Targeted degradation of KRAS protein in non‐small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles

Abstract

AbstractThe role of KRAS mutation in non‐small cell lung cancer (NSCLC) initiation and progression is well‐established. However, “undruggable” KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis‐targeting chimeras (PROTACs) have become a cutting‐edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC‐2 (LC‐2 LPs). Precise surface modifications using cell‐penetrating peptide R8 yielded R8‐LC‐2 liposomes (R8‐LC‐2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8‐LC‐2 LPs depended on concentration and time, showcasing the superior performance of R8‐LC‐2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE‐PEG2000 to prolong the circulation time of LC‐2, leading to higher plasma concentrations compared to free LC‐2. In vivo antitumor efficacy research underscored the remarkable ability of R8‐LC‐2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the “undruggable” KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.