Hyaluronated and PEGylated Liposomes as a Potential Drug-Delivery Strategy to Specifically Target Liver Cancer and Inflammatory Cells

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is characterized by poor clinical outcomes, with the majority of patients not being eligible for curative therapy and treatments only being applicable for early-stage tumors. CD44 is a receptor for hyaluronic acid (HA) and is involved in HCC progression. The aim of this work is to propose HA- and PEGylated-liposomes as promising approaches for the treatment of HCC. It has been found, in this work, that CD44 transcripts are up-regulated in HCC patients, as well as in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Cell culture experiments indicate that HA-liposomes are more rapidly and significantly internalized by Huh7 cells that over-express CD44, compared with HepG2 cells that express low levels of the receptor, in which the uptake seems due to endocytic events. By contrast, human and murine macrophage cell lines (THP-1, RAW264.7) show improved and rapid uptake of PEG-modified liposomes without the involvement of the CD44. Moreover, the internalization of PEG-modified liposomes seems to induce polarization of THP1 towards the M1 phenotype. In conclusion, data reported in this study indicate that this strategy can be proposed as an alternative for drug delivery and one that dually and specifically targets liver cancer cells and infiltrating tumor macrophages in order to counteract two crucial aspect of HCC progression.

Freeze Drying of Polymer Nanoparticles and Liposomes Exploiting Different Saccharide-Based Approaches

“…Since it is highly hydrophilic, HA (4.8 kDa or 14.8 kDa) was linked to the DPPE phospholipid, which is able to associate with a polymer matrix or phospholipid bilayer and obtain HA-coated nanoparticles. These conjugates have already been used in several settings to prepare HA-decorated liposomes for cell targeting that have been proposed for either intravenous or cutaneous administration [ 47 , 48 , 49 , 50 ]. For PLGA nanoparticles, HA-DPPE conjugates were added into the aqueous phase since they are not soluble in acetone, while for liposomes, conjugates were added during the hydration of the lipid film.…”

Advances of Nanotechnology in the Diagnosis and Treatment of Hepatocellular Carcinoma

“…Furthermore, they report that dosing doxorubicin in liposomal form decreases resistance to doxorubicin due to the downregulation of MDR1 expression by targeting AEG-1 [81]. On the other hand, Cannito S. et al prepared nanolipids with diameters between 165 and 225 nm using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol (CHOL), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (mPEG2000-DSPE, PEG) (55:40:2 molar ratio) or only DSPC/CHOL [83]. These were decorated with hyaluronic acid (HA) because it binds to the N-terminal CD44 protein, which has been observed to be increased in patients with HCC.…”

Liver Cell Type-Specific Targeting by Nanoformulations for Therapeutic Applications

“…Two intravenous injections of anti-collagen 1-specific siRNA-loaded nanohydrogel particles (2 mg/kg siRNA) reduced the hepatic collagen load to the levels of healthy control mice [97,98]. N-acetylgalactosamine [106-108] CD44 [109] Hyaluronic acid [110][111][112] CXC motif chemokine receptor 4 (CXCR4) [113] CTCE-9908 peptide [102]…”