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Cancer-multidrug resistance (MDR) is recognized as one of the barriers to the treatment of advanced hepatocellular carcinoma (HCC). We aim to inhibit ABCB1 overexpression observed in HCC-MDR phenotypes with N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotides (ASOs). In this study, three ASOs (GalNAc-ASO1, GalNAc-ASO2, and GalNAc-ASO3) targeting ABCB1 mRNA and a scrambled-negative control (GalNAc-ASO4) were designed. Simulations of molecular docking were performed to determine the inhibitory efficacy of ASOs. GalNAc C3 phosphoramide ligand was added to the 5′‑end of the ASO sequences, and phosphorothioate modifications were added to the DNA backbone. HepG2 cells were directly treated with different doses of GalNAc-ASOs conjugates. To evaluate the inhibitory effect of GalNAc-ASOs conjugates, the protein level of ABCB1 was measured by western blotting. The cell viability assays of GalNAc-ASO4 conjugates on HepG2 were evaluated by colorimetric-MTT and fluorometric-resazurin assays. Varying scrambled-negative control concentrations were applied to HepG2 for assessment of the cytotoxic effect of GalNAc-ASO4 conjugates, and it had no cytotoxic effect on cell viability up to 144 h. GalNAc-ASOs concentrations reducing ABCB1 protein expression after 72 h were detected by western blot. ASOs conjugated with the GalNAc ligand, which specifically targets the liver by binding to asialoglycoprotein receptors in hepatocyte cells, have the potential to increase the effect of anti-cancer therapies by reducing ABCB1 protein expression through gymnotic delivery to cells. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, typically diagnosed in advanced stages. Chemotherapy is necessary for treating advanced liver cancer; however, several challenges affect its effectiveness. These challenges include low specificity, high dosage requirements, high systemic toxicity and severe side effects, which significantly limit the efficacy of chemotherapy. These limitations can hinder the treatment of HCC. This review focuses on the prevalence of HCC, different types of liver cancer and the staging of the disease, along with available treatment methods. Additionally, explores recent and relevant studies on smart drug- and gene-delivery systems specifically designed for HCC. These systems include targeted endogenous and exogenous stimuli-responsive platforms. Liver cancer is the third leading cause of cancer deaths in the world that is usually diagnosed in the last stages. Chemotherapy is commonly used to treat advanced liver cancer, but it faces several challenges that reduce its effectiveness. These challenges include low specificity (not targeting cancer cells specifically), high dosage requirements and side effects that can affect anywhere in the body. As a result, the efficacy of chemotherapy is significantly limited, making it difficult to treat liver cancer. This review discusses the prevalence of liver cancer, different types of liver cancer and how the disease is staged. It also explores various treatment methods available for liver cancer. Furthermore, the article explores recent and relevant studies on smart drug- and gene-delivery systems that are specifically designed to target liver cancer. These systems include platforms that respond to targeted and internal or external stimuli. They aim to improve the effectiveness of treatment for liver cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Asialoglycoprotein receptors (ASGPRs) are highly expressed on hepatocytes and have been used for liver-targeted delivery and hepatocellular carcinoma (HCC) therapy. However, targeted delivery of bortezomib (BTZ) to HCC has not been reported. In this study, N-stearyl lactobionamide (N-SALB) with galactose (Gal) moiety was synthesized as a targeting agent and its structure was confirmed by FT-IR and NMR analyses. N-SALB surface-modified solid lipid nanoparticles (SLNs) loaded with BTZ (Gal-SLNs/BTZ) were developed to target BTZ delivery into HCC cancer cells. The Gal-SLNs/BTZ had an average particle size of 116.3 nm, polydispersity index (PDI) of 0.210, and zeta potential of −13.8 mV. TEM analysis showed their nanometer-sized spherical morphology. The encapsulation efficiency (EE) and drug loading (DL) capacity were 84.5 % and 1.16 %, respectively. Release studies showed that BTZ loaded inside the SLNs was slowly released over a period of 72 h at pH 7.4. Flow cytometry analysis showed significantly higher intracellular uptake of N-SALB-targeted nanoparticles than non-targeted nanoparticles in HepG2 cells. All lipid formulations showed good biocompatibility in the cytotoxicity study using MTT assay. Concentration-dependent cytotoxicity was observed for all formulations, with N-SALB-targeted nanoparticles demonstrating more cytotoxicity against HepG2 cells. The highest percentage of apoptosis was obtained for N-SALB-targeted nanoparticles compared to non-targeted nanoparticles (42.2 % and 8.70 %, respectively). Finally, biodistribution studies in HepG2 bearing nude mice showed that the accumulation of targeted nanoparticles in the tumor was significantly higher than non-targeted nanoparticles. [ABSTRACT FROM AUTHOR]

[Display omitted] For specific targeting of cancer tissues, adequate information about the cancer tissue environment, cancer cell pathology, and available methods and limits of such methods is essentially required. It is already been established that cancer cells express certain receptors, that distinct them from non-cancerous cells. Since past decades, extensive research is on-going for targeting cancer cells via certain ligands that act specifically at such over-expressed receptors. Galactose is one such ligand that is being explored as for targeting different types of cancer cells, especially hepatic cells since they express asialoglycoprotein receptors that have great affinity towards galactose. So different nano-carriers such as micelles, polymeric nanoparticles, SLN, liposomes etc are being modified with galactose to provide specific targeting effect. Also, given that tumor cells show "Warburg effect" that leads to high carbohydrates uptake by tumor cells, galactosylated nano-carriers are taken up by the tumor cells, where the nano-carriers are released, further liberating the therapeutic agent that then shows anti-tumor effect, particularly at the site of action. This article discusses about the development of galactose-modified nano-carriers for drug, gene delivery and galactosylated fluroscent probes for detection of sulphur, nitrogen, oxygen in cancer cells. Also, a brief introduction to the mechanism of cancer cell targeting and receptor-ligand theory has been included. [ABSTRACT FROM AUTHOR]

Peptide nucleic acids (PNAs) are used/applied in various studies to target genomic DNA and RNA to modulate gene expression. Non-specific targeting and rapid elimination always remain a challenge for PNA-based applications. Here, the synthesis, characterization, in vitro and in vivo study of di lactobionic acid (diLBA) and tris N-acetyl galactosamine (tGalNAc) conjugated PNAs for liver-targeted delivery are reported. For proof of concept, diLBA, and tGalNAc conjugated PNAs (anti-miR-122 PNAs) were synthesized to target microRNA-122 (miR-122) which is over-expressed in the hepatic tissue. Different lengths of anti-miR-122 PNAs conjugated with diLBA and tGalNAc are tested. Cell culture and in vivo analyses to determine biodistribution, efficacy, and toxicity profile are performed. This work indicates that diLBA conjugates show significant retention in hepatocytes in addition to tGalNAc conjugates after in vivo delivery. Full-length PNA conjugates show significant downregulation of miR-122 levels and subsequent de-repression of its downstream targets with no evidence of toxicity. The results provide a robust framework for ligand-conjugated delivery systems for PNAs that can be explored for broader biomedical applications., (© 2023 Wiley-VCH GmbH.)

[Display omitted] • The relationship between the hydrophile–lipophile balance of the linker in Gal/GalNAc ligands and affinity for ASGPR was explored. • Novel GalNAc ligands targeting ASGPR were synthesized by enzymatic catalysis. • The novel GalNAc ligands displayed significant ASGPR recognition efficiency. • Molecular-dynamics simulations were used to acquire a comprehensive understanding of how Gal/GalNAc ligands behave within the liposome bilayer. In this study, we explored the effect of the hydrophile–lipophile balance (HLB) in the linker unit of Galactose (Gal)/N-acetylgalactosamine (GalNAc) ligands on their affinity toward asialoglycoprotein receptors (ASGPRs). Two Gal/GalNAc ligands with lipophilic linkers—{(5-cholesten-3b-ol)[(2-acetamido-2-deoxy-d-galactopyranose-6-o)sebacate]} (CHS-6-GalNAc) and {(5-cholesten-3b-ol)[(d-galactopyranose-6-o)sebacate]} (CHS-6-Gal)—and two with hydrophilic linkers—{(5-cholesten-yl)[(4-O-b-D-galactopyranosyl)-D-glucitol-6-yl]sebacate} (CHS-1-Gal) and {(5-cholesten-3a-ol)[(2-acetamido-2-deoxy-d-galactopyranose-6-o)3,6-dioxa-octanedioate]} (CHS-PEG 2 -6-GalNAc)—were synthesized by enzymatic catalysis. Compared with unmodified liposomes, all Gal/GalNAc ligand–modified liposomes showed higher efficiency toward the hepatocyte target as evaluated by weighted-average overall drug-targeting efficiency (Te*) in vivo and HepG2 cell uptake efficiency in vitro. The ligands containing linkers with high HLB values (i.e. , CHS-PEG 2 -6-GalNAc and CHS-1-Gal) exhibited higher ASGPR affinity than those containing linkers with low HLB values (i.e. , CHS-6-GalNAc and CHS-6-Gal). We used molecular-dynamics (MD) simulations to investigate the structure–activity relationship between the HLB value of the linker in a ligand and ASGPR affinity. MD simulation results indicated that a Gal/GalNAc ligand with a more hydrophilic linker (i.e. , higher HLB value) unit tended to have a higher solvent-accessible surface area (SASA), leading to lower steric hindrance for effective ASGPR recognition. The results of this study will provide an improved design for Gal/GalNAc ligand–based surface-modified liposomes with high ASGPR affinity. [ABSTRACT FROM AUTHOR]

Hepcidin, a key regulator of iron homeostasis, has been implicated in the pathogenesis of various iron-related diseases. Although small interfering RNA (siRNA) are potent to modulate the expression of hepcidin, their bioavailability remains a major issue. The β-galactopyranoside-conjugated liposomes (GAL-liposome) targeting liver synthesized hepcidin were prepared by thin lipid film hydration method to encapsulate siRNA and the conjugation of β-galactopyranoside to the lipid nanocarrier was achieved by covalent chemistry. The prepared siRNA loaded GAL-lip were spherical with around 50 nm radius in size as observed by HR-TEM. The zeta potential and polydispersity index of the prepared liposomes were − 19.9 ± 0.96 mV and 0.44 ± 0.05, respectively. The encapsulation efficiency as determined by dialysis bag method was around 91.76 ± 1.74%. The cell viability and cellular uptake analysis was examined in HepG2 cells by MTT assay and flow cytometry, respectively. The stability and cumulative release of siRNA was also assessed. The hepcidin mRNA expression on administration of siRNA loaded GAL-lip was determined in HepG2 cells and in lipopolysaccharide-induced mice model followed by examining itsin vivo biodistribution by fluorescence microscopy. The results suggested thatsiRNA loaded GAL-lip reduced the hepcidin levels, thus, highlighting a novel ligand conjugated ionizable lipid-based nanocarrier for inducing RNA interference. • An ionizable lipid-based nanocarrier was prepared by combination of thin lipid film hydration method and extrusion technique. • The actual size as observed by HR-TEM was around 50 nm radius with release of 97% of siRNA from the lipid shield in 24 h at pH 5.5. • The prepared siRNA GAL-lip served as a potent delivery vehicle for efficiently delivering and suppressing the hepcidin levels. [ABSTRACT FROM AUTHOR]