Development of Liposomal Vesicles for Osimertinib Delivery to EGFR Mutation—Positive Lung Cancer Cells

Paulina Skupin-Mrugalska,Tamara Minko

doi:10.3390/pharmaceutics12100939

Abstract

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.

Highlights

For several decades, lung cancer has been the most common cancer worldwide and has been accounted for the most common cause of cancer-related deaths [1,2]
The ultimate goal of the presented study was the development of a liposome-based carrier capable of delivering a novel tyrosine kinase inhibitor (TKI), osimertinib
TKIs comprise a large group of therapeutic compounds that have revolutionized anticancer therapy, leading to personalized treatment based on molecular profiling [4,5]

Summary

Introduction

Lung cancer has been the most common cancer worldwide and has been accounted for the most common cause of cancer-related deaths [1,2]. Genetic and molecular profiling of NSCLC has led to the discovery of molecular alterations that drive tumor initiation and progression [4]. EGFR mutations were the first molecular alterations in NSCLC, discovered in 2004 [7], and they occur in 10–28% of NSCLC patients [8]. In response to the discoveries at a molecular level, drugs targeting the EGFR pathway, tyrosine kinase inhibitors (TKIs) have been developed and shown clinical benefits. First-generation (gefitinib and erlotinib) and second-generation (afatinib) TKIs demonstrated superior progression-free survival, objective response rate, and quality of life compared to standard chemotherapy in patients whose tumors harbored canonical activating EGFR mutations [9,10,11]. Third-generation inhibitors were created to target the T790M mutations while maintaining activity against the original exon19del and L858R mutations [6]

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Conclusion