溫度和酸鹼應答型固態脂質奈米粒子包覆mitoxantrone之製備及性質探討

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溫度和酸鹼應答型固態脂質奈米粒子包覆mitoxantrone之製備及性質探討

Preparation and characterization of temperature and pH responsive mitoxantrone-loaded solid lipid nanoparticles

羅秀玉 , Masters　　Advisor：邱信程　　Co-advisor ：呂瑞梅

繁體中文

固態脂質奈米粒子； mitoxantrone ；二次乳化法；癌症治療； solid lipid nanoparticles ； mitoxantrone ； double emulsion ； cancer therapy

Abstract │ Reference (53) │ Altmetrics

Abstract 〈TOP〉

本研究主要探討以固態脂質(trilaurin)為基材製備成固態脂質奈米粒子(solid lipid nanoparticle, SLN)，探討其製備方法、物理性質及藥物釋放行為。利用二次乳化法製備包覆親水性抗癌藥物-mitoxantrone之SLN，實驗結果顯示，配方中添加1,2-Dipalmitoyl-sn-glycero-3-phosphorylglycerol (DPPG)和lauric acid sodium salt負電荷之脂質，利用正負電荷相吸的原理，可將mitoxantrone包覆於SLN內。DPPG配方之平均粒徑範圍為164~190 nm，lauric acid sodium salt配方之平均粒徑範圍為220~250 nm。DPPG配方之包覆率大於90%以上，lauric acid sodium salt配方之包覆率為60%。於DPPG配方中添加d-α-Tocopheryl Polyethylene glycol succinate (TPGS)，可以降低配方粒徑20 nm，但是同時也降低藥物包覆率5~10 %。藉由表面電位分析儀發現製備之奈米粒子表面均帶有負電荷，DPPG配方具有強的負電荷(-38.5 mV)，在添加TPGS的配方中，同時也具有強的負電荷(-29.52 ~ -31.9 mV)，因此DPPG配方之間彼此具有高的排斥性而不易聚集發生粒徑變大現象，配方貯存於4℃下經過35天仍保持良好的穩定性。在lauric acid sodium salt配方表面電荷為-4.51 mV，因此容易發生聚集而使粒徑變大，甚至發生沉澱的現象。經由DSC的熱性質分析得知，各配方之熔點會較trilaurin之熔點低2~3 ℃，而且波峰會變的較寬，此現象是因為配方中具有多種材料所組成，經過吸熱的熔化過程所產生的相變化情形將會與trilaurin不同，而造成熔點會有差異。利用穿透式電子顯微鏡發現TD、TDT6和TDT12配方之SLN均為實心圓球狀。
在藥物釋放實驗中，藉由不同溫度(25oC~50oC)和不同pH值(pH2.2~pH7.4)的調控觀察藥物釋放行為。DPPG配方加熱至50oC於pH2.2釋放環境中，經過三天後可達100%釋放量，而lauric acid sodium salt配方加熱至50oC於pH5緩衝溶液，經過2小時即可達100%釋放量。當釋放環境的pH低於負電荷脂質之pKa時，負電荷脂質與mitoxantrone所形成的複合物會於此時解離，即可將mitoxantrone釋放出來。在高於pKa的環境下，mitoxantrone所形成緊密的複合物，造成釋放速率變緩慢，此時會隨著溫度增加而增加藥物釋放速率。於配方中添加TPGS有助於藥物的溶解度，因而可促進藥物釋放速率。
綜合以上SLN包覆mitoxantrone藥物的實驗結果發現，利用正負電荷相吸的原理，可以將親水性mitoxantrone藥物利用二次乳化法包覆於SLN，此SLN載體同時具有酸鹼和溫度應答性，SLN將有潛力作為mitoxantrone藥物傳送的載體，未來將可應用於癌症治療等領域。

Parallel Abstract 〈TOP〉

Aim of this study was to investigate the influence of the preparation, physical characterizations and drug release profiles on the solid lipid nanoparticles (SLN) prepared using trilaurin as the principal material. A hydrophilic drug, mitoxantrone-loaded SLNs were prepared by double emulsion (w/o/w) method. The addition of negative charged lipid, such as 1,2-Dipalmitoyl-sn-glycero-3-phosphorylglycerol (DPPG) and lauric acid sodium salt which using of positive and negative charge of the principle of attraction, mitoxantrone could be loaded in the SLN. The mean particle size of DPPG formula was between 164 and 190 nm and then lauric acid sodium salt formula was between 220 and 250 nm. The encapsulation efficiency of DPPG formula was above 90% and then lauric acid sodium salt formula was 60%. Additionally, the surface of the particles could be modified through the incorporation of d-α-Tocopheryl Polyethylene glycol succinate (TPGS) into the formulation. TPGS could decrease the formulation particle size but also decrease encapsulation efficiency. Zeta potential of DPPG formula was -38.5 mV by the zeta potential analyzer. The negative charge could give the particles more stable. DPPG formaula had good stability after 35 days at 4oC. Zeta potential of lauric acid sodium salt formula was -4.51 mV by the zeta potential analyzer. The lower zeta potential could occur aggregation. The result of DSC analysis, the melting point of SLN formula could decrease 2 and 3 oC and the peak became more borad. This was because the formulations composed of a variety of materials, the endothermic process of formulations phase change would be different trilaurin, there would be differences caused by the melting point. The morphology of TD, TDT6 and TDT12 formula were solid and spherical shape by using the transmission electron microscope. 
In the drug release experiments, the DPPG formula could reach 100% release content after 3 days at 50oC and pH2.2 relase medium. The lauric acid sodium salt formula could reach 100% release content after 2 hours at 50 oC and pH5 release medium. Controlled release with pH and temperature from DPPG and lauric acid sodium salt formulas could be explained the pKa of different function groups were main effect on the release profile. The negative charge lipids were protonated, the mitoxantrone-lipid complex were dissociated that it could be improve release rate. Higher than the pKa of the lipid in the relase medium, mitoxantrone integrated with negative charge lipids closely, caused slow release rate, at this condition as the temperature increased the rate of drug release increased. In addition, TPGS could improve solubility of drug that would enhance drug release rate. These results demonstrated mitoxantrone-loaded solid lipid nanoparticles had pH and temperature responsive. The mitoxantrone-loaded solid lipid nanoparticles would have potential for cancer therapy combine with hyperthermia.

Reference ( 53 ) 〈TOP〉

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