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Nanotechnology for Gene Delivery to the Eye
Table 1: Key Advances in the Application of Nanotechnology to Ocular Gene Delivery
Nanosystem Route of Animal Observation Reference
Type Administration Model
Nanoplexes Intravitreal Rats Complex of fibronectin antisense oligonucleotide with polyoxyethylene–polyspermine block co-polymer 23
persisted in retinal vascular cells until 6 days and significantly reduced fibronectic mRNA and protein levels.
Intravitreal Rats Anti-TGFβ-2- oligonucleotide/polyethyleneimine complexes are preferentially localised in retinal muller cells 20
at 72 hours after injection.
Subretinal Rats Basic fibroblast growth factor complexed with two oligopeptides (K8 and JTS-1) efficiently transfected retinal 21
and choroidal cells. At 60 days after injection, a delay in photoreceptor degeneration was observed.
Intravitreal Mice Intravitreal injection resulted in gene expression in the inner plexiform layer and retinal ganglion cells. 10
Subretinal Subretinal injection resulted in gene expression in the neural retina, retinal pigment epithelium, choroid
and sclera.
Dendrimer Intravitreal Rats Anti-VEGF oligonucleotide–amino acid dendrimer significantly inhibited the development of choroidal 8
neovascularisation for 4–6 months. CNV was induced in rats using a Krypton laser (647.1nm). 6–9 burns
were applied to each eye (100µm, 0.1 seconds, 150mW).
Micelles Topical Mice and The micelles were prepared using poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) block 24
rabbits co-polymers. β-galactosidase expression was observed in the sclera, conjunctiva, iris and tendon of the lateral
rectus muscles. Low-level gene expression was also observed in the anterior chamber, cornea, retinal pigment
epithelium and vitreous body.
Nanoparticles Intravitreal Mice Human serum albumin nanoparticles protected the loaded Cu/Zn superoxide dismutase plasmid against 9
nuclease degradation, sustained plasmid release for up to 6 days, transfected ARPE-19 cells with 80%
transfection efficiency and expressed detectable levels of protein in 48 hours in vivo.
Intravitreal Rats Poly-lactide nanoparticles injected into the eyes led to preferential expression of red nuclear fluorescent 29
protein in the retinal pigment epithelial layer.
Intravenous Rats Administration of anti-VEGF intraceptor-loaded poly-(lactide-co-glycolode) nanoparticles targeted gene 17
expression to the neovascular eye and the inhibited laser induced choroidal neovascularisation.
Liposomes Topical Rats β-galactosidase expression in the cornea, conjunctival epithelial cells and retinal ganglion cells for up 32
to 1 month.
Intracameral Rats and HVJ fusogenic liposomes express β-galactosidase in the trabecular meshwork. 38
rhesus
monkeys
Intravitreal Rabbits Liposomes increased stability of oligonucleotide in the vitreous. Significant levels of oligonucleotide (37%) 39
were detected in the vitreous at 15 days after injection.
Intravitreal Rabbits Cationic liposomes transfected the cornea, aqueous humour, iris-ciliary body, lens, vitreous and retina. 40
Gene expression peaked at 3 days after injection and lasted for at least 7 days.
Intravenous Mice Pegylated immunoliposomes resulted in widespread expression of β-galactosidase gene loaded in the 14
ciliary body, iris, sebaceous glands of tarsal plate and retina.
CNV = choroidal neovasculrisation; HVJ = haemagglutinating virus of Japan; mRNA = messenger RNA; TGF-β2 = transforming growth factor-β2; VEGF = vascular endothelial growth factor.
retinal cell layers. Immunohistochemistry revealed that the dendrimers expression was observed on days two to three in the iris, sclera,
were well tolerated and showed no observable signs of inflammation. conjunctiva and lateral rectus muscle in rabbits. In mice, gene
expression was also observed in intraocular tissues such as the
Micelles for Ocular Gene Delivery anterior chamber and the retinal pigment epithelium.
Micelles are colloidal aggregates of amphiphilic molecules. Micellisation
is a self-assembling property exhibited by amphiphilic molecules in Nanoparticles for Ocular Gene Delivery
aqueous solution above a specific concentration, referred to as critical Nanoparticles are spherical particles with diameters in the
micelle concentration (CMC). Although any surfactant molecule is nanometer size range. They can be prepared with lipids, proteins,
suitable for forming a micelle, micelles based on block co-polymers polysaccharides or polymers,
25
and can be broadly classified as
made up of repeating hydrophilic and lipophilic blocks are being nanospheres or nanocapsules: nanospheres are nanoparticles with
extensively investigated as therapeutic carriers for drug and gene drug or gene molecules dispersed in a carrier matrix, while
delivery. Micelles can be spherical, rod-shaped or lamellar depending nanocapsules are composed of a reservoir of drug solution or solid
on the nature of the monomer units. An example of such a block coated by a rate-limiting layer.
26
Thus, nanocapsules have a distinct
co-polymer is Pluronic
®
, which consists of ethylene oxide (EO) 7 and core containing drug and an outer shell made up of a membrane.
propylene oxide (PO) blocks arranged in the following order:
EO
x
–PO
y
–EO
x
.
23
Our research has made significant contributions in proving
therapeutic efficacy and gene delivery to the eye using nanoparticles.
An interesting report by Liaw et al.
24
showed the delivery of reporter We are investigating the use of albumin (natural) and biodegradable-
lacZ gene after topical dosing in mice and rabbits. The micelles polymer (synthetic) -based nanoparticles for facilitating gene delivery
were formed using poly(ethylene oxide)–poly(propylene oxide)– to the eye. With the US Food and Drug Administration (FDA) approval
poly(ethyleneoxide) triblock co-polymers. The micelles had an of albumin nanoparticles (130nm) loaded with paclitaxel (Abraxane
®
)
average size of 160nm and a zeta potential of -4.4mV. After two in 2005, albumin serves as an acceptable carrier for preparing
days of topical instillation three times a day, the most intense gene nanoparticles. Albumin-based nanoparticles as a gene delivery
EUROPEAN OPHTHALMIC REVIEW 9
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