Abstract
Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug release. Accordingly, dexamethasone was conjugated to ~67 kDa pullulan through hydrazone bond, which was previously found to be slowly cleavable in the vitreous. Dynamic light scattering and transmission electron microscopy showed that the pullulan-dexamethasone containing 1:20 drug/glucose unit molar ratio (10% w/w dexamethasone) self-assembled into nanoparticles of 461 ± 30 nm and 402 ± 66 nm, respectively. The particles were fairly stable over 6 weeks in physiological buffer at 4, 25 and 37 °C, while in homogenized vitreous at 37 °C, the colloidal assemblies underwent size increase over time. The drug was released slowly in the vitreous and rapidly at pH 5.0 mimicking lysosomal conditions: 50% of the drug was released in about 2 weeks in the vitreous, and in 2 days at pH 5.0. In vitro studies with retinal pigment epithelial cell line (ARPE-19) showed no toxicity of the conjugates in the cells. Flow cytometry and confocal microscopy showed cellular association of the nanoparticles and intracellular endosomal localization. Overall, pullulan conjugates showed interesting features that may enable their successful use in intravitreal drug delivery.
Highlights
Ocular drug delivery is a major challenge in drug development [1,2]
We report here the development of a new pullulan-dexamethasone conjugate as a potential intravitreal drug delivery system
Cyanine3 is a hydrophobic molecule that contributes to the association process and intraparticle interactions, which results in smaller size and lower PDI compared to the nanoparticles obtained with pullulan-dexamethasone
Summary
Ocular drug delivery is a major challenge in drug development [1,2]. In particular, efficient delivery to the retina and other posterior tissues of the eye is difficult to be achieved, requiring invasive intravitreal injections. Pullulan can be properly derivatized to conjugate drugs or other chemical moieties along the polymer backbone to yield colloidal systems for controlled drug release. Hydrazone linker was found to provide slow drug release under neutral conditions resembling the vitreous compartment, whereas previous studies show that hydrazone is rapidly cleaved under acidic conditions For this reason, a variety of bioconjugates have been obtained by conjugating anticancer drugs to natural or synthetic polymer through hydrazone bond [19,20,21,22,23,24,25]. Pullulan-dexamethasone showed prolonged drug release in the vitreous as a result of the slow cleavage of the hydrazone linker used to conjugate the drug to the polysaccharide backbone
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