Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

Abstract

One of the main challenges in gene therapy is the issue of delivery, and it is especially relevant for the success of gene therapy in the cornea. In the present work, eye drops containing biocompatible non-viral vectors based on solid lipid nanoparticles (SLNs) as gene delivery systems to induce the expression of interleukin 10 (IL-10) were designed to address the treatment of corneal inflammation. Two kinds of SLNs combined with different ligands (protamine, dextran, or hyaluronic acid (HA)) and formulated with polyvinyl alcohol (PVA) were prepared. SLN-based vectors were characterized in terms of size, adhesiveness, viscosity, and pH, before topical administration to wild type and IL-10 knock out (KO) mice. The formulations showed a homogenous particle size below 400 nm and a positive surface charge to favor bioadhesion; the incorporation of PVA improved the corneal penetration. After three days of treatment by topical instillation, SLN-based vectors mainly transfected corneal epithelial cells, HA-formulations being the most effective ones. IL-10 was capable of reaching even the endothelial layer. Corneal sections showed no histological change and formulations seemed to be well tolerated after repeated topical administration. These promising results highlight the possible contribution of non-viral gene augmentation therapy to the future clinical approach of corneal gene therapy.

Preparation of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Drug Delivery and the Effects of Preparation Parameters of Solvent Injection Method

“…In addition to chemical compounds, SLNs and NLCs can deliver peptides and proteins with a high degree of efficiency and low toxicity [ 102 , 103 , 104 ]. They are also potential platforms for non-viral gene delivery [ 192 , 193 ]. A recent study prepared siFVII-loaded NLCs for intravenous injection in mice, and achieved >80% knock-down of plasma coagulation factor VII in liver [ 144 ].…”

mRNA-Based Nanomedicinal Products to Address Corneal Inflammation by Interleukin-10 Supplementation

“…SLN C were composed of behenic acid as the lipid matrix, coated by the suspending agent PVA 9000 and the cationizing agent DEAE-dextran, as previously described [32]. Briefly, sodium behenate and PVA 9000 were dissolved in water under hot agitation, and when the solution reached 80 • C and became translucent, NaOH was added.…”

“…This makes them suitable for topical drug administration by improving corneal permeation and retention [30,31]. Previously, our research group has used a gene augmentation strategy to induce IL-10 production into the cornea by the administration of SLNs containing plasmid DNA (pDNA) [32]. However, mRNA could be an alternative therapeutic option to tackle corneal inflammation, thanks to its high efficacy, safety profile, and versatility for fast protein production.…”

Biodegradable Nanoparticle for Cornea Drug Delivery: Focus Review

“…Solid based nanoparticle was developed by Torrecilla et al for short-hairpin RNA (shRNA) gene delivery with the main objective of downregulation metalloproteinase 9 (MMP-9) in cornea cells for neovascularization treatment [ 116 ]. Recently, two different types of positive surface charge solid nanoparticles with different ligands (protamine, dextran, or hyaluronic acid (HA)) and synthesized by polyvinyl alcohol (PVA) were developed by Vicente-Pascua et al [ 117 ]. Due to the presence of PVA in their formulation, the cornea penetration was enhanced, and based on their observations, no histological change was found in the cornea tissue.…”

“…Due to the presence of PVA in their formulation, the cornea penetration was enhanced, and based on their observations, no histological change was found in the cornea tissue. Moreover, among all the prepared solid nanoparticles, the one combined with hyaluronic acid (HA) proved to be the most efficient formulation [ 117 , 118 ].…”