Open Journal of Ophthalmology, 2013, 3, 127-133
Published Online November 2013 (
Open Access OJOph
Nanobiotechnology in the Management of Glaucoma*
Pho Nguyen1, Alex Huang1, Samuel C. Yiu2,3#
1Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, USA; 2The Wilme r
Eye Institute, Baltimore, USA; 3King Khaled Eye Specialist Hospital, Riyadh, KSA.
Received September 2nd, 2013; revised October 5th, 2013; accepted October 15th, 2013
Copyright © 2013 Pho Nguyen et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
As the prevalence of glaucoma continues to rise, clinicians and researchers are confronted with an age-old problem:
how to reduce risk factors and preserve vision in glaucoma. Current management options revolve around a validated
paradigm—intraocular pressure reduction. Active investigations to improve drug delivery efficacy and surgical out-
comes are flourishing. This article aims to provide the interested readers with a review of recent discoveries in nano-
biotechnology for the management of glaucoma. Targeted drug-delivery systems using mesoscale vectors demonstrate
promising delivery profiles. The utility of nanoparticulate therapies to support retinal ganglion cell survival is being
investigated. Studies to modulate tissue regeneration and remodeling and improve post-trabeculectomy outcomes are
underway. Though these modalities promise new avenues to manage glaucoma, immediate market availability is not
anticipated soon.
Keywords: Glaucoma; Nanotechnology; Nanomedicine; Drug Delivery; Wound Healing; Nanoparticle
1. Introduction
Glaucoma is a group of diseases having characteristic
optic neuropathy with associated visual function deficits.
Early disease detection and vision preservation con stitute
the management of glaucoma. Currently, therapeutic
strategies involve medical and surgical reduction of in-
traocular press ure (IOP). However, maintaining lo cal ther-
apeutic bioavailability of hypotensive agents remains a
challenge in the field of ophthalmic drug delivery. Sur-
gical modalities are effective but have associated com-
plications [1]. Given that 60 million people worldwide
are afflicted by this disease [2] and 27% of those af-
flicted are at risk of developing glaucoma-related blind-
ness in one eye after 20 years [3], the demand for viable
treatment alternatives, particularly improved drug deliv-
ery models, is self-evident.
2. Nanobiotechnologies for Glaucoma
Previously, many clinical trials demonstrated that initial
medical management is an effective option for IOP re-
duction and vision preservation [4-11]. Although topical
instillation is the predominant route, ensuring effective
local concentration is a fundamental challenge. Precor-
neal factors such as small load, poor tissue penetration,
mechanical removal by tears and blinking, and nasolac-
rimal elimination prevent the medication from reaching a
sustained therapeutic level and necessitate multiple dos-
ings per day, ultimately, leading to poor patient adher-
ence [12-14]. Other studies further report that many pa-
tients waste much of the topical medications because of
incorrect instillation techniques [13-15]. Systemic ab-
sorption may precipitate adverse effects [16-21]. There-
fore, efforts are directed toward developing better drug
delivery systems, e.g. ophthalmic inserts, smart hydrogel,
vesicular and particulate carrier systems.
*Financial Support(s): Alex Huang is supported by the Heed Ophthal-
mic Foundation.
Pho Nguyen is supported by the Heed Ophthalmic Foundation and the
Fletcher Jones Foundation.
Financial Disclosure(s): The authors have no financial interests in the
topic of this manuscript. No conflicting relationship exists for any
#Corresponding author.
Nanoscale drug delivery systems offer the therapeutic
advantages of targeted tissue penetration, enhanced re-
lease kinetics, and increased local biodistribution [22-24].
In the field of tissue engineering and regenerative medi-
Nanobiotechnology in the Management of Glaucoma
cine, the biologic length scale of nanostructures promotes
meaningful interactions for tissue repa ir and regeneration
[23]. “Nano” was originally defined for the semiconduc-
tor industry as having at least one dimension less than
100 nanometer; but the definition of “nano-” has been
recast in an operational fashion and many authors use
“nano-” to include biologically relevant length scale,
such as larger macromolecules and organelles for the
fields of nanobiotechnology and nanomedicine [22-24].
Below, we summarize the recent discoveries in nanobio-
technology for the management of glaucoma.
2.1. Drug Delivery Systems
2.1.1. Vesicular Platforms—Liposomes, Discomes ,
and Niosomes
Modeled after biologic organelles, liposomal systems are
designed fo r encapsulation of therapeutic agen ts for drug
delivery and have found to have increased efficacy and
decreased toxicity. Their diverse systemic applications
encompasses liposomal daunorubicin for Kaposi’s sar-
coma, micellar paclitaxel for ovarian and breast cancer,
and liposomal amphotericin B for systemic fungal infec-
tions or leishmaniasis. Surface modifications, such as
PEGylation of the liposome, extend systemic circulating
time and reduce toxicity.
Liposomal preparations of topical ophthalmic medica-
tions are particularly well studied for ocular surface in-
fections. Use of liposomal amphotericin B for the treat-
ment of fungal keratitis has been repo rted to significan tly
reduce toxicity compared to non-liposomal formulation
[25,26]. Topical liposomal acyclovir shows better deliv-
ery than commercial acyclovir ointment in in vitro stud-
ies and animal models [27]. Liposomal formulations of
gatifloxacin, ciprofloxacin and fluconazole have shown
prolonged delivery profiles, leading to better in vitro
transcorneal permeation compared to aqueous formula-
tions [28-30].
Other investigators are evaluating the feasibility of
liposome-encapsulated ocular antihypertensive drugs.
Topical liposomal and niosomal formulations of aceta-
zolamide, a carbonic anhydrase inhibitor, are being in-
vestigated for their ability to overcome acetazolamide’s
limited aqueous solubility and improve its corneal per-
meation [31-34 ]. In vitro and in vivo studies demonstrate
sustained release kinetics with good intraocular hypoten-
sive effect [32].
In addition to liposomes, other vesicular platforms,
such as discomes and niosomes, are also being explored
for ocular antihypertensive medications. Discomes are
non-ionic surfactant-based discoidal vesicles, which also
improve drug delivery. Some authors have reported that
discoidal vesicles containing timolol maleate produce a
sustained activity profile upon introduction to the ocular
cavity [35]. Niosomes are another non-ionic bilayered
vesicle that can entrap both hydrophilic and lipophilic
drugs, either in the aqueous layer or in the vesicular
membrane. Compared to liposomes, niosomes offer some
advantages, such as chemical stability and lower produc-
tion cost. A recent study reported that a mucoadhesive-
coated niosomal system for timolol maleate can achieve
higher peak concentrations for an extended period com-
pared to the conventional dose form [36]. Sizes of these
discomes and niosomes are in the micron range [35,36].
Lastly, a more recent nanovesicular formulation of bri-
monidine tartrate has been constructed using sorbitan
stearate and cholesterol, and the authors report signifi-
cant intraocular pressure-lowering activity for a pro-
longed period of time compared to the commercial pre-
paration [37-39]. Most of the above studies report no
short-term toxicity to the ocular surface of the animal
2.1.2. Nanop a rti cul ate Platforms
Development of nanoparticulate platforms for drug de-
livery has gained significant traction over recent years.
The nanoscale size range and surface functionalization
offer the advantages of targeted delivery and resistance
to degradation. Particulate delivery systems also provide
more stable storage media, compared to vesicular sys-
tems. Biodegradable polymeric platforms present an ex-
citing opportunity for investigators, where the pharma-
cokinetics is determined by the particulate size and car-
rier material, which is ultimately controlled by synthesis
Biodegradable poly(lactic-co-glycolic) acid (PLGA)
polymers have promise as potential couriers for anti-
hypertensive agents. Timolol maleate integrated into
PLGA polymers via a solvent evaporation method has
been reported to have sustained release kinetics [40]. The
release mechanism is proposed to be polymeric degrada-
tion, rather than microporous diffusion. Another study
suggests that PLGA and poly(l-lactide) acid (PLLA) mi-
cro- and nanoparticles can deliver timolol maleate con-
tinually over a 3-month period [41]. Intravitreal injection
of PLGA is safe in a rabbit model, where only a localized
foreign body reaction is reported [42]. In this study, the
authors observed that the choroid and retina maintain
normal appearence and no clinical inflammation was
detected. Accordingly, some investigators are optimistic
that these biodegradable polymeric micro- and nano-
spheres may find application as subconjunctival depots to
improve patient adherence [41]. Similarly, nanoparticu-
late platforms for carbonic anhydrase inhibitors are being
investigated as well. Methazolamide nanoparticles are
reported to have longer and higher therapeutic efficacy
compared to suspension formulation and commercial eye
drops [43,44].
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Nanobiotechnology in the Management of Glaucoma 129
Another polymer of ophthalmic interest is chitosan, a
polycationic biodegradable polymer composed of re-
peating glucosamine units. The chitosan nanoparticles
are thought to have longer precorneal residence time and
increased corneal penetration. Gatifloxacin-loaded chi-
tosan nanoparticles show sustained released kinetics [45].
Chitosan/polylactic acid nanoparticles containing rapa-
mycin demonstrate improved corneal allograft survival in
a rabbit model compared to aqueous suspension [46].
With respect to ocular anti-hypertensive agents, nanopar-
ticulate formulations of chitosan and timolol maleate or
dorzolamide hydrochloride have also been described [47].
These investigators find that modification of these
nanoparticles with hyaluronic acid, which improves mu-
coadhesion, significantly decreases intraocular pressure
in a rabbit model, compared to plain solutions of these
2.1.3. Dendrimeric Platforms
Dendrimers comprise a fascinating drug carrier system.
These hyperbranched globular macromolecules with den-
dritic subunits have modifiable properties depending on
their subunits and surface terminal groups. Therapeutic
agents can either be encapsulated in the core of the den-
drimer scaffold or conjugated on the surface. The den-
drimer diameter can be customized based on its genera-
tion and terminal groups.
Some therapeutic agents being investigated include
propranolol, sulfasalazine, folic acid, adriamycin, meth-
otrexate, paclitaxel, and penicillin. Photodynamic ther-
apy and gene therapy using dendrimers for corneal, reti-
nal, and choroidal neovascularization have been pub-
lished [48-50]. For glaucoma, poly(amidoamine) den-
drimeric constructs have been constructed to deliver pi-
locarpine and tropicamide [51]. These dendrimers appear
to have greater corneal residence time, increased bio-
availability, and low ocular irritation index in animal
model. A recent study reported increased uptake of ti-
molol maleate and brimonidine using poly(amidoamine)
dendrimer hydrogel as delivery modality in bovine cor-
neal model [52].
2.2. Tissue Protection
Currently, IOP control drives glaucoma management.
However, some investigators are evaluating the feasibil-
ity of neuroprotection as well. Apoptosis of retinal gan-
glion cells (RGC) has b een associated with glaucomatous
optic neuropathy [53]. Studies using RGC death after
optic nerve injury in an animal mode l suggest that n euro-
trophic factors, e.g. brain-derived growth factors, insu-
lin-like growth factors, glial-derived neurotrophic factor,
and ciliary neurotrophic factors (CNTF) may support
RGC survival [54-56]. Accordingly, the roles of neuro-
trophic factors in neuroprotection in glaucoma are being
explored. Lentiviral-mediated transfer of CNTF into
Schwann cells for optic nerve repair has been found to
significantly increase RGC survival in animal models
[57]. Others investigators have used biodegradable PLGA
polymers to construct nano- and microspheres for CNTF
encapsulation [58]. These authors report bioactivity in an
in vitro neural stem cell model and note that the process
of protein encapsulation with the polymer did not reduce
its potency. Others incorporate CNTF nanospheres into
photopolymerizable hydrogel to create a tissue engineer-
ing scaffold with intrinsic sustained drug delivery capa-
bility [59]. This scaffold provides an enhanced substra-
tum for neural tissue repair and regeneration. Recently,
induction of heat shock protein for neuroprotection using
superparamagnetic nanoparticles has also been reported
[60]. In the near future, successful commercial deploy-
ment of these and other developments will add another
set of tools in the armamentarium of the glaucoma spe-
cialist to preserve vision.
2.3. Modulation of Postsurgical Wound Healing
in Filtration Surgery
Successful glaucoma filtering surgery necessitates ade-
quate passage of the aqueous humor from the anterior
chamber to an extraocular reservoir. Exuberant cicatricial
changes to the conjunctiva following glaucoma filtration
procedures present a threat to long-term success [61,62].
Antifibrotic agents have been demonstrated to promote
longer bleb survival but are associated with severe com-
plications such as leakage, infection, hypotony, and en-
dophthalmitis [63-65]. Currently, antifibrotic agents are
mostly frequently introduced intraoperatively via a soaked
sponge. As with drug delivery of intraocular pressure
lowering medications, nanobiotechnology can be directed
toward improvement of bleb survival.
A disc carrying biodegradable poly(lactic acid) mi-
crospheres loaded with 5-fluorouracil for subconjunctival
implant has been developed and tested in a rabbit model
[66]. The authors show that delivery of 5-fluorouracil
using the carrier resulted in greater decrease in intraocu-
lar pressure, prolonged bleb persistence, and less corneal
toxicity. Syntheses of various nanoparticulate 5-fluorour-
acil and mitomycin have also been reported [67-69].
However, ophthalmic applications of these nanoparticles
have yet to be investigated.
Other investigators target the growth factor mediated
cellular proliferation. In one study, glucosamine and
glucosamine 6-sulfate dendrimers were used to target
fibroblast growth factor-2 mediated endothelial cell pro-
liferation and neoangiogenesis in a rabbit model of scar
tissue formation after glaucoma filtration surgery [70].
The authors report that postoperative day 30 bleb sur-
vival improves from 30% to 80%. Histologic examina-
tion revealed less cicatricial proliferation in the den-
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Nanobiotechnology in the Management of Glaucoma
drimer group. In another approach, biodegradable porous
PLGA microspheres containing antisense-TGF-β2 oli-
gonucleotide nanocomplexes have been found to pro-
mote bleb survival in a rabbit model of filtering surgery
[71]. The antisense oligonucleotide reduces synthesis of
the cytokine TGF-β2, which promotes wound healing. In
this study, the nanocomplexes are encapsulated into po-
rous microspheres and administered subconjunctivally.
The authors report increased penetration of the encapsu-
lated oligonucleo tides in conjunctival cells and increased
time to filtering bleb failure. Steroids may also be pack-
aged via nanoparticles to modulate postoperative wound
healing. Dexamethasone entrapped in biodegradable
poly(d,l-lactide-co-glyco lide) (PLGA) nanoparticles has
been reported [72]. These nanoparticles can find applica-
tions both in preventing filtering bleb scarring and in the
investigation of steroid response in glaucoma.
Viral vectors constitute another form of particulate
nanoparticles that can be directed toward glaucoma sur-
gical management. Adenovirus-mediated gene therapy
has been performed to prevent bleb scarring in a rabbit
model of glaucoma filtration surgery [73]. The authors
find that topical, intraoperative application of recombi-
nant adenovirus containing the human p21 gene demon-
strates inhibition of wound healing and fibroproliferation
after filtration surgery, comparable to mitomycin but
with fewer adverse effects. Similar results are seen with
an Ad-p27 vector [74]. Interestingly, attempts to use viral
vectors to blunt steroid response are also underway.
Novel glucocorticoid-inducible adenovirus vectors have
been developed to overproduce metalloprotein 1, which
degrades collagen type I after specific activation by
dexamethasone [75]. Therefore, patients who presumably
need long-term steroid treatment may benefit by having
increased metalloproteinase activity to aid trabecular
flow while on st eroi d s.
3. Conclusion
This brief review highlights the recent advances and ad-
vantages of nanobiotechnology for improving our under-
standing of glaucoma and its management. In essence,
nanobiotechnolo gy offers th e potential f or more effectiv e
delivery of pharmaceutical agents that can influence both
the medical and surgical arms of glaucoma management.
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