RESUMEN
Successful siRNA therapy requires suitable delivery systems with targeting moieties such as small molecules, peptides, antibodies, or aptamers. Galactose (Gal) residues recognized by the asialoglycoprotein receptor (ASGPR) can serve as potent targeting moieties for hepatocellular carcinoma (HCC) cells. However, efficient targeting to HCC via galactose moieties rather than normal liver tissues in HCC patients remains a challenge. To achieve more efficient siRNA delivery in HCC, we synthesized various galactoside derivatives and investigated the siRNA delivery capability of nanoparticles modified with those galactoside derivatives. In this study, we assembled lipid/calcium/phosphate nanoparticles (LCP NPs) conjugated with eight types of galactoside derivatives and demonstrated that phenyl ß-d-galactoside-decorated LCP NPs (L4-LCP NPs) exhibited a superior siRNA delivery into HCC cells compared to normal hepatocytes. VEGF siRNAs delivered by L4-LCP NPs downregulated VEGF expression in HCC in vitro and in vivo and led to a potent antiangiogenic effect in the tumor microenvironment of a murine orthotopic HCC model. The efficient delivery of VEGF siRNA by L4-LCP NPs that resulted in significant tumor regression indicates that phenyl galactoside could be a promising HCC-targeting ligand for therapeutic siRNA delivery to treat liver cancer.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Galactosa , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas , ARN Interferente Pequeño , Animales , Receptor de Asialoglicoproteína/antagonistas & inhibidores , Receptor de Asialoglicoproteína/biosíntesis , Receptor de Asialoglicoproteína/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Galactosa/química , Galactosa/farmacología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genéticaRESUMEN
LecA is a galactose-binding tetrameric lectin from Pseudomonas aeruginosa involved in infection and biofilm formation. The emergent antibiotic resistance of P. aeruginosa has made LecA a promising pharmaceutical target to treat such infections. To develop LecA inhibitors, we exploit the unique helical structure of polyproline peptides to create a scaffold that controls the galactoside positions to fit their binding sites on LecA. With a modular scaffold design, both the galactoside ligands and the inter-ligand distance can be altered conveniently. We prepared scaffolds with spacings of 9, 18, 27, and 36â Å for ligand conjugation and found that glycopeptides with galactosides ligands three helical turns (27â Å) apart best fit LecA. In addition, we tested different galactose derivatives on the selected scaffold (27â Å) to improve the binding avidity to LecA. The results validate a new multivalent scaffold design and provide useful information for LecA inhibitor development.
