Improved ocular delivery of quercetin and resveratrol : A comparative study between binary and ternary cyclodextrin complexes

Peer reviewe

Characterization, Stability, and In Vivo Efficacy Studies of Recombinant Human CNTF and Its Permeation into the Neural Retina in Ex Vivo Organotypic Retinal Explant Culture Models

Ciliary neurotrophic factor (CNTF) is one of the most studied neuroprotective agents with acknowledged potential in treating diseases of the posterior eye segment. Although its efficacy and mechanisms of action in the retina have been studied extensively, it is still not comprehensively understood which retinal cells mediate the therapeutic effects of CNTF. As with therapeutic proteins in general, it is poorly elucidated whether exogenous CNTF administered into the vitreous can enter and distribute into the retina and hence reach potentially responsive target cells. Here, we have characterized our purified recombinant human CNTF (rhCNTF), studied the protein’s in vitro bioactivity in a cell-based assay, and evaluated the thermodynamic and oligomeric status of the protein during storage. Biological activity of rhCNTF was further evaluated in vivo in an animal model of retinal degeneration. The retinal penetration and distribution of rhCNTF after 24 h was studied utilizing two ex vivo retina models. Based on our characterization findings, our rhCNTF is correctly folded and biologically active. Moreover, based on initial screening and subsequent follow-up, we identified two buffers in which rhCNTF retains its stability during storage. Whereas rhCNTF did not show photoreceptor preservative effect or improve the function of photoreceptors in vivo, this could possibly be due to the used disease model or the short duration of action with a single intravitreal injection of rhCNTF. On the other hand, the lack of in vivo efficacy was shown to not be due to distribution limitations; permeation into the retina was observed in both retinal explant models as in 24 h rhCNTF penetrated the inner limiting membrane, and being mostly observed in the ganglion cell layer, distributed to different layers of the neural retina. As rhCNTF can reach deeper retinal layers, in general, having direct effects on resident CNTF-responsive target cells is plausible

Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

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

Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

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

Pharmacokinetics of Pullulan-Dexamethasone Conjugates in Retinal Drug Delivery

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 (approximate to 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 Muller 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.Peer reviewe

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

Due to continuously high production rates of rhodopsin (RHO) and high metabolic activity, photoreceptor neurons are especially vulnerable to defects in proteostasis. A proline to histidine substitution at position 23 (P23H) leads to production of structurally misfolded RHO, causing the most common form of autosomal dominant Retinitis Pigmentosa (adRP) in North America. The AAA-ATPase valosin-containing protein (VCP) extracts misfolded proteins from the ER membrane for cytosolic degradation. Here, we provide the first evidence that inhibition of VCP activity rescues degenerating P23H rod cells and improves their functional properties in P23H transgenic rat and P23H knock-in mouse retinae, both in vitro and in vivo. This improvement correlates with the restoration of the physiological RHO localization to rod outer segments (OS) and properly-assembled OS disks. As a single intravitreal injection suffices to deliver a long-lasting benefit in vivo, we suggest VCP inhibition as a potential therapeutic strategy for adRP patients carrying mutations in the RHO gene

Coupling circularity performance and climate action : from disciplinary silos to transdisciplinary modelling science

Technological breakthroughs and policy measures targeting energy efficiency and clean energy alone will not suffice to deliver Paris Agreement-compliant greenhouse gas emissions trajectories in the next decades. Strong cases have recently been made for acknowledging the decarbonisation potential lying in transforming linear economic models into closed-loop industrial ecosystems and in shifting lifestyle patterns towards this direction. This perspective highlights the research capacity needed to inform on the role and potential of the circular economy for climate change mitigation and to enhance the scientific capabilities to quantitatively explore their synergies and trade-offs. This begins with establishing conceptual and methodological bridges amongst the relevant and currently fragmented research communities, thereby allowing an interdisciplinary integration and assessment of circularity, decarbonisation, and sustainable development. Following similar calls for science in support of climate action, a transdisciplinary scientific agenda is needed to co-create the goals and scientific processes underpinning the transition pathways towards a circular, net-zero economy with representatives from policy, industry, and civil society. Here, it is argued that such integration of disciplines, methods, and communities can then lead to new and/or structurally enhanced quantitative systems models that better represent critical industrial value chains, consumption patterns, and mitigation technologies. This will be a crucial advancement towards assessing the material implications of, and the contribution of enhanced circularity performance to, mitigation pathways that are compatible with the temperature goals of the Paris Agreement and the transition to a circular economy

Bang for Your Buck: STI Risk and Pregnancy Risk as Sources of the Price Premium for Unprotected Sex

Sex workers receive a price premium for unprotected sex. Research has inferred that the source of this premium is a compensating differential for STI risk. I introduce a compensating differential for pregnancy risk as a novel source through a simple model that incorporates both STI risk and pregnancy risk. I empirically test this using a rich panel dataset of 19,041 sexual transactions by 192 sex workers in Busia, Kenya collected during 2005 and 2006. I run sex worker-fixed effects regressions and find that compensating differentials for STI risk and pregnancy risk are sources of the price premium for unprotected sex. The price premium for pregnancy risk is USD 10, and USD 2 for STI risk (24 percent of average price). I also test for clients' disutility for condoms, another competing theory, and find that it is not a statistically significant source of the premium. Identifying and estimating sources of the price premium for unprotected sex will allow policymakers to implement interventions that will reduce both the supply and the demand for unprotected sex

Coupling circularity performance and climate action: from disciplinary silos to transdisciplinary modelling science

Technological breakthroughs and policy measures targeting energy efficiency and clean energy alone will not suffice to deliver Paris Agreement-compliant greenhouse gas emissions trajectories in the next decades. Strong cases have recently been made for acknowledging the decarbonisation potential lying in transforming linear economic models into closed-loop industrial ecosystems and in shifting lifestyle patterns towards this direction. This perspective highlights the research capacity needed to inform on the role and potential of the circular economy for climate change mitigation and to enhance the scientific capabilities to quantitatively explore their synergies and trade-offs. This begins with establishing conceptual and methodological bridges amongst the relevant and currently fragmented research communities, thereby allowing an interdisciplinary integration and assessment of circularity, decarbonisation, and sustainable development. Following similar calls for science in support of climate action, a transdisciplinary scientific agenda is needed to co-create the goals and scientific processes underpinning the transition pathways towards a circular, net-zero economy with representatives from policy, industry, and civil society. Here, it is argued that such integration of disciplines, methods, and communities can then lead to new and/or structurally enhanced quantitative systems models that better represent critical industrial value chains, consumption patterns, and mitigation technologies. This will be a crucial advancement towards assessing the material implications of, and the contribution of enhanced circularity performance to, mitigation pathways that are compatible with the temperature goals of the Paris Agreement and the transition to a circular economy