Leveraging growth factor induced macropinocytosis for targeted treatment of lung cancer

Abstract

Targeted therapy focused on highly expressed growth factor receptors is increasingly becoming popular for the treatment of lung cancer. Cancer cells exhibit higher levels of macropinocytosis than the normally quiescent non-cancerous cells, which can further be enhanced by growth factors. Here, we show the targeted enhancement of macropinocytosis in lung cancer cells for the delivery of the mitochondriotoxic peptide (KLAKLAK)2 using keratinocyte growth factor (KGF). We report the formation of a nanoparticle (NP) comprising of two chimeric fusion proteins, both fused to elastin-like polypeptide (ELP), (KLAKLAK)2-ELP and KGF-ELP. We show that (KLAKLAK)2-ELP nanoparticles are internalized via macropinocytosis and its internalization is facilitated by the interaction of the ELP domain with cell surface heparin sulfate proteoglycans. This internalization leads to mitochondrial depolarization and subsequent cell death. Also, we demonstrate that KGF-ELP selectively enhances macropinocytosis in cancer cells expressing high levels of the keratinocyte growth factor receptor (KGFR). Finally, the heterogeneous NPs consisting of (KLAKLAK)2-ELP and KGF-ELP selectively kill KGFR-expressing lung cancer cells. Hence, this multipronged approach of targeting highly active processes and receptors in cancer cells will be tremendously selective in the treatment of both early-stage and advanced-stage lung cancers, thereby improving patient's prognosis and survival rate.