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1.
RSC Med Chem ; 14(1): 56-64, 2023 Jan 25.
Article in English | MEDLINE | ID: mdl-36760736

ABSTRACT

Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipophilicity. Targeted delivery of statins to the liver is considered as a way to reduce unwanted side effects. Herein we report on synthesis and evaluation of atorvastatin conjugates targeting the galactose-specific hepatic asialoglycoprotein receptor (ASGPR). The prepared conjugates showed greater water solubility compared to unmodified atorvastatin. The synthesised compounds demonstrated potent binding to the ASGPR with submicromolar K D values. The conjugates with an amide bond connecting atorvastatin and the targeting moiety displayed the optimal stability under model conditions, as they underwent hydrolysis only when incubated with the intracellular protease. The hydrolysis products effectively inhibited HMG-R activity. The results suggest that the designed amide-based compounds have the potential to be further developed as orally administered prodrugs of atorvastatin.

2.
Bioconjug Chem ; 32(4): 763-781, 2021 04 21.
Article in English | MEDLINE | ID: mdl-33691403

ABSTRACT

Herein, we describe the design, synthesis, and biological evaluation of novel betulin and N-acetyl-d-galactosamine (GalNAc) glycoconjugates and suggest them as targeted agents against hepatocellular carcinoma. We prepared six conjugates derived via the C-3 and C-28 positions of betulin with one or two saccharide ligands. These molecules demonstrate high affinity to the asialoglycoprotein receptor (ASGPR) of hepatocytes assessed by in silico modeling and surface plasmon resonance tests. Cytotoxicity studies in vitro revealed a bivalent conjugate with moderate activity, selectivity of action, and cytostatic properties against hepatocellular carcinoma cells HepG2. An additional investigation confirmed the specific engagement with HepG2 cells by the enhanced generation of reactive oxygen species. Stability tests demonstrated its lability to acidic media and to intracellular enzymes. Therefore, the selected bivalent conjugate represents a new potential agent targeted against hepatocellular carcinoma. Further extensive studies of the cellular uptake in vitro and the real-time microdistribution in the murine liver in vivo for fluorescent dye-labeled analogue showed its selective internalization into hepatocytes due to the presence of GalNAc ligand in comparison with reference compounds. The betulin and GalNAc glycoconjugates can therefore be considered as a new strategy for developing therapeutic agents based on natural triterpenoids.


Subject(s)
Acetylgalactosamine/chemistry , Antineoplastic Agents/pharmacology , Asialoglycoprotein Receptor/drug effects , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Triterpenes/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Delivery Systems , Drug Discovery , Drug Screening Assays, Antitumor , Fluorescent Dyes/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Surface Plasmon Resonance
3.
Macromol Biosci ; 21(4): e2000371, 2021 04.
Article in English | MEDLINE | ID: mdl-33615675

ABSTRACT

Macrophages are desirable targets for gene therapy of cancer and other diseases. Cationic diblock copolymers of polyethylene glycol (PEG) and poly-L-lysine (PLL) or poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (pAsp(DET)) are synthesized and used to form polyplexes with a plasmid DNA (pDNA) that are decorated with mannose moieties, serving as the targeting ligands for the C type lectin receptors displayed at the surface of macrophages. The PEG-b-PLL copolymers are known for its cytotoxicity, so PEG-b-PLL-based polyplexes are cross-linked using reducible reagent dithiobis(succinimidyl propionate) (DSP). The cross-linked polyplexes display low toxicity to both mouse embryonic fibroblasts NIH/3T3 cell line and mouse bone marrow-derived macrophages (BMMΦ). In macrophages mannose-decorated polyplexes demonstrate an ≈8 times higher transfection efficiency. The cross-linking of the polyplexes decrease the toxicity, but the transfection enhancement is moderate. The PEG-b-pAsp(DET) copolymers display low toxicity with respect to the IC-21 murine macrophage cell line and are used for the production of non-cross-linked pDNA-contained polyplexes. The obtained mannose modified polyplexes exhibit ca. 500-times greater transfection activity in IC-21 macrophages compared to the mannose-free polyplexes. This result greatly exceeds the targeting gene transfer effects previously described using mannose receptor targeted non-viral gene delivery systems. These results suggest that Man-PEG-b-pAsp(DET)/pDNA polyplex is a potential vector for immune cells-based gene therapy.


Subject(s)
Cations , Gene Transfer Techniques , Macrophages/metabolism , Mannose/chemistry , Polyethylene Glycols/chemistry , Polylysine/chemistry , Polymers/chemistry , Animals , Aspartame/chemistry , Chromatography, Gel , Cross-Linking Reagents/chemistry , DNA/chemistry , Fibroblasts/metabolism , Humans , Ligands , Light , Magnetic Resonance Spectroscopy , Male , Mannose Receptor , Mice , Microscopy, Atomic Force , NIH 3T3 Cells , Plasmids/metabolism , Polyelectrolytes , Scattering, Radiation , Succinimides/chemistry
4.
Mol Pharm ; 18(1): 461-468, 2021 01 04.
Article in English | MEDLINE | ID: mdl-33264010

ABSTRACT

In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21-75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20-35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Docetaxel/administration & dosage , Glycoconjugates/administration & dosage , Liver Neoplasms/drug therapy , Small Molecule Libraries/administration & dosage , A549 Cells , Asialoglycoprotein Receptor/metabolism , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Drug Carriers/chemistry , HEK293 Cells , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Liver/drug effects , Liver Neoplasms/metabolism , PC-3 Cells
5.
Bioconjug Chem ; 31(5): 1313-1319, 2020 05 20.
Article in English | MEDLINE | ID: mdl-32379426

ABSTRACT

Since the asialoglycoprotein receptor (also known as the "Ashwell-Morell receptor" or ASGPR) was discovered as the first cellular mammalian lectin, numerous drug delivery systems have been developed and several gene delivery systems associated with multivalent ligands for liver disease targeting are undergoing clinical trials. The success of these systems has facilitated the further study of new ligands with comparable or higher affinity and less synthetic complexity. Herein, we designed two novel trivalent ligands based on the esterification of tris(hydroxymethyl) aminomethane (TRIS) followed by the azide-alkyne Huisgen cycloaddition with azido N-acetyl-d-galactosamine. The presented triazolyl glycoconjugates exhibited good binding to ASGPR, which was predicted using in silico molecular docking and assessed by a surface plasmon resonance (SPR) technique. Moreover, we demonstrated the low level of in vitro cytotoxicity, as well as the optimal spatial geometry and the required amphiphilic balance, for new, easily accessible ligands. The conjugate of a new ligand with Cy5 dye exhibited selective penetration into HepG2 cells in contrast to the ASGPR-negative PC3 cell line.


Subject(s)
Asialoglycoprotein Receptor/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Alkynes/chemistry , Asialoglycoprotein Receptor/chemistry , Azides , Chemistry Techniques, Synthetic , Drug Design , Esterification , Galactosamine/chemistry , Hep G2 Cells , Humans , Ligands , Methane/chemical synthesis , Methane/chemistry , Methane/metabolism , Methane/pharmacology , Molecular Docking Simulation , PC-3 Cells , Protein Conformation
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