RESUMO
The development of personalized and non-invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over-expression of a membrane lectin, the cation-independent mannose 6-phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose-6-phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for inâ vitro and exâ vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic.
Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Receptor IGF Tipo 2/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Humanos , Masculino , Manosefosfatos/síntese química , Manosefosfatos/química , Nanopartículas/química , Nanopartículas/uso terapêutico , Tamanho da Partícula , Fotoquimioterapia , Porosidade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptor IGF Tipo 2/genética , Dióxido de Silício/química , Propriedades de SuperfícieRESUMO
The cation-independent mannose 6-phosphate receptor (CI-M6PR) is essential for the endocytosis of proteins bearing the mannose 6-phosphate (M6P) recognition marker. This study described the synthesis of M6P and M6S analogs presenting greater affinity for CI-M6PR than their natural compounds. Moreover, the finding of their lack of cytotoxicity for human cells and of their increased stability in human serum supports the high potential of these isosteric derivatives in therapies requiring CI-M6PR targeting.
Assuntos
Ligação Competitiva , Manosefosfatos/sangue , Organofosfonatos/síntese química , Receptor IGF Tipo 2/sangue , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Ácidos Sulfônicos/síntese química , Glicoproteínas/metabolismo , Humanos , Lisossomos/enzimologia , Manosefosfatos/química , Estrutura Molecular , Neoplasias/tratamento farmacológico , Organofosfonatos/sangue , Organofosfonatos/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/sangue , Ácidos Sulfônicos/químicaRESUMO
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is involved in multiple physiological pathways including targeting of lysosomal enzymes, degradation of IGF2, and cicatrization through TGFbeta activation. To target potential therapeutics to this membrane receptor, four carboxylate analogues of mannose 6-phosphate (M6P) were synthesized. Three of them, two isosteric carboxylate analogues and a malonate derivative, showed a binding affinity for the M6P/IGF2R equivalent to or higher than that of M6P. Contrary to M6P, all these analogues were particularly stable in human serum. Moreover, these derivatives did not present any cytotoxic activity against two human cell lines. These analogues represent a new potential for the lysosomal targeting of enzyme replacement therapy in lysosomal diseases or to prevent the membrane-associated activities of the M6P/IGF2R.
Assuntos
Ligação Competitiva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Manosefosfatos/metabolismo , Receptor IGF Tipo 2/metabolismo , Biomarcadores/química , Sequência de Carboidratos , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Manosefosfatos/química , Manosefosfatos/farmacologia , Dados de Sequência Molecular , Ligação ProteicaRESUMO
The regioselective monobenzyloxycarbonylation of secondary alcohols in methyl 6-O-(4-methoxytrityl)-alpha-D-manno-, gluco- and galactopyranoside has been achieved in high yields (74-85%) by using benzyl chloroformate in the presence of 4-dimethylaminopyridine and/or 1,4-diazabicyclo[2.2.2]octane.
