Employing low-density lipoprotein-based delivery systems for the treatment of hepatocellular carcinoma

Circulating plasma low-density lipoprotein (LDL) is a natural nanoscale carrier designed to transport cholesterol throughout the body through specific receptor mediated processes. During malignant transformation, cancer cells upregulate their LDL receptors (LDLR) to scavenge LDL from their environments to support their rapid membrane turnover. This aberrant activity has prompted many research teams to investigate the potential of LDL as a drug carrier against cancer. In this article, we reviewed preclinical studies aimed at evaluating LDL-based nanoparticles for the treatment of hepatocellular carcinoma (HCC). Prior to assessing each research study, we examined the impact of chronic liver disease/cirrhosis and HCC progression on lipoprotein homeostasis, as well as the status of LDLR in these tissues. Various approaches have been used to functionalize LDL for drug delivery. These include: conjugation of cholesterol moieties to drug molecules for enhanced incorporation into LDL; development of LDL-nanoparticle hybrid formulation for increased drug versatility; and reconstitution of the apolar cholesterol core with alternative bioactive lipids. We highlight each of these LDL-based nanoconstructs, discussing their capacity to home to LDLR and induce cytotoxic effects against HCC. Concerns regarding the safety of these LDL nanomedicines in the diseased liver were raised and pathways for clinical translation are discussed.