Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo

Abstract

At present, no satisfactory anti‐liver fibrosis drugs have been used clinically due to the poor targeting ability and short half‐life period. This study aimed to explore the effects of a new TRAIL ( TNF ‐related apoptosis‐inducing ligand) preparation that can target aHSC s (activated hepatic stellate cells) on liver fibrosis and explain the possible underlying mechanism. Using our self‐made drug carrier pPB ‐ SSL that specifically targets aHSC s, recombinant human TRAIL (rh TRAIL ) protein was embedded in (named as pPB ‐ SSL ‐ TRAIL ) and applied to treat liver fibrotic mice as well as 3T3 fibroblast cells and aHSC s. Through in vitro and in vivo experiments, we found that, compared with the groups treated with TRAIL (free rh TRAIL ) and SSL ‐ TRAIL (rh TRAIL capsulated within unmodified liposome), the group treated with pPB ‐ SSL ‐ TRAIL nanoparticles showed significantly lower cell viability and higher cell apoptosis in vitro. The targeting delivering system pPB ‐ SSL also significantly enhanced the anti‐fibrotic effect, apoptosis induction and long circulation of rh TRAIL . After the treatment with pPB ‐ SSL ‐ TRAIL , apoptosis of aHSC s was notably increased and hepatic fibrosis in mice was remarkably alleviated. In vitro, pPB ‐ SSL ‐ TRAIL nanoparticles were mainly transported and located on membrane or into cytoplasm, but the particles were distributed mainly in mouse fibrotic liver and most on the cell membrane of aHSC s. In conclusion, rh TRAIL carried by pPB ‐ SSL delivering system has prolonged circulation in blood, be able to target aHSC s specifically, and alleviate fibrosis both in vitro and in vivo. It presents promising prospect in the therapy of liver fibrosis, and it is worthwhile for us to develop it for clinical use.

Antibody-drug conjugates targeting CD248 inhibits liver fibrosis through specific killing on myofibroblasts

“…Recently, it was found that resistance of myofibroblasts to apoptosis played a critical role in fibrotic diseases, and the induction of apoptosis in myofibroblasts could be an effective strategy to alleviate liver fibrosis (Hinz and Lagares 2020 ; Li et al 2019 , 2020 ; Oh et al 2016 ). In addition, Aghajanian et al ( 2019 ) reported that cardiac fibrosis could be alleviated through specific killing of activated cardiac fibroblasts by FAP-specific CAR T cells, indicating that specific killing of activated fibroblasts could also be an effective way to inhibit tissue fibrosis.…”

Antibody‐drug conjugates targeting CD248+myofibroblasts effectively alleviate renal fibrosis in mice

“…To induce specific cell killing, besides inducing apoptosis by nanoparticle 35,36 or liposomes 28 and CAR-T cellmediated cell killing, ADCs are also a highly specific and effective strategy because of the high binding affinity and specificity of the antibody. 37,38 Generally speaking, ADC is composed of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker.…”

Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics

“…The platelet-derived growth factor receptor beta (PDGFR-beta) on the surface of HSCs is recognized by the cyclic peptide known as the pPB, which may also recognize vitamin A. In a study, pPB-altered liposomes were used to convert recombinant human tumor necrosis factor-related cell apoptosis-inspired ligands to the HSC surface membrane, maintaining recombinant human-TNF-related apoptosis-inspired ligands circulation in living organisms and reducing fibrosis in both vitro and vivo [ 90 ]. Likewise, CXCR4 antagonist AMD3100 has the potential to attack HSCs.…”