Conjugación de gluconolactona a micelas poliméricas mediante apertura de anillo asistida por radiación microondas para el direccionamiento activo de fármacos

GLISONI R.J.; SOSNIK A.

Buenos Aires, Argentina

Simposio; IV Simposio de Jóvenes Investigadores. IV Escuela de Nanomedicina.; 2014

Asociación Argentina de Nanomedicina

Surface decoration of drug nanocarriers with pendant carbohydrate moieties impacts the biorecognition and modulates the uptake by cells, potentially optimizing the specificity of the targeting.1-4 Notwithstanding, the functionalization of polymeric micelles (PMs) based of poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymers with sugar ligands has not been sufficiently explored, especially, from the perspective of ensuring fast, efficient and scalable conjugation pathways; conjugation extents are usually far below 100%.5-7 Here, we investigated for the first time the conjugation of glucose residues by the microwave assisted ring-opening of gluconolactone.8 Figure 1 presents the synthetic pathway of the reaction. The glucosylated copolymer (F127-O-Glu) was obtained with a high yield (90%) and fully characterized by 1H-NMR, 13C-NMR, ATR/FT-IR, DSC and MALDI-TOF. A conjugation extent of approximately 100% was achieved within 15 min. The self-aggregation of the pristine and modified PMs were characterized by dynamic light scattering and nanoparticle tracking analysis. The modification sharply reduced the critical micellar concentration and increased the size of the micelles, probably due to the interaction of superficial sugar residues. The agglutination of the modified PMs in presence of a soluble lectin that binds glucose, concanavalin A (Con A), confirmed their recognizability of this surface modified nanocarrier by sugar-binding receptor. The agglutination was confirmed by TEM where Con A led to the gradual fusion of the micelles of F127-O-Glu to form large aggregates that lost their original spherical shape. Finally, the solubilization of darunavir, a first-line protease inhibitor used to treat the HIV infection, was assessed. Results showed a sharp increase of the aqueous solubility from 91 ug/mL to 14.2 and 18.9 mg/mL for 10% w/v pristine and glucosylated PMs, respectively, representing solubility improvements of 156 and 209 times. Moreover, the beneficial effect of glucosylation on micellization was supported by the significantly greater encapsulation capacity of the modified nanocarriers.