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

Abstract

Hepatocellular carcinoma (HCC) is the second most lethal tumor, with a 5-year survival rate of 18%. Early stage HCC is potentially treatable by therapies with curative intent, whereas chemoembolization/radioembolization and systemic therapies are the only therapeutic options for intermediate or advanced HCC. Drug resistance is a critical obstacle in the treatment of HCC that could be overcome by the use of targeted nanoparticle-based therapies directed towards specific tumor-associated antigens (TAAs) to improve drug delivery. Glypican 3 (GPC3) is a member of the glypican family, heparan sulfate proteoglycans bound to the cell surface via a glycosylphosphatidylinositol anchor. The high levels of GPC3 detected in HCC and the absence or very low levels in normal and non-malignant liver make GPC3 a promising TAA candidate for targeted nanoparticle-based therapies. The use of nanoparticles conjugated with anti-GPC3 agents may improve drug delivery, leading to a reduction in severe side effects caused by chemotherapy and increased drug release at the tumor site. In this review, we describe the main clinical features of HCC and the common treatment approaches. We propose the proteoglycan GPC3 as a useful TAA for targeted therapies. Finally, we describe nanotechnology approaches for anti-GPC3 drug delivery systems based on NPs for HCC treatment.

Keywords: drug delivery; glypican 3; hepatocellular carcinoma; nanomedicine; polymeric nanoparticles; targeted therapy.

Figure 1

HCC pathogenesis. Chronic liver diseases involve changes leading from a normal and healthy liver to a state of cirrhosis presenting inflammatory damage and fibrotic tissue. The continuous inflammation caused by cirrhosis produces somatic genomic alterations and epigenetic mutations, which progress to HCC. HCC cells present an increased nuclear-to-cytoplasm ratio. Furthermore, HCC is characterized by several alterations in the proliferation pathways, protein expression and folding, and oxidative stress.

Figure 2

Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy. The scheme shows the classification of HCC and the possible treatments for each stage. Figure based on the BCLC group guidelines of 2022.

Figure 3

Glypican 3 structure. GPC3 protein presents a structure that similar to the other glypicans. A cleavage site for furin-like convertases is localized between Arg358 and Ser359. Once cleaved, two subunits are formed, bound to each other by a single disulfide bond. In the N-terminal subunit, there is the N-terminal secretory signal peptide while at the C-terminal subunit, there are two sites for the insertion of the HS chains at Ser495 and Ser509 and a GPI anchor at the end.

Figure 4

Types of targeting in a drug delivery approach using NPs. (a) Leaky and fenestrated vasculature allows the NPs to leave blood circulation and reach the tumor site by passive targeting. (b) Active targeting relies on the presence of ligands on the NPs surface, which interact with their TAA, increasing NPs’ specificity.