Skupin-Mrugalska Paulina, Minko Tamara
Department of Inorganic & Analytical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers: The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Pharmaceutics. 2020 Sep 30;12(10):939. doi: 10.3390/pharmaceutics12100939.
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.
奥希替尼（OSI，AZD9291）是一种第三代不可逆的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），可选择性抑制EGFR-TKI敏感突变和EGFR T790M耐药突变。奥希替尼已被批准作为EGFR突变型肺癌的一线治疗药物，以及用于转移性EGFR T790M突变的非小细胞肺癌。基于脂质体的奥希替尼递送可以提供一种新的药物制剂，该制剂可以通过替代给药途径（静脉内、吸入）给药。在本手稿中，我们首次报道了直径约为115 nm的脂质体奥希替尼制剂的开发和表征。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。脂质体通过被动方式装载奥希替尼，使药物溶解在磷脂基质中，或通过远程装载的主动方式，导致奥希替尼沉淀在脂质体核心中形成。远程装载的脂质体具有近100%的包封率，是奥希替尼的一个储存库。被动装载的囊泡按照Peppas-Sahlin模型释放奥希替尼，其机制是药物扩散和脂质体松弛相结合。与游离奥希替尼相比，由l-α-磷脂酰胆碱（鸡蛋PC）组成的载奥希替尼脂质体在具有EGFR T790M耐药突变的非小肺癌细胞（H-1975）中表现出更高的毒性。所开发的奥希替尼制剂在没有EGFR突变的健康肺上皮细胞（MRC-5）中体外未显示抗增殖活性。
