Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

Abstract

The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan–dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan–dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan–dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan–dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.

A Microfluidic Eye Facsimile System to Examine the Migration of Stem-like Cells

“…Reservoirs were designed to maintain large, fluidic volumes for multi-day testing, and the electrode assembly can apply a range of electrical fields to stimulate SC motility ( Figure 5 ). This design facilitates the application of electric fields currently used in animal studies and in the clinic, such as treatments with biochemical agents [ 76 , 77 ] and low level electric fields [ 78 , 79 ]. Electrical activity is known to play an important role in the formation and connectivity of neural circuits, where EF can modify synaptic connectivity, the structure of neuronal projections, and induce changes in gene expression, protein synthesis, and intrinsic excitability (reviewed in [ 80 , 81 ]).…”

“…The μ-Eye represents the first bioengineering system to integrate microfluidic environments with models of whole, enucleated eyes [ 72 ]. This is a significant step towards using in vitro and ex vivo technologies to aid development of in vivo strategies for transplantation, such as the use of EF and/electrodes [ 84 ], biomaterials [ 85 ], or pharmacological injection [ 77 ]. While a variety of in vitro and ex vivo platforms have been developed to examine SC behaviors (reviewed in [ 82 , 86 ]), the μ-Eye can bridge microfluidics with ocular explants to build hybrid, quantitative platforms for transplantation study in adult tissue environments.…”

Recent achievements in nano-based technologies for ocular disease diagnosis and treatment, review and update

“…They showed that these pullulan-based drug conjugates are safe in rabbit, mouse, and rat eyes, have a long residence time in the vitreous, and are approximately wholly eliminated through the aqueous humor outflow. The findings of this study revealed that pullulan–dexamethasone conjugates might release active and free dexamethasone in the vitreous humor for higher than 16 days, although a big dexamethasone fraction might be deleted from the eye as bound pullulan–dexamethasone [ 162 ].…”

“…Regarding all reported polysaccharide-based materials for treating eye disorders, it seems that the therapeutic system reported by Eva Kicková and coworkers provides great intravitreal drug delivery systems because they could diminish the frequency of injection and transfer of drugs into retinal tissues. Besides, this nanoplatform showed good biosafety and long residence time in the vitreous [ 162 ]. Also, the nanogels-based on chitosan reported by Buosi et al offered successful nanocarriers delivery systems with respect to non-cytotoxic and non-inflammatory effects in human ARPE-19 cells, opening the good opportunity for its use in ocular disease [ 157 ].…”

Self-Healing Thermosensitive Hydrogel for Sustained Release of Dexamethasone for Ocular Therapy

“…24 The obtained in vitro release rate constant (k) of dexamethasone from the PNADEX-CA hydrogel was used for simulation of intravitreal pharmacokinetics of dexamethasone in humans. Pharmacokinetics were simulated using a compartmental model reported and validated in the literature for vitreal kinetics of sustained release of dexamethasone from nanomaterials (Supporting Information, Figure S1) 25,26 using the parameters shown in Table S1. When applicable, parameters for dexamethasone phosphate were used in the model, due to the lack of available reported kinetic parameters for dexamethasone in the literature.…”