Efficient Delivery of Hydrophilic Small Molecules to Retinal Cell Lines Using Gel Core-Containing Solid Lipid Nanoparticles

Abstract

In this study, we developed a novel solid lipid nanoparticle (SLN) formulation for drug delivery of small hydrophilic cargos to the retina. The new formulation, based on a gel core and composite shell, allowed up to two-fold increase in the encapsulation efficiency. The type of hydrophobic polyester used in the composite shell mixture affected the particle surface charge, colloidal stability, and cell internalization profile. We validated SLNs as a drug delivery system by performing the encapsulation of a hydrophilic neuroprotective cyclic guanosine monophosphate analog, previously demonstrated to hold retinoprotective properties, and the best formulation resulted in particles with a size of ±250 nm, anionic charge > −20 mV, and an encapsulation efficiency of ±60%, criteria that are suitable for retinal delivery. In vitro studies using the ARPE-19 and 661W retinal cell lines revealed the relatively low toxicity of SLNs, even when a high particle concentration was used. More importantly, SLN could be taken up by the cells and the release of the hydrophilic cargo in the cytoplasm was visually demonstrated. These findings suggest that the newly developed SLN with a gel core and composite polymer/lipid shell holds all the characteristics suitable for the drug delivery of small hydrophilic active molecules into retinal cells.

Strategies for Improved pDNA Loading and Protection Using Cationic and Neutral LNPs with Industrial Scalability Potential Using Microfluidic Technology

“…In a previous study, we demonstrated the importance of a liquid core to load hydrophilic molecules, like nucleic acids. 74 In this view, microfluidics offered two huge and unexpected advantages for the delivery of pDNA over the limited standard post-modification approach normally seen in the literature. First, the “pre” addition allowed to have almost 100% of pDNA bound to LNPs even with 100 µg/mL while maintaining their physical characteristics, which fall within the limits for good biodistribution and monodispersity, compared to the “pre” addition leading to poor NMed formation even at only 15 µg/mL, demonstrating how when this new technique is optimized could be incredibly advantageous for gene delivery.…”

Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain

“…Subsequently, PARP may indirectly activate calpains via its excessive consumption of NAD + and a resultant breakdown of cellular energy metabolism [ 25 ]. Loss of intracellular ATP will impair the function of plasma membrane Ca 2+ ATPase (PMCA), an active transporter that is crucial for keeping intracellular Ca 2+ levels low [ 65 ]. Remarkably, HDAC inhibition has been found to increase PMCA activity [ 66 , 67 ], which thus could enhance intracellular Ca 2+ clearance and reduce calpain activity.…”

Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles

“…Toxicity of NPs was assessed as previously published [ 57 ]. Briefly, 661W-A11 cells were cultured in 96-well plates at a density of 6000 cells/well and increasing dilutions of NPs were added to the culture medium.…”