How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches

Abstract

Introduction:
Drug delivery to the back of the eye requires strategic approaches that guarantee the long-term therapeutic effect with patient compliance. Current treatments for posterior eye diseases suffer from significant challenges including frequent intraocular injections of anti-VEGF agents and related adverse effects in addition to the high cost of the therapy. Areas covered: Treatment challenges and promising drug delivery approaches for posterior segment eye diseases, such as age-related macular degeneration (AMD) are summarized. Advances in the development of several nanotechnology-based systems, including stimuli-responsive approaches to enhance drug bioavailability and overcome existing barriers for effective ocular delivery are discussed. Stem cell transplantation and encapsulated cell technology (ECT) approaches to treat posterior eye diseases are elaborated. Expert opinion: There are several drug delivery systems demonstrating promising results. However, a better understanding of ocular barriers, disease pathophysiology, and drug clearance mechanisms is required for better therapeutic outcomes. The stem cell transplantation strategy and ECT approach provide positive results in AMD therapy, but there are a number of challenges that must be overcome for long-term efficiency. Ultimately, there are numerous multidimensional challenges to cure vision problems and a collaborative approach among scientists is required.

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How are we improving the delivery to back of the
eye? Advances and challenges of novel therapeutic
approaches
Vibhuti Agrahari, Vivek Agrahari, Abhirup Mandal, Dhananjay Pal & Ashim K.
Mitra
To cite this article: Vibhuti Agrahari, Vivek Agrahari, Abhirup Mandal, Dhananjay Pal & Ashim
K. Mitra (2017) How are we improving the delivery to back of the eye? Advances and challenges
of novel therapeutic approaches, Expert Opinion on Drug Delivery, 14:10, 1145-1162, DOI:
10.1080/17425247.2017.1272569
To link to this article: http://dx.doi.org/10.1080/17425247.2017.1272569
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REVIEW
How are we improving the delivery to back of the eye? Advances and challenges of
novel therapeutic approaches
Vibhuti Agrahari*, Vivek Agrahari*, Abhirup Mandal, Dhananjay Pal and Ashim K. Mitra
School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
ABSTRACT
Introduction: Drug delivery to the back of the eye requires strategic approaches that guarantee the
long-term therapeutic effect with patient compliance. Current treatments for posterior eye diseases
suffer from significant challenges including frequent intraocular injections of anti-VEGF agents and
related adverse effects in addition to the high cost of the therapy.
Areas covered: Treatment challenges and promising drug delivery approaches for posterior segment
eye diseases, such as age-related macular degeneration (AMD) are summarized. Advances in the
development of several nanotechnology-based systems, including stimuli-responsive approaches to
enhance drug bioavailability and overcome existing barriers for effective ocular delivery are discussed.
Stem cell transplantation and encapsulated cell technology (ECT) approaches to treat posterior eye
diseases are elaborated.
Expert opinion: There are several drug delivery systems demonstrating promising results. However, a
better understanding of ocular barriers, disease pathophysiology, and drug clearance mechanisms is
required for better therapeutic outcomes. The stem cell transplantation strategy and ECT approach
provide positive results in AMD therapy, but there are a number of challenges that must be overcome
for long-term efficiency. Ultimately, there are numerous multidimensional challenges to cure vision
problems and a collaborative approach among scientists is required.
ARTICLE HISTORY
Received 1 October 2016
Accepted 12 December 2016
KEYWORDS
Ocular barriers; posterior eye
diseases; age-related
macular degeneration; drug
delivery; stimuli-responsive;
stem cell transplantation;
encapsulated cell
technology; nanocarriers;
nanotechnology
1. Introduction
Vision loss poses a major problem and it is estimated that
about 285 million people worldwide are visually impaired and
39 million are blind (http://www.who.int/mediacentre/fact
sheets/fs282/en/). The number of blind individuals increases
by approximately 7 million/year (http://www.who.int/blind
ness/Vision2020_report.pdf). In the United States, about 3.4
million individuals over the age of 40 are blind or living with
significant visual impairment [1]. The major diseases that sig-
nificantly impact vision are macular degeneration, diabetic
retinopathy, diabetic macular edema, cataract, uveitis, kerati-
tis, and glaucoma [2]. Current treatments for posterior eye
diseases suffer from significant challenges including frequent
intraocular injections, related adverse effects, and high cost of
the treatment [3]. Because of several anatomical/physiological
barriers present in the eye, drug delivery to the posterior
ocular segment is significantly impaired [4,5]. However, the
application of nanotechnology combined with various routes
of administration has been shown improvement in ocular drug
delivery. Nanotechnology offers several treatment options to
reduce the gap of limitations [6].
Considering the aforementioned facts, this review aims to
emphasize major challenges and promising drug delivery solu-
tions for the treatment of posterior eye diseases such as age-
related macular degeneration (AMD). An overview of treat-
ment strategies for AMD, highlighting the progress and
limitations in the current therapeutic approaches are
described. Various routes of drug administration to the back
of the eye and nanoformulations for the posterior eye diseases
are discussed. Further, retinal cell transplantation using stem
cells, and encapsulated cell technology (ECT) approaches are
elaborated.
1.1. Barriers and various routes of drug delivery to the
posterior eye
The interior of the human eye is subdivided into anterior and
posterior segments. Drug bioavailability in the eye is limited
due to several anatomical/static (conjunctiva, cornea, sclera,
blood aqueous and retinal barriers) and physiological/dynamic
(choroid blood flow, efflux transporters, tear washing, nasola-
crimal drainage) barriers [7]. These barriers effectively limit the
drug access to the back of the eye [8]. The usual routes for
posterior eye drug delivery are topical [9], systemic, intraocular
(suprachoroidal, intravitreal), and periocular (subconjunctival,
subtenon, retrobulbar) [10]. These routes are schematically
represented by Figure 1 and summarized below.
Topical drug administration provides high patient compli-
ance and lower side effects. Corneal and conjunctival routes
are two local pathways for drug entry from a topical adminis-
tration (Figure 2). However, topical route remains challenging
due to several constrains such as blurring of vision, precorneal
CONTACT Ashim K. Mitra mitraa@umkc.edu
*These authors contributed equally to this work
EXPERT OPINION ON DRUG DELIVERY, 2017
VOL. 14, NO. 10, 1145–1162
https://doi.org/10.1080/17425247.2017.1272569
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drug losses, nasolacrimal drainage, and limited volume of drug
administration (~30μl). In addition, normal intraocular fluid
flow gradient is from vitreous to aqueous compartment
which further limits the passage of topically applied drugs to
the back of the eye [9]. These all limit the drug absorption and
only ~5% of the drug dose reaching the interior of the eye,
mostly entering the systemic circulation [7,11].
The drug absorption through intravenous route is con-
trolled by the presence of blood–retinal barrier (BRB), thus,
requires high drug doses to achieve adequate therapeutic
levels with the risk of several adverse effects. In addition, efflux
transporters expressed on apical and basolateral cell mem-
branes of human retinal pigment epithelium (RPE) stand
against drug permeation from choroid to retina after intrave-
nous administration [12].
Intravitreal drug delivery is one of the most efficient routes
for posterior segment due to its proximity to the retina, chor-
oid, and RPE. Though invasive, this route has the potential to
provide highest intraocular bioavailability by circumventing
several barriers of the posterior eye segment [13]. However,
intravitreal administration is associated with serious risks such
as hemorrhage, persistent discomfort, retinal detachment,
degeneration of photoreceptors (PRs), increase in intraocular
pressure (IOP), cataract formation, and bacterial endophthal-
mitis [14,15].
Periocular route involve injecting the drug outside the
globe of the eye and in the proximity of the sclera. This
route utilizes the trans-scleral pathway to deliver drugs next
to the choroid provides a significant barrier of macromole-
cules drug permeation) [16]. However, drug losses via con-
junctival, episcleral blood, and lymphatic flow are limiting
factors to posterior eye delivery of small molecules following
periocular administration [10].
Suprachoroidal injections may be the most appropriate
route to reach the choroid and vitreous humor [17]. The
suprachoroidal space lies internal to the sclera and provides
a natural route for drugs injected across the sclera along the
inner surface of the eye into the posterior segment. This route
has recently been utilized to inject bevacizumab for the treat-
ment of AMD [18]. However, postoperative inflammation and
choroid hemorrhage remain a concern.
Article highlights
●Drug delivery to the eye is challenging. Conventional formulations
are unable to efficiently deliver a drug into the back of the eye due to
the presence of complex barriers, elimination mechanisms, thus,
resulting in a low ocular drug bioavailability.
●Various routes of drug administration to the back of the eye, elim-
ination pathways, delivery barriers, advantages and challenges are
elaborated.
●At present, frequent intravitreal injections are the preferred method
for the treatment of posterior eye diseases but have several side
effects and high treatment costs.
●The current treatment options and major challenges for AMD and
future therapeutics have been described.
●Several nanosystems in addition to their clinical applications for the
back of eye diseases emphasizing on AMD are discussed.
Furthermore, the current status and clinical applications of ocular
implants are reviewed. Stimuli-responsive NCs for back of the eye
diseases are also summarized.
●Retinal cell transplantation using stem cells sources and ECT
approaches; their challenges with future implications for the retinal
diseases are elaborated.
This box summarizes key points contained in the article
Figure 1. Administration routes (topical, intravenous, intravitreal, periocular, and suprachoroidal) for delivering therapeutics to the posterior of the eye.
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2. Posterior segment eye diseases and age-related
macular degeneration (AMD)
Normal aging of the posterior eye segment is characterized by
a continuous loss of PRs, Bruch’s membrane (BM) thickening,
choroid thinning, scleral stiffening, vitreous degradation, and
accumulation of debris. Among the posterior segment eye
diseases, diabetic retinopathy, glaucoma, and macular degen-
eration are the leading causes of age-related vision loss, and
represents 14% of the total causes of blindness globally
[19,20]. Macular degeneration occurs when a small area in
the retina (macula) deteriorates, and it develops as person
ages, hence referred to as AMD which is a degenerative dis-
ease that damages the RPE and PRs. It is projected that the
number of people with AMD will be at about 196 million in
2020, and 288 million in 2040 [21]. About 1.75 million
Americans are affected by AMD, and this number is expected
to increase about 3 million by 2020 [21].
In earlier stages of AMD, BM slows down the transport of
metabolites resulting in druses formation. Druses are small,
yellowish extracellular subretinal deposits of lipid, cellular
debris and protein, including complement components and
categorized as small (<63 μm), medium (63–124 μm), or large
(>124 μm) in diameter [22]. In early stages of AMD, druses are
small and semitransparent. However, excess druses can lead to
the RPE damage, and a chronic inflammatory response leads
to geographic atrophy (GA) and angiogenesis. The extent of
druses accumulation under the RPE and the amount of RPE
pigmentation changes (hypo or hyper) are clinical hallmark of
AMD progress [23].
As the disease progresses, AMD can be classified into the
dry and wet forms. Based on the absence or presence of
vascular growth progressing from the choroidal side toward
the retina, it is broadly subdivided into nonneovascular (NNV)
and neovascular (NV) AMD (also called as wet-AMD). In wet-
AMD, new blood vessels from the choroid may leak, resulting
in macular edema and hemorrhage. The risk of getting
advanced AMD increases from 2% at ages 50–59 years, to
nearly 30% for those over the age of 75 years [24]. Multiple
factors such as oxidative stress, lipid metabolism, immune
system activation, and angiogenesis play a key role in AMD
pathogenesis. The protein aggregation and immunologic pro-
cesses are also involved, including the inflammatory molecules
in BM, recruitment of macrophages, dendritic cells, and com-
plement system components in the macula area. In addition,
smoking is a major oxidative stress factor in AMD progression
[25]. The comprehensive effects of these factors can be
explored elsewhere [26,27].
2.1. Current treatments for AMD
Over the past decade, significant progress has been made in
the treatment of AMD owing to an increased understanding of
the mechanisms of ocular angiogenesis [28]. Several factors
are involved in ocular angiogenesis, with vascular endothelial
growth factor (VEGF) playing a central role [29]. VEGF-A is a 46
kDa glycoprotein produced by ocular cells in response to
oxidative stress. VEGF-A is the most potent mediator of both
retinal and choroidal angiogenesis. It stimulates endothelial
cell growth, promotes vascular permeability and induces dis-
sociation of tight junction components. Currently, no therapy
exists for dry-AMD and only dietary modifications such as
increase in intake of antioxidants, cessation of smoking, and
control of blood pressure appears to slowdown disease pro-
gression. The only approved treatment for dry-AMD is Age-
Related Eye Disease Study (AREDS) recommended vitamin
Figure 2. Schematic representation of disposition of drug or nanocarriers (NCs) in the eye following ocular administration.
EXPERT OPINION ON DRUG DELIVERY 1147
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supplements that lower the risk of developing advanced
stages of AMD [30].
In wet-AMD, a high level of VEGF has been reported to be
present below the RPE cell layer and around PRs. VEGF inhibi-
tion via intraocular anti-VEGF treatments to prevent the for-
mation of new blood vessels represents the cornerstone of
wet-AMD therapies. However, the primary atrophic compo-
nent of AMD still progresses despite anti-VEGF therapy [25].
Recombinant humanized anti-VEGF antibody fragments or
soluble receptor decoys (e.g. ranibizumab: Lucentis®;
Genentech/Roche), bevacizumab (off label drug: Avastin®;
Genentech/Roche), pegaptanib (Macugen®), and aflibercept
(Eylea®; Regeneron Pharmaceuticals) are currently Food and
Drug Administration (FDA) approved therapies for wet-AMD.
The physicochemical and pharmacokinetics parameters of
anti-VEGF therapeutics are summarized in Table 1. Another
available treatment for wet-AMD includes photodynamic ther-
apy (PDT). Studies suggested that a combination of PDT with
angiogenic inhibitors may reduce the frequency of intravitreal
injections thereby lowering the risks associated with long-term
intravitreal therapy [31]. Although PDT approach showed pro-
mising potential, more efforts are needed to develop an effi-
cient delivery system in ocular applications.
2.2. Challenges with current intravitreal anti-VEGF
treatments
Despite the facts that effective, intravitreal anti-VEGF therapies
for AMD have several drawbacks as summarized below
[3,15,38,39].
●Intravitreal injections are associated with multiple
adverse effects including retinal detachment, vitreous
hemorrhage, intraocular inflammation, tachyphylaxis,
retinal vascular occlusion, cataract, and endophthalmitis.
Moreover, intravitreal injections require a high degree of
sterility to prevent infection to nonspecific ocular tissues
and cells. Furthermore, an elevation in IOP is associated
with intravitreal injections [15].
●VEGF plays a protective role in the retinal tissue. The
knockout of VEGF in retina can lead to severe side effects
such as defects in the RPE choroid complex or the loss of
interaction between RPE and PRs outer segments.
●A prolonged suppression of the plasma VEGF due to
anti-VEGF therapy may lead to an increased risk of car-
diovascular diseases.
●The low intraocular retention of anti-VEGF drugs is a
major issue due to the high clearance rate from the
posterior section of the eye, thus requiring frequent
administration.
●An effective and safe anti-VEGF therapy should not
damage normal blood vessels and preserve the physio-
logic functions of the retinal neurons and other cells.
However, this is not the case with current anti-VEGF
therapy for posterior ocular diseases.
●Current anti-VEGF therapies do not address the under-
lying cause of AMD development.
●Patients suffering from recurrent NV-AMD may develop
resistance to anti-VEGF therapy, which can result in a
diminished therapeutic effect [32].
●The long-term anti-VEGF treatment carries a high cost
(Table 1).
To improve the safety, cost-effectiveness and impact on
patients receiving intravitreal anti-VEGF treatments, a reduc-
tion in the frequency of drug administration is required.
Hence, there remains a need for the development of new
agents, and/or novel strategies for sustained and efficient
anti-VEGF therapy. Newer anti-VEGF agents may offer longer
duration, minimize the treatment burden and overall cost of
therapy [3,38]. However, a long-term, continuous therapy with
a low financial burden remains an unmet need in AMD treat-
ment. Modifying the drug physicochemical properties, such as
the size, charge, and lipophilicity may improve the drug effi-
cacy administered through intravitreal, intraocular and supra-
choroidal routes. However, conventional formulations and
chemical modification of the drug only cannot overcome
static and dynamic barriers to ocular delivery and to reduce
the frequency of intraocular injections. In this respect, nano-
technology based approaches especially the sustained release
dosage forms can possibly overcome the current limitations of
anti-VEGF treatments [4,5].
3. Nanotechnology based drug delivery systems for
the posterior eye diseases
Nanocarriers (NCs) are colloidal systems and capable of encap-
sulating small as well as macromolecule, lipophilic and hydro-
philic drugs. Due to their small size and use of biodegradable
materials in the formulation development, NCs offer signifi-
cant advantages in ocular and other drug delivery applications
as explained below [4,5,40,41]. The therapeutic potential of
these carriers in the posterior eye diseases is summarized in
Table 2.
3.1. Liposomes
Liposomes are lipid vesicles in the size range of 0.1–10 µm.
These systems have been comprehensively used in ocular
therapeutics due to several advantages they provide such as
versatile surface modification chemistry, control in drug
release depending on the number of lipid bilayers and
composition, and potential of providing a stimuli-sensitive
drug release [69,70]. Also, the physiochemical properties
(size, surface charge, functional chemistry) of liposomes
can be modified by mixing different lipids during the for-
mulation development. The beneficial effects of liposomes
in prolonging the residence time of bevacizumab in the
vitreous after intravitreal administration is studied [44].
However, liposomes present certain limitations, such as
low reproducibility, instability of macromolecules during
the formulation process, manufacturing cost and scale up
issues, and variable size distribution [71].
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Table 1. Characteristics of anti-VEGF agents in the clinical management of AMD.
Anti-VEGF agents Structure
Biological target
and mechanism K
D
,IC
50
for VEGF Mol wt. Approval Vitreous half-life Intravitreal dose Regimen
Cost
(approx.) Ref.
Pegaptanib
sodium
(Macugen®)
Pegylated RNA
aptamer (28 base)
VEGF-A
165
200 pM 50 kDa FDA (2004),
EMA (2005)
10 days (human) 0.30 mg Every 6 weeks US $995 [32–35]
Bevacizumab
(Avastin®)
Recombinant
humanized mAb
lgG1
All isoforms of
VEGF-A
58 pM, 423 pM 149 kDa FDA (2004),
EMA (2005),
CFDA (2010)
6.7 days (human),
4.32–6.61 days (in
rabbits)
1.25 mg Every 4 weeks US $50 [32,33,35]
Ranibizumab
(Lucentis®)
Recombinant
humanized lgG1-κ
isotype mAb
fragment
All isoforms of
VEGF-A
46 pM, 343 pM 48 kDa FDA (2006),
EMA (2007),
CFDA (2012)
9 days (human), 2.88–
2.89 days (in rabbits
0.50 mg Every 4 weeks US $2000 [32,33,35]
Aflibercept
(Eylea®)
Fusion protein:
domain 2 of VEGFR-
1 and domain 3 of
VEGFR-2 fused with
lgG1 Fc
All isoforms of
VEGF-A, VEGF-B,
and PIGF
0.50 pM, 8 pM 115 kDa FDA (2011),
EMA (2012)
7 days 2.0 mg Every 4 weeks for
3 months and
then once every
8 weeks
US $1850 [32,33,35]
Conbercept Fusion protein:
domain 2 of VEGFR-
1 and domains 3 &
4 of VEGFR-2 fused
with lgG1 Fc
All isoforms of
VEGF-A, VEGF-B,
VEGF-C, and
PIGF
0.50 pM, 10 pM 143 kDa CFDA (2013) 4.2 days (in rabbits) 0.50 or 2.0 mg Every 4 weeks - [35]
Brolucizumab Immunoglobulin Fv
fragments; mAb.
Humanized, single-
chain Ab fragment
inhibitor of VEGF-A
Binds all isoforms
of VEGF-A
- 26 kDa Phase III 4.9 days 1.25 mg Every 4 weeks - [3,36]
Abicipar Small molecule:
(DARPins)
Inhibits all
subtypes of
VEGF-A
- 34 kDa Phase II 6 days 1 or 2.0 mg Every 4 weeks - [3,37]
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3.2. Polymeric nanoparticles (NPs) and microparticles
(MPs)
Polymeric NPs and MPs are biodegradable/biocompatible colloi-
dal systems in the size range of 10–1000 nm [69]and1–1000 µm
[72], respectively. In addition to the advantages similar to lipo-
somes, NPs/MPs provide flexibility in routes of administration,
stimuli-responsive system, encapsulation of multiple drugs in a
single particle, and flexibility in modifying size, shape, and surface
functionality in ocular drug delivery [1,5]. However the drawbacks
are, burst drug release may lead to drug toxicity, NPs/MPs rapid
phagocytic clearance, formulations scale-up issues, particle aggre-
gation due to large surface area, and nonuniformity in size dis-
tribution. PLGA based MPs loaded with Chitosan-NPs for the
delivery of ranibizumab have been developed [45]. Results
showed that the delivery system has the potential for improved
intravitreal delivery of therapeutic proteins.
3.3. Nanomicelles
Nanomicelles are self-assembled systems in the size range
of~10–100 nm made from biodegradable/biocompatible
amphiphilic block polymers. These vesicles can encapsulate
poorly and highly water soluble drugs in the core and outer
hydrophilic shell, respectively [73]. Nanomicelles offer numer-
ous advantages in ocular drug delivery applications, such as
easy and reproducible formulation, easy sterilization by filtra-
tion, prevention or minimization of drug degradation, possibi-
lities of changing polymer block arrangements as needed, and
improved drug permeation through ocular epithelia with mini-
mal or no irritation, thus, enhanced ocular bioavailability
[5,74]. A micelle formulation of lipid derivatized cidofovir is
developed [56]. The intravitreal injection provided a sustained
drug release in vitreous for chronic retinal diseases. Drawbacks
of nanomicelles include instability in the biological/
Table 2. Nanocarrier (NC) drug delivery systems in posterior eye diseases.
Delivery system and stimulus Therapeutics Polymer Route of administration Target disease Ref.
Liposomes pDNA Polyethylenimine (PEI) Topical AMD [42]
Bevacizumab Annexin A5-associated liposomes Topical Posterior eye diseases [43]
Bevacizumab Phospholipid (egg
phosphatidylcholine or 1,2-
dipalmitoyl-sn-glycero-3-
phosphocholine) and cholesterol
Intravitreal Posterior eye diseases [44]
Nanoparticles Ranibizumab PLGA MPs entrapping chitosan NPs Intravitreal AMD [45]
UV light Nintedanib Light-sensitive polymer Intravitreal Macular degeneration and DR [46]
Temperature Triamcinolone
acetonide
PEGylated PLGA NPs incorporated into
a PLGA-PEG-PLGA thermo-
reversible gel
Intravitreal AMD [47]
Bevacizumab PLGA Intravitreal AMD [48]
Ultrasound FITC-BSA Silk fibroin Transscleral Posterior eye diseases [49]
Coumairn-6 Chitosan and poloxamer 407 Topical Posterior eye diseases [50]
Microparticles/microspheres Ranibizumab PLGA Intravitreal AMD [51]
Bevacizumab PLA NPs encapsulated into PLGA MPs Intravitreal Posterior eye diseases [52]
Bevacizumab PLGA Intravitreal Posterior eye diseases [53]
Temperature Ovalbumin PLGA MPs in poly(N-isopropyl
acrylamide)-hydrogel
Intravitreal Posterior eye diseases [54]
Nanomicelles Dexamethasone Polyoxyl 40 stearate and polysorbate
80
Topical Posterior uveitis [55]
Hexadecyloxypropyl-
cidofovir
- Intravitreal Chronic retinal diseases [56]
Dendrimers Dexamethasone Poly (amidoamine) Topical and subconjunctival DR [57]
Light 5-Aminosalicylic acid G2 lysine dendrimers with a
silsesquioxane core
Intraperitoneal Retinal degeneration [58]
Nanowafers Dexamethasone Carboxymethyl cellulose polymer Topical Dry eye [59]
Axitinib PVA, polyvinylpyrrolidone,
(hydroxypropyl) methyl cellulose,
and carboxymethyl cellulose
CNV [60]
Nanocrystals Brinzolamide Different polymer stabilizers Topical Prolonged reduction of IOP [61]
Temperature Forskolin Poloxamer 407 and polycarbophil Topical Glaucoma [62]
Hydrogels Bevacizumab Oxidized alginate and glycol chitosan Intravitreal AMD [63]
UV light Bevacizumab PCL dimethacrylate and hydroxyethyl
methacrylate
Suprachoroidal CNV [64]
Temperature Bevacizumab PEG-poly-(serinolhexamethylene
urethane)
Intravitreal Posterior eye diseases [65]
Temperature Bevacizumab Poly(2-ethyl-2-oxazoline)-b-poly(ε-
caprolactone)-b-poly(2-ethyl-2-
oxazoline)
Intraocular Posterior eye diseases [66]
Bevacizumab PLGA-PEG-PLGA Intravitreal Posterior eye diseases [67]
Composite nanosystems
Temperature IgG-Fab PCL-PLA-PEG-PLA-PCL based NPs
suspended in a thermo-sensitive
gelling copolymer (mPEG-PCL-PLA-
PCL-PEGm)
Intravitreal Posterior eye diseases [14]
Temperature Octreotide, insulin,
lysozyme, IgG-Fab,
IgG, and catalase
Pentablock polymers with different
molecular weight and
arrangements.
Intravitreal Posterior eye diseases [68]
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physiological environment, premature drug release, and diffi-
culty in formulation scale-up.
3.4. Dendrimers
Dendrimers are branched polymeric systems in the size range
of 10–100 nm. Drugs can be either entrapped in the dendri-
mers network through hydrogen bonds, hydrophobic and
ionic interactions or conjugated through covalent bonds [75].
These systems have terminal end groups of amine/hydroxyl/
carboxyl functionalities which may be utilized to conjugate
targeting ligand and/or therapeutic molecules. Due to their
unique structure, dendrimers exhibit improved physicochem-
ical properties, uniform size distribution, and higher biocom-
patibility in ocular drug delivery. A dendrimer conjugate of 5-
aminosalicylic acid is studied for the treatment of retinal
degeneration [58]. However, the complexity in formulation
process may limit dendrimers applicability.
3.5. Nanowafers
Nanowafers are disk-like or rectangular membrane that con-
tains drug loaded nanoreservoirs. Nanowafers can be readily
applied in the eye and release the drug for a longer duration,
thus improving the overall therapeutic efficacy. During the
course of the drug release, nanowafer slowly dissolves in
aqueous media and fades away. Recently, topically applied
nanowafers with extended drug release and enhanced efficacy
have been developed to treat dry eye diseases [59,60]. Slow
drug release from the nanowafer increases the ocular surface
drug residence time and subsequent absorption into the sur-
rounding tissue. Although, nanowafers are in early develop-
ment, they have the potential to treat posterior eye diseases.
3.6. Nanocrystals
Nanocrystals are particles (size: 10–1000 nm) stabilized by the
surfactant or polymeric stabilizers. Nanocrystals possess out-
standing features enabling to overcome the solubility pro-
blems of poorly soluble drugs and provide an enhanced
bioavailability, high drug load, minimal side effects, rapid
onset of action, and an overall high efficiency and safety
[76]. Nanocrystals have been explored for the delivery of anti-
glaucoma drugs forskolin [62] and brinzolamide [61]. Thus,
nanocrystals can be designed for the treatment of posterior
eye diseases.
3.7. Hydrogels
Hydrogels have several potential applications in ophthalmol-
ogy [10]. Porous, soft nature and high water content of hydro-
gels are suitable for encapsulation of water soluble drugs
including proteins and peptides. Hydrogels are excellent for
encapsulating biomacromolecules since they are processed at
ambient temperatures and organic solvents are rarely needed
[10,77]. Hydrogels can be designed from natural or synthetic
polymers. Natural polymers provide biocompatibility, and bio-
degradability to hydrogel however, suffers from weak
mechanical strength, high batch-to-batch variability, and
immunogenicity. Synthetic polymers provide tunable mechan-
ical properties and prolonged stability. Hydrogels permit var-
ious mechanisms (diffusion/swelling/chemically controlled
and stimuli-responsive) of drug release. However, high water
content and soft nature of hydrogel may result in a rapid
release of biomolecules from the gel matrix. Moreover, the
rapidly gelling systems may affect the injectability of hydro-
gels [77].
3.8. Composite nanosystems
Composite nanosystems (NPs suspended in a gel matrix) are
made of biodegradable, FDA approved polymers. These systems
are emerging as a versatile platform in ocular drug delivery
applications [14,68]. The suspended NPs in the thermo-respon-
sive gel matrix encounter an additional diffusion barrier which
provides the long-term drug release especially for macromole-
cules. Similarly, it minimizes burst effect, and provides long-term
zero order kinetics. In addition, composite nanosystems provide
stability to macromolecules from enzymatic degradation and
helps in improving the biological half-life. The physicochemical
characteristics of composite nanosystems can be modified by
varying the chemistry, molecular weight, and block arrange-
ments of the polymers used. However, premature drug release
from the NPs and drug accumulation in the gel matrix may cause
burst effect and needs careful evaluation.
3.9. Ocular implants
Intraocular implants are designed to provide localized controlled
drug release over an extended period of time. Implants are placed
intravitreally by making an incision on the posterior globe through
minor surgery [10,78]. Though implantation is invasive, these
devices are frequently used due totheirseveraladvantagessuch
as sustained and local drug release to diseased ocular tissues at
therapeutic levels, reduced side effects and ability to circumvent
BRB [11,79]. Biodegradable ocular implants of polylactic acid (PLA),
polyglycolic acid (PGA), PLGA, and polycaprolactone (PCL) are
gaining attention due to high biocompatibility and sustained
drug release properties [79,80]. Drug release may vary depending
on the surface area, polymer degradation, swelling rates, molecu-
lar weight, and nature of the encapsulated drug [78].
Nonbiodegradable implants using polymers such as poly-
vinyl alcohol (PVA), and ethylene vinyl acetate (EVA), offer
long-lasting near zero order release kinetics [79]. However,
these devices have to be implanted and removed after drug
depletion, which renders the treatment expensive and patient
noncompliance. Moreover, adverse events such as
endophthalmitis, pseudoendophthalmitis, vitreous haze,
hemorrhage, cataract development and retinal detachment
limit their applications. In general, nonbiodegradable poly-
mers are preferred for implant fabrication to release the drug
in a more controlled manner over long-time, and the device
can be easily removed in case of adverse reactions. The ocular
implant systems for the posterior eye diseases are summarized
in Table 3.
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Table 3. Ocular implants for posterior eye diseases.
Implant Status Polymer (biodegradable/nonbiodegradable) Therapeutics Route of administration Target disease Ref.
Vitrasert FDA approval in 1996 PVA and EVA, nonbiodegradable polymers Ganciclovir Intravitreal Cytomegalo virus retinitis [78,81]
Retisert FDA approval in 2005 PVA, nonbiodegradable polymer Fluocinolone acetonide Intravitreal Chronic posterior uveitis [78,81,82]
Ozurdex (formerly
Posurdex®)
FDA approval in 2009 PLGA, biodegradable Dexamethasone Intravitreal ME [78,81,82]
Iluvien (formerly
Medidur®)
FDA approval in 2014 PVA, nonbiodegradable Fluocinolone acetonide Intravitreal DME [78,83].
I-vation™Phase 2 (terminated) Poly (methyl methacrylate), EVA, nonbiodegradable Triamcinolone Intravitreal DME [78,81,83]
Brimonidine
implant
Phase 2 Biodegradable Brimonidine Intravitreal Dry-AMD and retinitis pigmentosa [78]
Verisome®(IBI-20089) Phase 2 Benzyl benzoate, biodegradable Various drugs including
proteins, triamcinolone
acetonide (with
ranibizumab)
Intravitreal NV-AMD [78,82–84]
Durasert Phase I/II Bioerodible Latanoprost Subconjunctival space Ocular hypertension, glaucoma
Port delivery system Phase 1 Nonbiodegradable Ranibizumab Scleral incision CNV [78,83,84]
Cortiject Phase I completed Injectable emulsion Dexamethasone prodrug Intravitreal DME [78,84]
Abiciparpegol
(anti-VEGF
DARPin)
Phase II completed Anti-VEGF Intravitreal NV-AMD [78,84]
Mini drug pump (MEM
electronically
activated device)
Preclinical Polydimethylsiloxane, nonbiodegradable Variety of drugs via an
actuator based mechanism
Transscleral [78,85,86]
ODTx (laser activated) Preclinical Nonbiodegradable Multiple drug reservoirs Injectable Posterior eye diseases [78]
ENV705™Preclinical Biodegradable Bevacizumab/trehalose [78]
Nanoporous film device Preclinical Biodegradable, impermeable Ranibizumab Intravitreal [78]
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The route of administration of anti-VEGF based NCs sys-
tems is critical in the targeting of posterior eye diseases. The
route of injection for a given therapeutic depends upon the
nature of the disease and the drug molecule. The nanofor-
mulations administration should also not imbalance the
clear vitreous media with drug precipitates or particle aggre-
gates. Intravitreal injections are effective but, this route is
invasive and associated with serious side effects.
Subconjunctival, subtenon, retrobulbar and transscleral
(periocular) routes present challenges from both dynamic
and static anatomical barriers that pose significant hurdles
in ocular drug delivery. Although, the periocular or trans-
scleral routes avoid the physical barriers posed by the con-
junctiva, they require drugs to traverse several layers of
ocular tissues such as episclera, sclera, choroid, BM, and
RPE, before entering the posterior of the eye. The suprachor-
oidal route can overcome the static and dynamic ocular
barriers and has the advantage of providing higher drug
concentrations in the retina. This allows for the administra-
tion of lower doses and less frequent dosing of drugs. Thus,
suprachoroidal injections may be the most appropriate
option to reach the choroid and vitreous humor for the
treatment of posterior eye diseases [17]. Furthermore,
drugs injected into the suprachoroidal space are less likely
to reach the RPE, interact with the rods and cones of the PR
cells that can trigger the immunologic responses.
Considering the advantages and therapeutic potential of
the suprachoroidal route, a less invasive and efficient drug
delivery approach is required.
Microneedles have been recently introduced as a minimally
invasive means for delivering drug solutions or drug formula-
tion within the target ocular tissues through the suprachoroi-
dal route [87,88]. Microneedles can overcome the ocular
barriers with several potential advantages such as minimizing
pain, lower risk of infection, thus, high patient compliance can
be achieved. These needles help to deposit drug or carrier
system into sclera or into the suprachoroidal space which may
facilitate diffusion of drug into deeper ocular tissues, choroid
and retina. However, a number of parameters such as an
optimum microneedle design, safety, accuracy, reproducibility,
and manufacturing costs issues warrant further investigation.
4. Stimuli-responsive nanosystems for the posterior
eye diseases
Developing a stimuli-responsive NC system is an attractive
area for drug delivery to the posterior segment since vari-
able drug concentrations may be required at different time
points depending on the individual’s and the disease state
[78,89]. These novel systems such as NPs, microspheres,
nanofibers, and hydrogels are able to control/trigger the
drug release in a spatial and temporal manner within a
particular site in response to a number of intrinsic (pH,
temperature, enzymes, oxidative stress) and extrinsic (mag-
netic field, light, ultrasound, heat) stimuli [67,90–93]. A
schematic of stimuli-responsive delivery approaches to the
posterior eye diseases is shown by Figure 3 and are briefly
discussed below.
4.1. Light-activated systems
The transparent cornea and the lens make the eye an organ of
choice for light activated delivery system [78,94]. These sys-
tems incorporate light sensitive materials responsive to a spe-
cific wavelength. A NP drug delivery depot for on-demand
light-triggered drug release postimplantation has been formu-
lated [46]. These NPs rapidly release encapsulated drugs upon
exposure to 365 nm light. An implant system has been devel-
oped by On Demand Therapeutics (ODTx), containing several
drug reservoirs activated individually by laser light [78]. This
system provides a controlled drug delivery platform in the
treatment of posterior eye diseases. Recently, suprachoroidal
delivery of bevacizumab is performed using a light-activated
in situ gel [64].
4.2. Thermo-responsive systems
Thermosensitive polymers undergo abrupt change in solubi-
lity in response to a small change in temperature [95]. This
transition can cause conformational changes in the polymer
material that triggers drug release. An injectable thermore-
sponsive hydrogel for intravitreal sustained release of bevaci-
zumab has been designed [67]. Results show an initial burst
release followed by a sustained release of bevacizumab from
hydrogel.
4.3. In situ gelling systems
In situ gelling systems have been designed to increase the
precorneal residence time of drugs due to sol–gel phase
transition in the presence of various stimuli such as pH, tem-
perature, or ionic strength [96]. Several in situ gelling systems
with natural and synthetic polymers have been developed for
ocular applications [97,98]. Hydrogels are mostly preferred for
these systems because of their porous structures and swelling
properties. Although, in situ gelling system allows easy admin-
istration of sustained release materials to the desired site, it is
difficult to provide long-term release of macromolecules at a
therapeutic level. A thermosensitive in situ gelling system with
a high intraocular biocompatibility and extended bevacizu-
mab release has been developed for ocular delivery [66].
4.4. Ultrasound-responsive systems
Recent studies demonstrated the significant potential of ultra-
sound mediated drug release for ocular applications [49,99].
Ultrasound application has shown to enhance the delivery of
dexamethasone sodium phosphate, through the cornea in
vivo [100]. However, the physical effect of ultrasound on the
stability of the NCs is yet to be evaluated in addition to the risk
of sonication side effects, patient’s compliance and cost issues.
4.5. Conducting polymer based systems
Conducting polymers offer exciting opportunities in stimuli-
responsive implantable devices to treat posterior eye condi-
tions [78]. These polymers are biocompatible, nontoxic, pos-
sess both polymer- and metal-like properties, and offer
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excellent control over drug release through electrochemical
stimulation [101]. An electrically tunable release of dexa-
methasone from polypyrrole films has been designed for the
treatment of posterior eye diseases [102]. Results suggested
the suitability of these films for the development of electro-
responsive implants for posterior eye diseases.
4.6. Micro electro mechanical (MEM) systems
MEM systems consist of one or more drug reservoirs and
actuators which are responsible for pushing the drug out of
the reservoir by mechanical means in response to the stimulus
such as temperature, electrical stimulus, magnetic field, and
osmotic pressure [78]. A MEM based ocular implant has been
reported for phenylephrine delivery [103]. This approach has
been later modified using a mini drug pump (hydrolysis based
actuation) [85] to provide a control over the drug release
in response to the stimulus, exhibiting accurate drug delivery.
4.7. Oxidative-stress responsive systems
Oxidative stress can lead to cellular or molecular damage caused
by reactive oxygen species (ROS), which also occurs in AMD as a
result of an imbalance between the productions of ROS and the
antioxidant defense response [27,104]. Oxidative-responsive
polymers show great potential in the biomedical and drug
delivery applications to trigger the drug release [105].
Although, no known oxidative-stress responsive system has
been developed for ocular delivery, this stimulus can be targeted
in future drug delivery approaches for the posterior eye diseases.
5. Cell transplantation and delivery approaches for
AMD therapy
Cell transplantation aims to achieve the direct replacement of
endogenous cells, and/or the delivery of cells that can secrete
trophic factors to rescue degenerating cells [106]. In general,
AMD starts with the deposit of druses between RPE and BM,
leading to RPE and PRs degeneration and eventually leads to the
loss of vision [25]. RPE performs a variety of functions for proper
visual acuity including the formation of BRB by tight junctions,
transportation of nutrients from blood to PRs, light absorption,
secretion of cytokines/growth factors, and phagocytosis of outer
segments of PRs [25,107]. RPE provides nutrients, omega-3 fatty
acids for building PR outer segment-membranes and glucose for
energy metabolism needed to maintain visual function by outer-
segments of the PRs. The primary functions of BM include
regulating the diffusion of bio-molecules, minerals, antioxidants,
etc. between the choroid and RPE.
In case of dry-AMD, a gradual deterioration of RPE leads to
subsequent PR loss at the macula. The VEGF produced by the
Figure 3. (a) Nanocarriers (NCs) (liposome, nanoparticle, nanowafer, hydrogel, nanocrsytal, composite nanosystem, dendrimer, implant, and microparticle) in ocular
therapeutics. (b) Intrinsic/extrinsic stimuli and stimuli-responsive nanocarriers (NCs) approach in ocular therapeutics. Drug release from NCs can be designed to be
triggered with various stimuli (extrinsic or intrinsic) based on the NCs biomaterial (polymer) characteristics.
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basal side of RPE cells is essential to the health of the chor-
iocapillaris. In wet-AMD, RPE produces excessive VEGF, which
contributes to the breakdown of BRB and sprouting of imma-
ture blood vessels from choroid through BM into retina. This
process is called as neovascularization. Leakage of blood from
these abnormal vessels causes an acute loss of vision. As RPE
cells age, the efficiency of recycling of waste products decline
that may lead to a build-up of toxic waste products deposited
beneath the RPE cells on BM [108,109]. Usually, BM doubles in
thickness between the age of 10 and 90 years, slowing the
import of nutrients and export of waste materials from RPE
[25,110]. Together with other BM abnormalities, this may lead
to the dysfunction and ultimately death of RPE cells [109].
The cell based AMD treatment strategies provide support
and replacement to stressed/degenerated RPE to maintain its
function. Although AMD has different origins, in general, ret-
inal diseases can be attributed to the degeneration of the RPE,
RPE cells, PR cells, and BM [25]. Thus, an enticing possibility for
AMD therapy is the replacement of PR cells, either alone or in
addition to RPE transplantation. However, replacing PRs is a
challenging task due to the highly complex organization of
the retina and PRs must integrate well in order to be func-
tional. Thus, the preservation of PRs through the replacement
of the RPE is a promising option and can potentially restore
vision [20,25,107].
5.1. Sources of RPE for cell transplantation in AMD
The replacement of RPE monolayer can be performed by stem
cells. The stem cells can be differentiated into the desired cell
type to replace damaged tissue in order to integrate and
restore function [20,25,111]. There are currently several stem
cells sources used in RPE transplantation as discussed below.
Generally, an ideal cell source should have minimal ethical
concerns, able to expand in in vitro culture easily and has
minimal costs associated [20,25,111]. Several clinical trials are
ongoing to test the safety and efficacy of stem cell transplan-
tation in the eye [106,112,113].
Embryonic stem cells (ESCs) are pluripotent cells from the
inner cell mass of blastocyst. These cells have the ability to
self-renew and differentiate into any cell type such as the PRs,
RPE, and retinal progenitor cells (RPCs) [20,25,111]. However,
the application of ESC is challenging due to ethical concern,
immunological reactions, and the risk of teratoma formation.
Efforts are also needed to explore culturing techniques and
methods for their large-scale production. Moreover, ESCs
express human leukocyte markers that mediate immune
responses, thus making ESC-RPE grafts susceptible to rejection
response by the recipient.
Induced pluripotent stem cells (iPSCs) can be derived from
the patient’s own tissue thus poses fewer ethical concerns
compared to ESCs. Similar to ESCs, iPSCs can be differentiated
using a combination of soluble factors into various cells of the
retina [20,25,111]. iPSC-RPE cells are shown to have a full
range of morphologic and functional properties of RPE cells
[114,115]. However, grafts of in vitro differentiated RPE from
allogenic iPSCs may evoke immune response with subsequent
rejection in addition to the challenges of the risk of malignant
tumors.
Adult-derived stem cells include mammalian ciliary body,
Müller glia derived cells and nonretinal cells (mesenchymal
stroma cells) [20,25,111]. These cells are multipotent, have no
rejection issues, and can be easily cultured with a low risk of
contamination. But, these cells are relatively difficult to harvest
and have pro-oncogenic potential.
Retinal stem cells (RSCs) such as retinal neurospheres
(RNSs) provide relatively large availability of the RPE cells
[25,107]. RPE differentiation from RNS requires limited cell
expansion in vitro and short culture time relative to ESC or
iPSC. RNS have molecular features of RPCs with a negligible
tumorigenic potential. However, further analysis is required to
fully characterize the RNS-derived cells. RNSs also show a
limited ability to be expanded in vitro.
5.2. Challenges with cell transplantation approaches
RPE cell transplantation approaches offer considerable hope
for the treatment of AMD [116]. Despite encouraging results,
there remain a number of challenges that must be overcome
for long-term efficiency. The cell delivery method must be
carefully considered since it may trigger the inflammatory
response in cell transplantation [20]. Development of low
cost, reliable and robust sources of RPE is necessary.
Optimization methods to deliver stem cell derived-RPE into
the subretinal space needs to be performed including long-
term survival and function of the implanted cells. In addition,
long-term safety such as the lack of tumor formation years
after the cell transplantation should be evaluated [117].
Further, in vivo monitoring methods are required to assess
the function of implanted cells in real time. Therapeutics
success of transplantation of stem cell-derived RPE cells may
be limited unless the transplanted cells can adhere and sur-
vive for a long period.
5.3. Cell delivery approaches in retinal cell
transplantation
There are two key approaches for retinal cell transplantation:
(i) injection of a cell suspension, and (ii) surgical implantation
of an RPE monolayer. Although, less invasive, the injection of
the cell suspension leads to poor cell survival and engraft-
ment which tend to form clusters [20]. Further, cells that do
not integrate may secrete pro-apoptotic signals and create
debris, causing further damage to the surrounding tissue.
The degeneration in AMD is accompanied by pathological
changes to BM and direct RPE transplantation onto aged BM
resultsinpoorcellsurvival,andadhesion[118,119]. This
necessitates the design of an artificial BM onto which RPE
cells can be cultured and subsequently transplanted. Various
biomaterials scaffolds have been studied for the develop-
ment of porous BM membranes designed to promote cell
survival, integration by protecting cells from the hostile host
environment [20,120–122].
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5.4. Encapsulated cell technology (ECT) for AMD
ECT is a cell-based technology in which specific cells are
genetically engineered to overexpress the desired therapeutic
proteins [123,124]. These cells are then encapsulated into a
semipermeable biomaterials carrier that facilitates the diffu-
sion of nutrients and proteins to the host system (Figure 4).
ECT has the potential for continuous, long-term, and con-
trolled delivery of ocular therapeutics, bypassing the BRB with-
out any systemic exposure. In addition, a relatively low
sustained dose of drug emitted into the vitreous with an ECT
implant. Therefore, this system produces minimal adverse
events relative to the bolus injections.
NT-503 ECT implant containing genetically modified human
RPE cells can constantly secrete a controlled amount of solu-
ble VEGF-R at high levels to provide a therapeutic effect in
wet-AMD (http://www.neurotechusa.com/ect-platform.html).
Long-term cell survival due to the semipermeable hollow
fiber membrane of the device allows influx of oxygen and
nutrients and simultaneously creates an immune-isolation
chamber that prevents direct cell contact with the immune
system. In summary, ECT technology offers several advantages
such as avoidance of frequent intravitreal injections, expensive
treatment regimen as well as reduction of associated side
effects [124]. Since encapsulated cells allow continuous deliv-
ery of the product, the potential risks associated with high
concentrations of anti-VEGF therapeutics can be avoided.
6. Conclusion and future directions
Ocular drug delivery approaches to the posterior eye diseases
such as AMD are extremely challenging. Though the current
anti-VEGF treatments are effective, the financial burden on the
patient is substantial. To address the need, a sustained long-
term drug release from an ocular drug delivery platform is
required to reduce the frequency of the intravitreal injections.
The uses of nanotechnology approaches provide several
advantages in ocular applications. Thus, current research to
target posterior eye diseases is mostly focused on developing
NC drug delivery systems. However, a number of obstacles
need to be overcome prior to translation of these nanosys-
tems in clinical application such as, the reproducible and
large-scale fabrication of NCs, safety evaluation, and long-
term stability in biological fluids. The stem cell transplantation
provides positive responses but, remains questionable. ECT
offers the long-term delivery of therapeutics but, have chal-
lenges to solve.
Researchers are further investigating other delivery meth-
ods to extend the duration of action of anti-VEGF agents. A
capsule drug ring (CDR) has been designed for the treatment
of wet-AMD with a sustained delivery of anti-VEGF agent [125].
Results showed that the CDR device is biocompatible and may
release bevacizumab for more than 90 days. Other targets for
the treatment of wet-AMD such as the platelet derived growth
factor (PDGF) needs to be evaluated [126]. VEGF and PDGF
play separate but correlated roles in the formation and growth
of new blood vessels. PDGF binds to the pericytes (outside of
endothelial cells) in contrast to VEGF which binds to the inner
lining of blood vessels endothelial cells. While VEGF stimulates
abnormal blood vessel growth in the retina and macula, PDGF
stabilizes the maturing blood vessels and protects the inner
endothelial cells, despite anti-VEGF treatment. Therefore, a
combined anti-VEGF and anti-PDGF treatment may be more
effective than anti-VEGF mono therapy. Fovista, an anti-PDGF
drug from Ophthotech is under development for the potential
treatment of wet-AMD in combination with anti-VEGF
drugs [127].
This review summarized several nanosystems in addition to
the stem cell based cell transplantation approaches for the
posterior eye diseases such as AMD. Clinical pathogenesis and
Figure 4. Encapsulated cell technology (ECT) for the treatment of age-related macular degeneration (AMD). Retinal cells are encapsulated into a semi-permeable
scaffold made of biomaterials that facilitate the influx of nutrients and oxygen to provide the diffusion of therapeutic proteins directly to retina (vitreous humor)
thus, bypassing the blood–retinal barrier (BRB).
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current treatment approaches in AMD are briefly summarized.
Several routes of ocular drug administration, elimination path-
ways, delivery barriers, their advantages and challenges are
discussed.
7. Expert opinion
The ultimate goals of a novel drug delivery system are to
improve the therapeutic efficacy and patient benefits.
Considering this, the purpose of an ocular dosage form is to
provide an optimal therapeutic effect with a minimum dose,
reduced injection frequency, and use of less invasive routes
with minimal side effects. Hence, an ideal ocular delivery
system should have several characteristic properties:
(a) Acceptability and patient compliance: the product should
be simple, nonirritating, easy to self-administer, have a conveni-
ent dosage regimen with a long-lasting action.
(b) Drug delivery system attributes: the product should allow
a high drug loading to reduce the instilled dose, appropriate size
to facilitate corneal uptake, provide no effects on vision, isotonic
and close to physiological pH to avoid irritation, provide a
controlled/sustained/stimuli-responsive drug release as required,
high specificity to the targeted tissues, and proper syringeability/
injectability to assure the administration of the prescribed dose.
(c) Therapeutic molecule characteristics: the drug molecule
should provide a long-term efficacy and higher compatibility
with other drugs, and amphipathic nature in order to pass
through different ocular tissues/cells.
(d) Safety concern, stability, and side effects: the product
should be safe with no or minimal localized and systemic toxi-
city, must be inert toward the ocular tissues, and have high
stability under diverse ocular/biological environmental and sto-
rage conditions.
(e) Feasibility of manufacturing and cost-effectiveness: the
product should be easily formulated and provide cost benefits to
the patients.
There is a rapid progress in the development of stimuli-
responsive nanoformulations such as NPs, MPs, and hydrogels
in ocular applications. However, these systems are not thor-
oughly investigated in ocular diseases. Translation is limited by
the complexity of formulation design and obstacles in scale-
up, toxicity of polymers and slow response of systems in the
presence of stimuli. For stimuli-responsive systems, the safety
and intraocular toxicity of final and degradation products
should be evaluated. Further, if stimuli-responsive approaches
can also be transformed into diagnostic application, this could
provide an emerging area of research in ocular therapeutics.
The cost-efficiency of the approach should also be carefully
evaluated along with scalability and regulatory requirements.
As the posterior ocular diseases progress, alteration in the
drug release pattern may require depending upon the treat-
ment and disease conditions. Out of several drug delivery
systems, ocular implants are promising platforms in the treat-
ment of posterior eye diseases. Currently available nonbiode-
gradable intraocular implants are designed to offer a long-
lasting near zero order release kinetics over an extended
period of time. The administration and removal procedure of
these implants increases the treatment cost significantly.
However, these nonbiodegradable implant systems could be
used for a longer duration (several years) if the drug can be
refilled using a nonsurgical approach. Moreover, controlling
the drug release using a stimuli-responsive approach based on
clinical needs may significantly enhance the treatment effi-
ciency in back of the eye diseases. Another exciting potential
strategy is the combination of delivery systems, such as NPs-
encapsulated hydrogel, for sustained and long-term drug
release. Composite nanosystems (NPs suspended in the ther-
moresponsive gel) have been formulated and in vitro results
showed positive responses [14,68]. These nanosystems pro-
vide a long-term sustained macromolecule drug release with
minimum burst effect. This can significantly reduce the dose
frequency, ultimately reduces the treatment cost burden to
the patients and could be a major breakthrough in targeting
of posterior eye diseases.
The physicochemical properties of NCs such as size, shape,
surface charge, and targeting ligand functionality are among
the key attributes that can influence their performances. These
parameters should be taken into account when designing an
effective ocular drug delivery system. The experimental design
approaches can be applied for the prescreening/optimization
of NC formulation and process variables. There are several
intraocular environments, formulation process development,
and NCs physicochemical parameters those can be considered
in the experimental design approaches to optimize NCs ther-
apeutic effects. Further studies are needed to facilitate the
understanding of the fundamentals of nanotechnology and
proper delivery routes. The efficacy of ocular delivery systems
depend not only the drug dose, but also, maintaining the
desired effects at the target site. Therefore, pharmacokinetics
models are important to assess the efficacy of ocular formula-
tions since they can significantly reduce the number of in vivo
experiments including the time and cost of the product devel-
opment. Several physicochemical properties of formulations
such as pH, viscosity, particle size, and osmolality, may affect
the ocular bioavailability and should be incorporated into
pharmacokinetics models. The selection of a suitable animal
model in the assessment of ocular toxicity is equally important
for the development of safe and effective delivery systems.
The stem cell transplantation strategy provides positive
results in AMD therapy, but, remains questionable due to the
lack of cell engraftment and survival in the host tissue after
transplantation. The success in restoring vision via cell trans-
plantation ultimately depends on the presence of residual PRs
in the retina. Hence, it is critical to accurately quantify PR cells.
Other major challenges in cell transplantation approach are to
develop an ethically acceptable treatment option without
immunological rejection issues. ECT offers the potential for
long-term and controlled delivery of therapeutics. One of the
major challenges of ECT approach is the potential for
increased macrophage activity in response to the presence
of artificial BM material and the cells must be able to survive
within the encapsulation matrix [25]. In addition, efforts
should be focused on the effects of BM scaffold thickness,
surface topography, mechanical properties, polymer degrada-
tion profile, and to find the most efficient way to sustain the
viability and functionality of the treatment [128]. Development
of diagnostic tests to assay retinal functions and transplanta-
tion methods for optimal delivery of RPE are essential. It is also
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necessary to determine the suitable storage conditions of the
ECT system to maintain the optimal function.
In summary, the most important aspects of posterior eye
disease therapeutics include the development of an effective
long-acting, and safe product that can be delivered with an
appropriate route of administration. There is a rapid develop-
ment of the technologies required to effectively deliver the
drugs to the back of the eye. However, a better understanding
of ocular barriers, and dynamic physiologic processes of the
eye such as clearance mechanisms and drug metabolism is
required. Ultimately, collaboration among scientists from aca-
demia, industry and clinics is needed for successful translation
of novel strategies to restore vision.
Funding
This study is supported by NIH R01EY09171 and NIH R01EY10659.
Declaration of interest
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
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