Dihydroartemisinin (DHA) is one of the main derivatives of artemisinin, which is a sesquiterpene lactones compound containing the specific endoperoxide bridge isolated from the traditional Chinese herb Artemisia annua L. It has been reported that DHA possesses a serious of pharmacological activities including anti-malaria, antitumor, antiviral and immunosuppression. Despite its well-known pharmacological activities, the poor solubility in water and fast clearance in the body, all of these lead to the delivery problem. The aim of this study was to develop a sustained-release nanoparticles loaded with a low lipophilic and poorly water-soluble drug dihydroartemisinin (DHA) encapsulated in the biodegradable poly (lactic-co-glycolic acid) (PLGA), where phospholipid was employed to improve the lipophilicity of DHA and encapsulation efficiency. Initially, a formulation consisting of 1 mg/mL drug, phospholipid/DHA at 8.5:1 weight ratio with reaction temperature of 55 ºC was optimized by Box-Behnken Design (BBD) response surface method. Then DHA-phospholipid complex-nanoparticles (DHAPLC-NPs) with the spherical shape were prepared by solvent evaporation method with the particle size, zeta potential, entrapment efficiency and drug loading of (265.3±7.9) nm, (-21.4±6.3) mV, (74.2±6.5)% and (2.80±0.35)%, respectively. However, no stable nanoparticles could be formed without including phospholipid in the formulation. Compared to the rapid released free form, DHA was sustain-released from the nanoparticles up to 1 week. DHA-PLC-NPs presented stronger cell proliferation inhibition in vitro compared with those treatments with DHA alone as evidenced by both MTT assay and morphological observation. Moreover, much more apoptotic cells were induced after NPs treatment (p<0.05). In conclusion, DHA has been successfully encapsulated in PLGA nanoparticles by solvent evaporation method using phospholipid complex as a helpful intermediate to improve lipophilicity of drug and therefore to enhance encapsulation efficiency. Formation of the phospholipid complex as the intermediate to be encapsulated in the polymeric nanoparticles may be a promising delivery system to enhance the encapsulation efficiency for drugs with low lipophilicity and poor water-solubility.

雙氫青蒿素（DHA）是青蒿素的一種主要衍生物，是從傳統中藥材青蒿中 提取的具有過氧橋的倍半萜內酯化合物。據報導，雙氫青蒿素具有包括抗瘧疾、 抗腫瘤、抗病毒和免疫抑制等多種藥理學活性。但是它本身比較差的水溶性和 快速的體內消除作用，給雙氫青蒿素的給藥系統帶來了不便。 本文的主要目的是針對脂溶性和水溶性都很差的藥物 DHA，設計一個有磷 脂複合物參與的，幫助 DHA 包裹進 PLGA 形成納米粒的緩釋系統。其中，磷 脂可以有效提高 DHA 的脂溶性，增加其包封率。首先，通過 Box-Behnken Design (BBD)響應面法設計優化出複合率最高的磷脂複合物，具體優化條件如 下：藥物濃度 1 mg/mL，藥物和磷脂的質量比為 1:8.5，反應溫度 55 ºC。之後 通過單因素考察法設計優化雙氫青蒿素納米粒的製備方案。最終通過溶劑蒸發 法製備的球形納米粒平均粒徑大小、PdI 值、zeta 電位、包封率和載藥量分別為 (265.3±7.9) nm, (0.244±0.003), (-21.4±6.3) mV, (74.2±6.5)% 和(2.80±0.35)%。在沒 有磷脂的幫助下，DHA 和 PLGA 是很難形成納米粒的。在體外釋放實驗中，相 比於 DHA 溶液的快速釋放，包裹在 PLGA 納米粒中的藥物呈現出一個長達一 周的緩慢釋放過程。最後考察了雙氫青蒿素納米粒在體外細胞中的藥理活性， MTT 實驗和形態學觀察都說明了納米粒中的 DHA 具有更強的抑制細胞增殖作 用，並且凋亡作用更強。 總而言之，磷脂複合物作為一個有效的中間體，成功地將 DHA 通過溶劑 蒸發法包裹進 PLGA。由於磷脂的幫助，藥物提高了自身的脂溶性進而提高了 與 PLGA 的親和力，更易於包裹進 PLGA 增加包封率。本研究通過闡明在磷脂 幫助下，藥物增加脂溶性進而包裹進聚合物形成納米粒的設計思路，為脂溶性 和水溶性都較低的藥物提供了一個有前景和參考價值的藥物遞送系統。 關鍵字：雙氫青蒿素、親脂性、磷脂複合物、PLGA 納米粒、包封率、凋亡