Nanomedicine: Nanotechnology, Biology and Medicine
Original ArticlePreclinical development and ocular biodistribution of gemini-DNA nanoparticles after intravitreal and topical administration: Towards non-invasive glaucoma gene therapy
Graphical Abstract
Non-viral trifunctional gemini surfactant-phospholipid nanoparticles carrying Cy5-labeled plasmid DNA demonstrated excellent thermodynamic stability in the vitreous and tear fluid and distinct trafficking behavior and biodisposition within the eye in vivo after intravitreal or topical application with respect to pathways of movement and physicochemical stability. After intravitreal injection in mice, localized within the nerve fiber layer of the retina, whereas after topical application, GL-NPs were located in several anterior chamber tissues, including the limbus, iris and conjunctiva.
Section snippets
Background
Glaucoma is the second leading cause of blindness with 60.5 million patients worldwide in 2010, a figure that is expected to increase to 79.6 million by 2020.1 Risk factors of glaucoma include intraocular pressure (IOP) beyond the normal range of 10-21 mmHg,2, 3 vascular disorders that lead to reduced perfusion of the optic nerve head (ONH) (see review by Yanagi et al4), and certain biomechanical features of the ONH and retina.5, 6 IOP management, which is currently the main treatment for
Gemini nanoparticle formulation and optimization
Gemini NPs based on the pH-sensitive gemini surfactant 12-7NH-12 were prepared as described earlier.25 NPs (PG + L) were assembled in two steps: the plasmid (pCMV-tdTomato, Clontech Laboratories Inc., Mountain View, CA) and 12-7NH-12 gemini surfactant were mixed at room temperature for 15 min to form plasmid–gemini (PG) complexes at different cationic:anionic (ρ ±) charge ratios. Helper lipid vesicles (1 mM DOPE [Avanti Polar Lipids, Alabaster, AL] vesicles, prepared using the thin-film method25)
Physicochemical characterization and transfection efficiency of NPs
The two-step NP assembly process is illustrated in Figure 1, A and the parameters optimized during the formulation development process in Figure 1, B. Physicochemical parameters deemed relevant for intraocular performance such as surface charge, size, morphology and NP assembly technique are shown in Table 1. Particle size of PGLDOPE NPs ranged from 158.7 ± 4.7 nm to 220.1 ± 7.0 nm with a surface charge (ζ potential) of >+30 mV for all charge ratio conditions. The effect of charge ratio on
Discussion
The development of non-viral gene delivery systems for ophthalmic administration remains challenging due to several factors. The anatomy and physiology of the eye, limit particles and molecules to pass to the back of the eye (see review by Alqawlaq et al28). The tear film covers corneal and conjuctival layers, and limits the bioavailability of applied vectors due to the high tear turnover rate as well as the lacrimal and nasolacrimal drainage. Tissue barriers, namely the cornea, conjuctiva,
Acknowledgments
The research in this paper was supported by operating and equipment grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation and the Ontario Research Fund. The generous support of the Canada Research Chairs Program the Canada Foundation for Innovation and the Ontario Research Fund is also gratefully acknowledged (M. Foldvari). J Sivak is the TWH and TGH Foundation Glaucoma Research Chair.
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