TY - JOUR

T1 - Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems

AU - Зашихина, Наталья Николаевна

AU - Гладнев, Сергей Владиславович

AU - Шаройко, Владимир Владимирович

AU - Коржиков-Влах, Виктор Александрович

AU - Коржикова-Влах, Евгения Георгиевна

AU - Тенникова, Татьяна Борисовна

N1 - Zashikhina, N.; Gladnev, S.; Sharoyko, V.; Korzhikov-Vlakh, V.; Korzhikova-Vlakh, E.; Tennikova, T. Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems. Int. J. Mol. Sci. 2023, 24, 3702. https://doi.org/10.3390/ijms24043702

PY - 2023/2/12

Y1 - 2023/2/12

N2 - The use of dexamethasone for eye disease treatment is limited by its low solubility, bioavailability, and rapid elimination when applied topically. The covalent conjugation of dexamethasone with polymeric carriers is a promising strategy to overcome existing drawbacks. In this work, amphiphilic polypeptides capable of self-assembly into nanoparticles were proposed as potential delivery systems for intravitreal delivery. The nanoparticles were prepared and characterized using poly(L-glutamic acid-co-D-phenylalanine) and poly(L-lysine-co-D/L-phenylalanine) as well as poly(L-lysine-co-D/L-phenylalanine) covered with heparin. The critical association concentration for the polypeptides obtained was in the 4.2-9.4 μg/mL range. The hydrodynamic size of the formed nanoparticles was between 90 and 210 nm, and they had an index of polydispersity between 0.08 and 0.27 and an absolute zeta-potential value between 20 and 45 mV. The ability of nanoparticles to migrate in the vitreous humor was examined using intact porcine vitreous. Conjugation of DEX with polypeptides was performed by additional succinylation of DEX and activation of carboxyl groups introduced to react with primary amines in polypeptides. The structures of all intermediate and final compounds were verified by 1H NMR spectroscopy. The amount of conjugated DEX can be varied from 6 to 220 µg/mg of polymer. The hydrodynamic diameter of the nanoparticle-based conjugates was increased to 200-370 nm, depending on the polymer sample and drug loading. The release of DEX from the conjugates due to hydrolysis of the ester bond between DEX and the succinyl moiety was studied both in a buffer medium and a vitreous/buffer mixture (50/50, v/ v). As expected, the release in the vitreous medium was faster. However, the release rate could be controlled in the range of 96-192 h by varying the polymer composition. In addition, several mathematical models were used to assess the release profiles and figure out how DEX is released.

AB - The use of dexamethasone for eye disease treatment is limited by its low solubility, bioavailability, and rapid elimination when applied topically. The covalent conjugation of dexamethasone with polymeric carriers is a promising strategy to overcome existing drawbacks. In this work, amphiphilic polypeptides capable of self-assembly into nanoparticles were proposed as potential delivery systems for intravitreal delivery. The nanoparticles were prepared and characterized using poly(L-glutamic acid-co-D-phenylalanine) and poly(L-lysine-co-D/L-phenylalanine) as well as poly(L-lysine-co-D/L-phenylalanine) covered with heparin. The critical association concentration for the polypeptides obtained was in the 4.2-9.4 μg/mL range. The hydrodynamic size of the formed nanoparticles was between 90 and 210 nm, and they had an index of polydispersity between 0.08 and 0.27 and an absolute zeta-potential value between 20 and 45 mV. The ability of nanoparticles to migrate in the vitreous humor was examined using intact porcine vitreous. Conjugation of DEX with polypeptides was performed by additional succinylation of DEX and activation of carboxyl groups introduced to react with primary amines in polypeptides. The structures of all intermediate and final compounds were verified by 1H NMR spectroscopy. The amount of conjugated DEX can be varied from 6 to 220 µg/mg of polymer. The hydrodynamic diameter of the nanoparticle-based conjugates was increased to 200-370 nm, depending on the polymer sample and drug loading. The release of DEX from the conjugates due to hydrolysis of the ester bond between DEX and the succinyl moiety was studied both in a buffer medium and a vitreous/buffer mixture (50/50, v/ v). As expected, the release in the vitreous medium was faster. However, the release rate could be controlled in the range of 96-192 h by varying the polymer composition. In addition, several mathematical models were used to assess the release profiles and figure out how DEX is released.

KW - АМФИФИЛЬНЫЕ ПОЛИПЕПТИДЫ

KW - самооргнизующиеся наночастицы

KW - ДЕКСАМЕТАЗОН

KW - конъюгаты полимер-лекарство

KW - СИСТЕМЫ ДОСТАВКИ ЛЕКАРСТВ

KW - доставка в стекловидное тело

KW - Animals

KW - Swine

KW - Dexamethasone

KW - Lysine

KW - Nanoparticles/chemistry

KW - Polymers

KW - Peptides

KW - Drug Delivery Systems

KW - dexamethasone

KW - drug delivery systems

KW - intravitreal delivery

KW - amphiphilic polypeptides

KW - polymer-drug conjugates

KW - self-assembled nanoparticles

UR - https://www.mendeley.com/catalogue/74b44f10-b199-3836-8271-cfe1a4e7ac34/

U2 - 10.3390/ijms24043702

DO - 10.3390/ijms24043702

M3 - Article

C2 - 36835114

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 4

M1 - 3702

ER -