粒子能夠延長薑黃素在血液中的循環時間。PLD (4 mg/kg) + Cur SLNP和PLD (10 mg/kg)兩組對腫瘤的抑制結果相近，顯示薑黃素固體脂質奈米粒子能有效提升抗癌奈米藥物抑制腫瘤的效果。
並列摘要
Background: Curcumin (Cur) is a hydrophobic molecule, it has the characteristics of anti-oxidation, anti-inflammation, but low bioavailability. Solid Lipid Nanoparticle (SLNP) has good biocompatibility and long term physicochemical stability, and hence it can be an efficient drug carrier. Purpose: The research used SLNP to encapsulate Cur to form Cur SLNP and then combined with antitumor nanodrug Pegylated Liposomal Doxorubicin (PLD) to inhibit tumor growth and reduce the side effects of drug. Materials and Methods: GEC-Cholesterol and Cholesterol were used to compose SLNP to encapsulate Cur. Dynamic light scattering was used to analyze the particle size and zeta potential, and fluorescence spectrophotometer was used to measure the absorbance of Cur to calculate the encapsulation efficiency. The stability of Cur SLNP in different temperatures and the release rate of Cur in different pH solution were measured. 4T1 mouse breast cancer cells were used to perform cell toxicity testing for Cur SLNP and Free Cur. Pharmacokinetics and biodistribution of Cur SLNP in mice were studied. 4T1 mouse breast tumors were implanted in the backs of BALB/c female mice and the treatment started when the tumors grew up to 50 mm3. The experimental groups were divided into Control, Cur SLNP, PLD (4 mg/kg, 10 mg/kg), PLD (4 mg/kg) + Cur SLNP. 28 days later, the mice were sacrificed and the tumors were harvested, weighted, sectioned and paraffined for H&E staining. Result: The molar ratio of 3:4 for SLNP and Cur had the highest encapsulation efficiency, approximately 57.8 %. Cur SLNP at low temperature was more stable and Cur released faster in an acidic environment. Cell toxicity testing showed that Cur SLNP at alow concentration still had the ability to inhibit cancer cell growth. Pharmacokinetics study revealed that SLNP could prolong Cur circulation time in the blood. PLD (4 mg/kg) + Cur SLNP had the same performance for tumor growth inhibition as PLD (10 mg/kg), and H&E staining confirmed the result. Conclusion: Cur SLNP was stable at low temperatures. Cur SLNP remained the inhibition ability for cancer cellsat low concentrations. SLNP could prolong Cur circulation time in the blood. PLD (4 mg/kg) + Cur SLNP and PLD (10 mg/kg) had similar effectiveness for tumor growth inhibition. The results indicated that Cur SLNP could be used to assist antitumor nanodrug to inhibit tumor growth.