Controlled release strategy designed for intravitreal protein delivery to the retina

Delplace, Vianney; Ortín-Martínez, Arturo; Tsai, En Leh Samuel; Amin, Alan; Wallace, Valerie A.; Shoichet, Molly S.

doi:10.1016/j.jconrel.2018.11.012

Cited by 51 publications

(38 citation statements)

References 65 publications

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“…RPCs were observed to adhere and migrate collectively as clusters in all fields of the μLane system (Figure 6). Measured values of chemotactic index (CI) approaching 1 illustrated that retinal clusters of different sizes exhibited finely tuned chemotactic migration within different gradient fields of FGF [102]. Furthermore, concentration effects were seen to be significant in conjunction with gradient, as cells migrated in both the highest gradient fields and in fields with the highest FGF concentration.…”

Section: Discussionmentioning

confidence: 99%

Invertebrate Retinal Progenitors as Regenerative Models in a Microfluidic System

Pena

Zhang

Majeska

et al. 2019

Cells

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Regenerative retinal therapies have introduced progenitor cells to replace dysfunctional or injured neurons and regain visual function. While contemporary cell replacement therapies have delivered retinal progenitor cells (RPCs) within customized biomaterials to promote viability and enable transplantation, outcomes have been severely limited by the misdirected and/or insufficient migration of transplanted cells. RPCs must achieve appropriate spatial and functional positioning in host retina, collectively, to restore vision, whereas movement of clustered cells differs substantially from the single cell migration studied in classical chemotaxis models. Defining how RPCs interact with each other, neighboring cell types and surrounding extracellular matrixes are critical to our understanding of retinogenesis and the development of effective, cell-based approaches to retinal replacement. The current article describes a new bio-engineering approach to investigate the migratory responses of innate collections of RPCs upon extracellular substrates by combining microfluidics with the well-established invertebrate model of Drosophila melanogaster. Experiments utilized microfluidics to investigate how the composition, size, and adhesion of RPC clusters on defined extracellular substrates affected migration to exogenous chemotactic signaling. Results demonstrated that retinal cluster size and composition influenced RPC clustering upon extracellular substrates of concanavalin (Con-A), Laminin (LM), and poly-L-lysine (PLL), and that RPC cluster size greatly altered collective migratory responses to signaling from Fibroblast Growth Factor (FGF), a primary chemotactic agent in Drosophila. These results highlight the significance of examining collective cell-biomaterial interactions on bio-substrates of emerging biomaterials to aid directional migration of transplanted cells. Our approach further introduces the benefits of pairing genetically controlled models with experimentally controlled microenvironments to advance cell replacement therapies.

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Section: Discussionmentioning

confidence: 99%

Invertebrate Retinal Progenitors as Regenerative Models in a Microfluidic System

Pena

Zhang

Majeska

et al. 2019

Cells

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“…In addition, only small volumes can be injected using this method [16, 17]. Therefore, long-term delivery of therapeutics directly targeting the retina, RPE and choroid remains an unmet need [reviewed in 18].…”

Section: Introductionmentioning

confidence: 99%

In vivo MRI assessment of bioactive magnetic iron oxide/human serum albumin nanoparticle delivery into the posterior segment of the eye in a rat model of retinal degeneration

et al. 2019

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BackgroundRetinal degeneration diseases affect millions of patients worldwide and lead to incurable vision loss. These diseases are caused by pathologies in the retina and underlying choroid, located in the back of the eye. One of the major challenges in the development of treatments for these blinding diseases is the safe and efficient delivery of therapeutics into the back of the eye. Previous studies demonstrated that narrow size distribution core–shell near infra-red fluorescent iron oxide (IO) nanoparticles (NPs) coated with human serum albumin (HSA, IO/HSA NPs) increase the half-life of conjugated therapeutic factors, suggesting they may be used for sustained release of therapeutics. In the present study, the in vivo tracking by MRI and the long term safety of IO/HSA NPs delivery into the suprachoroid of a rat model of retinal degeneration were assessed.ResultsTwenty-five Royal College of Surgeons (RCS) pigmented rats received suprachoroidal injection of 20-nm IO/HSA NPs into the right eye. The left eye was not injected and used as control. Animals were examined by magnetic resonance imaging (MRI), electroretinogram (ERG) and histology up to 30 weeks following injection. IO/HSA NPs were detected in the back part of the rats’ eyes up to 30 weeks following injection by MRI, and up to 6 weeks by histology. No significant differences in retinal structure and function were observed between injected and non-injected eyes. There was no significant difference in the weight of IO/HSA NP-injected animals compared to non-injected rats.ConclusionsMRI could track the nanoparticles in the posterior segment of the injected eyes demonstrating their long-term persistence, and highlighting the possible use of MRI for translational studies in animals and in future clinical studies. Suprachoroidal injection of IO/HSA NPs showed no sign of adverse effects on retinal structure and function in a rat model of retinal degeneration, suggesting that suprachoroidal delivery of IO/HSA NPs is safe and that these NPs may be used in future translational and clinical studies for extended release drug delivery at the back of the eye.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0438-y) contains supplementary material, which is available to authorized users.

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“…Based on hydrodynamic radius estimations presented here, the calculated intravitreal half-life of rhCNTF are 4.67 days (R h 2.95 nm) and 4.96 days (R h 3.32 nm) (see Supplement ), estimates that do not differ drastically from experimentally determined half-lives of other IVT administered macromolecules [ 86 , 87 , 88 ] and definitely not in the order of minutes. Even so, the vitreal half-life of CNTF is nevertheless finite and sustained intraocular release, and retinal delivery of CNTF has been explored utilizing various strategies: for example, an intravitreally injected hydrogel [ 58 ], cell-based systems [ 89 ], and several gene therapy approaches [ 18 , 90 , 91 , 92 , 93 , 94 ]. The most clinically advanced, Renexus ® (NT-501; Neurotech Pharmaceuticals, Inc., Cumberland, RI, USA) is an implant with encapsulated, genetically engineered ARPE-19 cells, that secrete and maintain low concentrations of human CNTF in the vitreous over several years [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Controlled release strategy designed for intravitreal protein delivery to the retina

Cited by 51 publications

References 65 publications

Invertebrate Retinal Progenitors as Regenerative Models in a Microfluidic System

Invertebrate Retinal Progenitors as Regenerative Models in a Microfluidic System

In vivo MRI assessment of bioactive magnetic iron oxide/human serum albumin nanoparticle delivery into the posterior segment of the eye in a rat model of retinal degeneration

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

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