ABSTRACT
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.
Subject(s)
Biomarkers, Tumor/antagonists & inhibitors , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/drug therapy , Receptor, IGF Type 2/antagonists & inhibitors , Biomarkers, Tumor/genetics , Cell Line, Tumor , Humans , Male , Mannosephosphates/chemical synthesis , Mannosephosphates/chemistry , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Particle Size , Photochemotherapy , Porosity , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Receptor, IGF Type 2/genetics , Silicon Dioxide/chemistry , Surface PropertiesABSTRACT
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.
Subject(s)
Binding, Competitive , Mannosephosphates/blood , Organophosphonates/chemical synthesis , Receptor, IGF Type 2/blood , Receptors, Cytoplasmic and Nuclear/drug effects , Sulfonic Acids/chemical synthesis , Glycoproteins/metabolism , Humans , Lysosomes/enzymology , Mannosephosphates/chemistry , Molecular Structure , Neoplasms/drug therapy , Organophosphonates/blood , Organophosphonates/chemistry , Structure-Activity Relationship , Sulfonic Acids/blood , Sulfonic Acids/chemistryABSTRACT
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.
Subject(s)
Binding, Competitive , Carboxylic Acids/chemistry , Carboxylic Acids/chemical synthesis , Mannosephosphates/metabolism , Receptor, IGF Type 2/metabolism , Biomarkers/chemistry , Carbohydrate Sequence , Carboxylic Acids/pharmacology , Cell Line , Cell Proliferation/drug effects , Cells, Cultured , Humans , Mannosephosphates/chemistry , Mannosephosphates/pharmacology , Molecular Sequence Data , Protein BindingABSTRACT
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.