Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

Abstract Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment

Effect of PEG Pairing on the Efficiency of Cancer-Targeting Liposomes

Standardized poly(ethylene glycol)-modified (PEGylated) liposomes, which have been widely used in research as well as in pre-clinical and clinical studies, are typically constructed using PEG with a molecular weight of 2000 Da (PEG2000). Targeting ligands are also generally conjugated using various functionalized PEG2000. However, although standardized protocols have routinely used PEG2000, it is not because this molecular weight PEG has been optimized to enhance tumor uptake of nanoparticles. Herein, we investigated the effect of various PEG lipid pairings—that is, PEG lipids for targeting-ligand conjugation and PEG lipids for achieving 'stealth' function—on in vitro cancer cell- and in vivo tumor-targeting efficacy. A class of high-affinity peptides (aptides) specific to extra domain B of fibronectin (APTEDB) was used as a representative model for a cancer-targeting ligand. We synthesized a set of aptide-conjugated PEGylated phospholipids (APTEDB‑PEG2000‑DSPE and APTEDB‑PEG1000‑DSPE) and then paired them with methoxy-capped PEGylated phospholipids with diverse molecular weights (PEG2000, PEG1000, PEG550, and PEG350) to construct various aptide-conjugated PEGylated liposomes. The liposomes with APTEDB‑PEG2000/PEG1000 and APTEDB‑PEG1000/PEG550 pairings had the highest uptake in EDB-positive cancer cells. Furthermore, in a U87MG xenograft model, APTEDB‑PEG2000/PEG1000 liposomes retarded tumor growth to the greatest extent, followed closely by APTEDB‑PEG1000/PEG550 liposomes. Among the PEGylated liposomes tested, pairs in which the methoxy-capped PEG length was about half that of the targeting ligand-displaying PEG exhibited the best performance, suggesting that PEG pairing is a key consideration in the design of drug-delivery vehicles