RESUMO
Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the fourth most common cause of cancer-related mortality worldwide. Sorafenib is the first-line molecular therapy for patients in an advanced stage of HCC. However, the recommended clinical dose of Sorafenib is associated with several complications, which derive from its lack of cell specificity and its very low water solubility. To circumvent these drawbacks, in the present study we developed two sugar-coated polydiacetylene-based nanomicelles-Sorafenib carriers targeting mannose and asialoglycoprotein receptors (MR and ASGPR, respectively). The strategies allowed the inducement of apoptosis and reduction of cell proliferation at a nanomolar, instead of micromolar, range in liver cancer cells. The study showed that, contrary to literature data, Sorafenib included into the pMicMan (Man = mannose) vector (targeting MR) is more efficient than pMicGal (Gal = galactose) (targeting ASGPR). Indeed, pMicMan increased the endosomal incorporation with an increased intracellular Sorafenib concentration that induced apoptosis and reduced cell proliferation at a low concentration range (10-20 nM).
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Galactose/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Manose/administração & dosagem , Nanopartículas/administração & dosagem , Polímero Poliacetilênico/administração & dosagem , Sorafenibe/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Receptor de Asialoglicoproteína/metabolismo , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Endossomos/metabolismo , Galactose/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Manose/química , Receptor de Manose/metabolismo , Micelas , Nanopartículas/química , Polímero Poliacetilênico/química , Sorafenibe/químicaRESUMO
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense α-galactosidase A (α-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing α-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of α-Gal A, as confirmed by a 2.55 Å resolution cocrystal structure. Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Tioureia/análogos & derivados , Tioureia/farmacologia , alfa-Galactosidase/metabolismo , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Cristalografia por Raios X , Estabilidade Enzimática/efeitos dos fármacos , Doença de Fabry/genética , Doença de Fabry/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Simulação de Acoplamento Molecular , Mutação , Transporte Proteico/efeitos dos fármacos , Triexosilceramidas/metabolismo , alfa-Galactosidase/química , alfa-Galactosidase/genéticaRESUMO
Biomimetic nanoparticles prepared by self-assembly of iminosugar-based glycopolypeptides evidenced remarkable multivalency properties when inhibiting α-mannosidase activity. This approach paves the way to obtain biologically active drug delivery systems having glycosidase inhibition potency.