Effect of hyaluronic acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy

Martens, Thomas; Peynshaert, Karen; Nascimento, Thaís Leite; Fattal, Elias; Karlstetter, Marcus; Langmann, Thomas; Picaud, Serge; Demeester, Jo; Smedt, Stefaan C. De; Remaut, Katrien; Braeckmans, Kevin

doi:10.1016/j.ejps.2017.02.027

Cited by 34 publications

(18 citation statements)

References 44 publications

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“…LX here presented were surface-modified with covalently bind HA, which has been demonstrated to increase vectorization after intravenous administration in mice 60 and more efficient uptake by cells whereas LX electrostatically coated with HA were as inefficient as the uncoated LX. 23…”

Section: Resultsmentioning

confidence: 99%

Mucopenetrating lipoplexes modified with PEG and hyaluronic acid for CD44-targeted local siRNA delivery to the lungs

et al. 2019

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RNA interfering technology has become a successful strategy for targeted gene silencing through the use of efficient delivery systems. A nanocarrier must be especially designed when considering unusual routes due to RNA instability in biological medium. Lung delivery provides extensive area of absorption and alveolar deposition, non-invasiveness and local action. However, biological barriers such as lung mucus are a great challenge to the efficient delivery of nanocarriers for therapeutic purpose. Here, we studied the diffusion of mucopenetrating lipoplexes (LX) modified with hyaluronic acid (HA) and polyethylene glycol (PEG) for the local delivery of siRNA to the lungs. PEG is commonly used for the design of mucus-penetrating nanoparticles, while the combination with HA polymer provides additional selective targeting to lung tumor cells overexpressing CD44 receptors. Cationic liposomes modified with HA and PEG in the respective concentrations of 10 and 15% (w/v) and 5, 10 and 15% (molar ratio) were prepared by ethanol injection and mixed with siRNA molecules for LX formation. Multiple particle tracking (MPT) was performed ex vivo to evaluate the influence of the hydrophilic polymers in the particles movement in fresh human airway mucus. In vivo LX distribution in the lungs of mice was analyzed by fluorescence microscopy after intratracheal administration. LX modified with both polymers showed increasing diffusion with Brownian-like trajectories in mucus samples along with the presence of siRNA. PEG12%/HA15%-LX at the charge ratio ±4:1 were more widely distributed throughout mice lungs. Non-PEGylated HA15%-LX at the charge ratio ±4:1 diffused comparably to PEGylated LX, as opposed to non-modified LX, which were trapped in the mucus. LX interaction with A549 lung cells showed that the presence of HA improved cell uptake despite PEGylation, demonstrating that appropriate particle coating with mucoinert polymers and tuning surface charge compose an efficient strategy for siRNA delivery to CD44-expressing lung cells.

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Section: Resultsmentioning

confidence: 99%

Mucopenetrating lipoplexes modified with PEG and hyaluronic acid for CD44-targeted local siRNA delivery to the lungs

et al. 2019

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“…[29] For example, coating of polymeric nanocarriers and lipoplexes with HA significantly enhanced their intravitreal mobility compared to uncoated species. [41,42] We speculated that nanoparticles for intracameral injection may also benefit from an HA-coating because negatively charged, HA-coated nanoparticles may not be attracted to ECM components which have an overall net negative charge, thereby allowing them to diffuse through the TM more effectively. Indeed, significantly fewer negatively charged HA-NPs were intercepted in the inner TM compared to positively charged PEI-NPs of similar size (Figures 4 and 5).…”

Section: Discussionmentioning

confidence: 99%

“…It was not possible to completely inhibit nanoparticle binding and uptake by the addition of free HA, but this is in line with other studies where interaction of CD44 with HA-coated nanoparticles was investigated. [41–43] It is of interest that the cell-associated fluorescence after incubation with PEI-NPs was also slightly reduced in the presence of free HA. We assume that positively charged particles may have interacted with free negatively charged HA and thus been retracted from the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…A beneficial effect of a HA-coating has also been demonstrated for other gene delivery systems: a covalent coupling of HA to lipoplexes reached an 8-fold increase of transgene expression compared to uncoated lipoplexes. [41] Moreover, a very interesting result of gene silencing studies was that CTGF silencing seemed to depend on the basal cellular CTGF level (Figure 6E,F). This relationship might be a great therapeutic opportunity: if silencing with HA-functionalized nanoparticles is more effective in cells with high CTGF levels, healthy cells would remain unaffected by a potential therapy and undesired side-effects caused by “over-silencing” would be avoided.…”

Section: Discussionmentioning

confidence: 99%

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Intracameral Delivery of Layer‐by‐Layer Coated siRNA Nanoparticles for Glaucoma Therapy

Dillinger

Guter

Froemel

et al. 2018

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Glaucoma is the second leading cause of blindness worldwide, often associated with elevated intraocular pressure. Connective tissue growth factor (CTGF) is a mediator of pathological effects in the trabecular meshwork (TM) and Schlemm’s canal (SC). A novel, causative therapeutic concept which involves the intracameral delivery of small interfering RNA against CTGF is proposed. Layer-by-layer coated nanoparticles of 200–260 nm with a final layer of hyaluronan (HA) are developed. The HA-coating should provide the nanoparticles sufficient mobility in the extracellular matrix and allow for binding to TM and SC cells via CD44. By screening primary TM and SC cells in vitro, in vivo, and ex vivo, the validity of the concept is confirmed. CD44 expression is elevated in glaucomatous versus healthy cells by about two-to sixfold. CD44 is significantly involved in the cellular uptake of HA-coated nanoparticles. Ex vivo organ culture of porcine, murine, and human eyes demonstrates up to threefold higher accumulation of HA compared to control nanoparticles and much better penetration into the target tissue. Gene silencing in primary human TM cells results in a significant reduction of CTGF expression. Thus, HA-coated nanoparticles combined with RNA interference may provide a potential strategy for glaucoma therapy.

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“…Combination therapy can exert synergistic effects and bring about more efficacious therapies, since complex tissues can be targeted. For instance, polyplexes containing 1,2dioleoyl-3-trimethylammonium-propane (DOTAP) and the fusogenic lipid, 1,2-dioleoylsn-glycero-3-phosphoethanolamine (DOPE) coated with HA have shown more efficient cellular uptake and, consequently, higher transfection efficiency compared to polyplex only [66,67]. A strategy to overcome current hurdles could be to optimize particle design for specific targeting of the retina in order to improve the treatment modality.…”

Section: Novel Drug Delivery Systemsmentioning

confidence: 99%

Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

Pishavar

Luo

Bolander

et al. 2021

IJMS

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Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.

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Effect of hyaluronic acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy

Cited by 34 publications

References 44 publications

Mucopenetrating lipoplexes modified with PEG and hyaluronic acid for CD44-targeted local siRNA delivery to the lungs

Mucopenetrating lipoplexes modified with PEG and hyaluronic acid for CD44-targeted local siRNA delivery to the lungs

Intracameral Delivery of Layer‐by‐Layer Coated siRNA Nanoparticles for Glaucoma Therapy

Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

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