RESUMEN
The molecular weight (Mw) of dextran derivatives, such as regioselectively oxidized dicarboxydextran (DXA), is greatly influencing their faith in an organism, which could be possibly used to improve anticancer drug delivery. Here we present a modified method of sulfonation-induced chain scission allowing direct and accurate control over the Mw of DXA without increasing its polydispersity. Prepared DXA derivatives (Mw = 10-185 kDa) have been conjugated to cisplatin and the Mw of the carrier found to have a significant impact on cisplatin release rates, in vitro cytotoxicity, and migrastatic potential. Conjugates with the high-Mw DXA showed particularly increased anticancer efficacy. The best conjugate was four times more effective against malignant prostatic cell lines than free cisplatin and significantly inhibited the ovarian cancer cell migration. This was traced to the characteristics of spontaneously formed cisplatin-crosslinked DXA nanogels influenced by Mw of DXA and amount of loaded cisplatin.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Dextranos/química , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Células A549 , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Antineoplásicos/química , Movimiento Celular/efectos de los fármacos , Cisplatino/química , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Masculino , Peso Molecular , Nanogeles/química , Neoplasias/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Oxidación-Reducción , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismoRESUMEN
Oxidation of polysaccharides to 2,3-dicarboxypolysaccharides is a two-stage process, where selective oxidation by periodate is followed by secondary oxidation by chlorite. Addition of sulfamic acid before the secondary oxidation influences the molecular weight and degree of oxidation of the product. Here, mechanism of sulfamic acid-catalysed chain scission is elucidated for selectively oxidized cellulose and dextrin. Initially, sulfamic acid sulfonates the aldehyde groups of 2,3-dialdehydepolysaccharide. Introduced -SO3H groups are in ideal position to protonate the oxygen atom of 1-4' glycosidic bond and to trigger acidic hydrolysis. This can be used to obtain a direct control over the molecular weight of the product. Observed slightly lower degree of oxidation was ascribed to the ability of sulfamic acid to scavenge the hypochlorite and thus protect the intermolecular hemiacetals from oxidation. Usually undesirable hypochlorite thus seems to be necessary for preparation of selectively oxidized polysaccharides with degree of oxidation above 90%.
