title: Effect of drug precursor in cell uptake and cytotoxicity of redox-responsive camptothecin nanomedicines.
abstract: Novel redox-responsive nanomedicines have been synthesized by conjugating camptothecin prodrugs ((pyridine-2-yldisulfanil)alkyl carbonate derivatives) to hybrid porous silica nanoparticles through disulfide bond. After disulfide reduction, camptothecin may be released by an intramolecular cyclization mechanism or by carbonate bond hydrolysis. Samples have been characterized by physico-chemical techniques, and stability and drug release in PBS and human serum have been determined. Moreover, cell uptake was studied by fluorescence microscopy and flow cytometry, whilst cytotoxic activity was validated by MTT test. Obtained results indicate that prodrug side chain carbon number (n=1,2,3) determines material hydrophobic properties and, as a consequence, its stability in aqueous medium. When n value increases, the negative surface charge decreases dramatically due to a shielding effect provoked by hydrophobic ligands, which promotes particle aggregation and favors cell internalization. Furthermore, the n value determines the type of products released and, subsequently, the cytotoxic activity. Full disulfide bridge reduction takes place in all cases, but quick delivery of the free drug by intramolecular cyclization is only possible with the shortest linker (n=1), whereas other nanomedicines only present slow discharge of camptothecin by carbonate hydrolysis. Overall, the drug precursor incorporated to the inorganic nanoplatform modulates both cell uptake rate and cytotoxicity according to the different functionalization.
authors.affiliation: Instituto de Tecnología Química (UPV-CSIC), Avda. Los Naranjos s/n, 46022 Valencia, Spain. Electronic address: pbotella@itq.upv.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Botella
authors.affiliation: Instituto de Tecnología Química (UPV-CSIC), Avda. Los Naranjos s/n, 46022 Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Muniesa
authors.affiliation: Facultad de Medicina and Instituto Universitario de Investigación "Dr Viña Giner", Universidad Católica de Valencia "San Vicente Mártir", 46001 Valencia, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Vicente
authors.affiliation: Instituto de Tecnología Química (UPV-CSIC), Avda. Los Naranjos s/n, 46022 Valencia, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cabrera-García
mesh_terms: D002166:Camptothecin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D057446:Hydrodynamics; D020128:Inhibitory Concentration 50; D050997:Nanomedicine; D053758:Nanoparticles / Q000648:ultrastructure; D010084:Oxidation-Reduction; D010316:Particle Size; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012235:Rhodamines / Q000378:metabolism; D055672:Static Electricity
chemical_list: D011355:Prodrugs; D012235:Rhodamines; C029773:rhodamine B; D002166:Camptothecin
keywords: Camptothecin; Controlled release; Drug delivery; Mesoporous silica; Nanomedicines; Redox-responsive