Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2–9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.

Nanotechnology in the Diagnostic and Therapy of Hepatocellular Carcinoma

“…The ligand molecules that can be employed for active targeting are represented by biological (antibodies and enzymes) or pseudo-biological (aptamers and molecularly-imprinted polymers) elements, which can specifically recognize targets that are over-expressed on the surface of cancer cells. Such molecules can be represented by: P-selectin [ 55 ], serotonin 1 B and 2 B receptors, gamma-aminobutyric acid A receptors (theta subunit), epidermal growth factor (EGRF), fibroblast growth factor receptor 3 (FGRF3), somatostatin receptor, insulin receptor (present in two isoforms), prostaglandin E2, adeno-self receptors (A2b), insulin-like growth factor, asialoglycoprotein receptor 1 (ASGPR1) for galactosamine [ 56 ], folate receptor [ 56 ], transferrin receptor [ 56 ], AFP, glypcian-3 [ 56 ], and retinoic acid receptor-alpha. Specific delivery to the target using this method can reduce the systemic toxicity of active molecules as well as bypass chemotherapeutic resistance systems [ 57 ].…”

Novel Nanotechnology Approaches to Overcome Drug Resistance in the Treatment of Hepatocellular Carcinoma: Glypican 3 as a Useful Target for Innovative Therapies

“…In the HCC context, several proteins were identified as TAAs such as: AFP, new york esophageal squamous cell carcinoma-1 (NY-ESO-1), synovial sarcoma X breakpoint 2 (SSX-2), melanoma antigen gene (MAGE), midkine (MDK), hypoxia-inducible factor-1α and -2α (HIF-1α and HIF-2α), epithelial cell adhesion molecule (EpCAM), asialoglycoprotein receptor (ASGPR), transferrin receptor 1 (TfR1), folic acid receptor (FR), scavenger receptor class B type I (SR-B1), mucin-1 (MUC1), carcinoembryonic antigen (CEA), prostate-specific membrane antigen (PSMA), tumor endothelial marker 1 (TEM1), phosphatases of regenerating liver-1 and -3 (PRL-1 and PRL3), cluster of differentiation 147 (CD147), roundabout homolog 1 (ROBO1), programmed death-ligand 1 and 2 (PD-L1 and PD-L2), and GPC3 [ 38 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. AFP protein is detected during embryonic development, but its level decreased after birth.…”

“…ASGPR is a transmembrane protein made of two subunits: ASPGR1 and ASPGR2. It is abundant in hepatocytes and expressed in the sinusoidal and basolateral HCC cell membranes, showing an expression polarity and zonality [ 90 ]. A study performed on 177 HCC and 114 normal or non-cancerous liver samples showed that 75.2% and 88.2% of HCC and normal liver samples were ASGPR1 positive.…”

“…It is expressed universally among the different cell types and overexpressed in HCC. An increase in TfR1 positivity was detected from early tumor with well-differentiated histology to advanced HCC with poorly differentiated histology, with a 14.3% positivity in non-cancerous tissues [ 90 , 101 , 102 ]. FR is a GPI-anchored protein presenting two major isoforms: FR-α and FR-β.…”

“…The first is overexpressed in several cancers, including HCC, while the second is present in tumor-associated macrophages of different cancers, including liver cancer [ 90 , 103 ]. SR-B1 is part of lipoprotein receptors; it is able to bind cholesterol and it is expressed in many mammalian cells and tissues such as macrophages, intestine, endothelial cells, keratinocytes, smooth muscle cells, placenta, and adipocytes and it is widely present in hepatocytes and HCC [ 90 , 104 ]. MUC1 is a glycoprotein, which acts in the modulation of cell adhesion and metastasis.…”