Development of Liposomal Vesicles for Osimertinib Delivery to EGFR Mutation-Positive Lung Cancer Cells.
Development of Liposomal Vesicles for Osimertinib Delivery to EGFR Mutation-Positive Lung Cancer Cells.
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Osimertinib向EGFR突变阳性肺癌细胞输送脂质体的研制
DOI：
10.3390/pharmaceutics12100939
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发表时间：
2020-09-30
期刊：
影响因子：
5.4
通讯作者：
Minko T
中科院分区：
文献类型：
--
作者：
Skupin-Mrugalska P;Minko T
奥希替尼（OSI，AZD 9291）是第三代表皮生长因子受体（EGFR）的不可逆酪氨酸激酶抑制剂（TKI），可选择性抑制EGFR-TKI致敏突变和EGFR T790 M耐药突变。OSI已被批准作为EGFR突变型肺癌和转移性EGFR T790 M突变型非小细胞肺癌的一线治疗。基于脂质体的OSI递送可以提供一种新的药物制剂，可以通过替代递送途径（静脉内、吸入）给药。在这份手稿中，我们报告的第一次开发和表征的脂质体OSI制剂的直径约。115 nm。囊泡由具有不同饱和度和碳链长度的磷脂酰胆碱、胆固醇和聚乙二醇化磷酸乙醇胺组成。脂质体被动加载OSI，导致药物溶解在磷脂基质中，或通过远程加载主动加载，导致在脂质体核心中形成OSI沉淀。远程装载的脂质体的特征在于接近100%的包封效率，并代表了OSI的储库。被动加载囊泡释放OSI的Peppas-Sahlin模型，在一个机制相结合的药物扩散和脂质体松弛。与游离OSI相比，由1-α-磷脂酰胆碱（egg-PC）组成的载OSI脂质体对EGFR T790 M耐药突变（H-1975）的非小细胞肺癌细胞显示出更高的毒性。开发的OSI制剂在没有EGFR突变的健康肺上皮细胞（MRC-5）中未显示出体外抗增殖活性。
Osimertinib (OSI, AZD9291), is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. OSI has been approved as a first-line treatment of EGFR-mutant lung cancer and for metastatic EGFR T790M-mutant non-small cell lung cancer. Liposome-based delivery of OSI can provide a new formulation of the drug that can be administered via alternative delivery routes (intravenous, inhalation). In this manuscript, we report for the first time development and characterization of liposomal OSI formulations with diameters of ca. 115 nm. Vesicles were composed of phosphatidylcholines with various saturation and carbon chain lengths, cholesterol and pegylated phosphoethanolamine. Liposomes were loaded with OSI passively, resulting in a drug being dissolved in the phospholipid matrix or actively via remote-loading leading to the formation of OSI precipitate in the liposomal core. Remotely loaded liposomes were characterized by nearly 100% entrapment efficacy and represent a depot of OSI. Passively-loaded vesicles released OSI following the Peppas-Sahlin model, in a mechanism combining drug diffusion and liposome relaxation. OSI-loaded liposomes composed of l-α-phosphatidylcholine (egg-PC) demonstrated a higher toxicity in non-small lung cancer cells with EGFR T790M resistance mutation (H-1975) when compared with free OSI. Developed OSI formulations did not show antiproliferative activity in vitro in healthy lung epithelial cells (MRC-5) without the EGFR mutation.
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