Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.

Melanin binding is known to affect the distribution and elimination of ocular drugs. The purpose of this study was to evaluate if the extent of drug uptake to primary retinal pigment epithelial (RPE) cells could be estimated based on in vitro binding studies with isolated melanin and evaluate the suitability of single photon emission computed tomography/computed tomography (SPECT/CT) in studying pigment binding in vivo with pigmented and albino rats. Binding of five compounds, basic molecules timolol, chloroquine, and nadolol and acidic molecules methotrexate and 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF), was studied using isolated melanin from porcine choroid-RPE at pH 5.0 and 7.4. The uptake to primary porcine RPE cells was studied with timolol, chloroquine, methotrexate, and CDCF. The cell study setting was modeled using parameters from the in vitro binding study. In vivo kinetics of 3-[I-123]-iodochloroquine was studied by the SPECT/CT method in albino and pigmented rats. All basic compounds bound to melanin at both pH values, whereas the acidic compounds bound more at pH 5.0 than at pH 7.4. The basic compounds (chloroquine, timolol) showed significant cellular uptake, unlike the acidic compounds (methotrexate, CDCF). On the basis of the modeling, melanin binding was a major factor governing the overall drug distribution to the RPE cells. Likewise, melanin binding explained distribution of 3-[I-123]-iodochloroquine in the pigmented RPE, whereas drug accumulation was not seen in the albino rat. This study demonstrates the suitability of noninvasive SPECT/CT imaging in monitoring ocular melanin binding in vivo. These studies are a useful step toward understanding the pharmacokinetic impact of melanin binding.

The vitreous humor is the first barrier encountered by intravitreally injected nanoparticles. Lipid-based nanoparticles in the vitreous are studied by evaluating their diffusion with single-particle tracking technology and by characterizing their protein coronae with surface plasmon resonance and high-resolution proteomics. Single-particle tracking results indicate that the vitreal mobility of the formulations is dependent on their charge. Anionic and neutral formulations are mobile, whereas larger (>200 nm) neutral particles have restricted diffusion, and cationic particles are immobilized in the vitreous. PEGylation increases the mobility of cationic and larger neutral formulations but does not affect anionic and smaller neutral particles. Convection has a significant role in the pharmacokinetics of nanoparticles, whereas diffusion drives the transport of antibodies. Surface plasmon resonance studies determine that the vitreal corona of anionic formulations is sparse. Proteomics data reveals 76 differentially abundant proteins, whose enrichment is specific to either the hard or the soft corona. PEGylation does not affect protein enrichment. This suggests that protein-specific rather than formulation-specific factors are drivers of protein adsorption on nanoparticles in the vitreous. In summary, our findings contribute to understanding the pharmacokinetics of nanoparticles in the vitreous and help advance the development of nanoparticle-based treatments for eye diseases.

This work details the in situ dynamical behaviour of local anaesthetic bupivacaine (BUP)-loaded L 2 and H 2 phase precursors (preformulations of BUP) upon rapid exposure to phosphate buffer under physiological conditions (pH 7.4, 37 C). The hydration-induced structural transitions are characterized by time-resolved synchrotron SAXS.

Carbon assimilation is usually measured at fairly constant light intensities. Under natural conditions, however, planktonic algae are moved through the water column and experience light of fluctuating intensity and spectral composition. They may cope with strong UV for a short residence in the upper water layer. In order to estimate the effects of UV on primary production of phytoplankton under conditions of turbulent mixing, we compared carbon assimilation and exudation of algae incubated in UV-transparent quartz and in UV-absorbing glass bottles which were moved through different water layers. Computer-controlled elevators were used to simulate mixing depths between 2 and 14 meters. Compared to the glass bottles, particulate C assimilation in the quartz bottles was reduced by 20 -30 % at mixing depths between 2 and 10 m. There was no significant difference between both types of incubation bottles at a mixing depth of 14 m. Exudation was enhanced by UV near the water surface (mixing depth up to 4 m) but not in the deep-mixed samples. Our results indicate serious damage of planktonic algae by UV even under conditions of vertical mixing if the euphotic zone exceeds the mixing depth. Depression was low for circulation through the whole euphotic zone and may disappear at even deeper mixing. Our results indicate lower photoinhibition per UV dosage at fluctuating than at constant light intensities. A model predicting inhibition as function of weighted irradiance spectra was adapted to describe wavelength dependent photoinhibition occurring at different mixing depths. The model results agreed very well with the inhibition rates measured under fluctuating light. These preliminary results are used to discuss the importance of UV on photosynthesis of planktonic algae in aquatic environments of different mixing depths and stabilities of stratification.