Despite the higher rate of blindness due to population aging, minimally invasive and selective drug delivery to the eye still remains an open challenge, especially in the posterior segment. The posterior eye segment is composed by several cell layers, each one specialized in different functions. It is affected by several diseases, which account for the majority of blindness worldwide. One of the most effective routes to reach the eye posterior segment is represented by intravitreal (IVT) injections. However, current procedures have severe collateral effects due to the need of repetitive injections over the time, the unfavorable drug kinetics (the initial dose is very high and quickly drops to zero due to physiological washing), the lack of specificity for the target (all cell layers are exposed to the drug), etc. In this work we used a drug carrier, with the intent to release the drug in a specific region or tissue and to prolong its half-life. Specifically, we validated a carrier based on magnetic nanoparticles (MNPs). Our studies suggest that zebrafish embryos are an excellent animal model for proof of concept studies. In zebrafish, the IVT injection has been already used for the delivery of drugs to posterior segment, e.g., antioxidants [1] and growth factors [2]. We found that magnetic nanoparticle, after intraocular injection, are able to rapidly and persistently localize within the retinal pigment epithelium (RPE) in an autonomously manner [3]. Most importantly, our results show that surface functionalization could change the fate of the particles, driving their localization in different cell layers of the posterior eye chamber, such as the choroid or the retina [4]. We used MNPs to deliver neurotrophic factors, which have a very short half-life in vivo, usually making ineffective their clinical use. We developed a model of damage to the posterior eye chamber in zebrafish embryos (0-96 hours post fertilization). We found that the injection of MNPs functionalized with nerve growth factor (NGF) or brain derived nerve factor (BDNF) strongly prevents injuries to the posterior eye chamber and sustain the regeneration process compared to that obtained using the free factors. We postulate that the increase in stability and the localization of growth factors mediated by MNPs are responsible for the enhanced neuroprotective effects of NGF and BDNF in the MNP group compared with the sham group. Our data suggest that MNP could represent a powerful strategy for the design of novel minimally invasive carriers for cell-specific ocular delivery and neuroprotection.

Targeting drugs to specific cell layers of the posterior eye segment: implementation of “smart” strategies of ocular neuroprotection in zebrafish model

M. Giannaccini;A. Usai;L. Dente;V. Raffa
2017-01-01

Abstract

Despite the higher rate of blindness due to population aging, minimally invasive and selective drug delivery to the eye still remains an open challenge, especially in the posterior segment. The posterior eye segment is composed by several cell layers, each one specialized in different functions. It is affected by several diseases, which account for the majority of blindness worldwide. One of the most effective routes to reach the eye posterior segment is represented by intravitreal (IVT) injections. However, current procedures have severe collateral effects due to the need of repetitive injections over the time, the unfavorable drug kinetics (the initial dose is very high and quickly drops to zero due to physiological washing), the lack of specificity for the target (all cell layers are exposed to the drug), etc. In this work we used a drug carrier, with the intent to release the drug in a specific region or tissue and to prolong its half-life. Specifically, we validated a carrier based on magnetic nanoparticles (MNPs). Our studies suggest that zebrafish embryos are an excellent animal model for proof of concept studies. In zebrafish, the IVT injection has been already used for the delivery of drugs to posterior segment, e.g., antioxidants [1] and growth factors [2]. We found that magnetic nanoparticle, after intraocular injection, are able to rapidly and persistently localize within the retinal pigment epithelium (RPE) in an autonomously manner [3]. Most importantly, our results show that surface functionalization could change the fate of the particles, driving their localization in different cell layers of the posterior eye chamber, such as the choroid or the retina [4]. We used MNPs to deliver neurotrophic factors, which have a very short half-life in vivo, usually making ineffective their clinical use. We developed a model of damage to the posterior eye chamber in zebrafish embryos (0-96 hours post fertilization). We found that the injection of MNPs functionalized with nerve growth factor (NGF) or brain derived nerve factor (BDNF) strongly prevents injuries to the posterior eye chamber and sustain the regeneration process compared to that obtained using the free factors. We postulate that the increase in stability and the localization of growth factors mediated by MNPs are responsible for the enhanced neuroprotective effects of NGF and BDNF in the MNP group compared with the sham group. Our data suggest that MNP could represent a powerful strategy for the design of novel minimally invasive carriers for cell-specific ocular delivery and neuroprotection.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/878829
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