The potential advantages of the utilisation of nanotechnology within ophthalmology have been widely identified. This development is largely in relation to pharmacological developments aimed to improve targeted drug delivery. Zarbin et al1 describe, for example, a broad range of potential applications including:

  • Drug and trophic factor therapy for glaucoma, retinal degenerative and retinal vascular disease.
  • Gene therapy for retinal degenerative disease.
  • Regenerative medicine including optogenetics and optic nerve regeneration.

Thassau and Chader2 also outline emerging nanotechnology applications within ophthalmology. Kumara,3 in a more general theme, describes the broad thrust of nanotechnology developments within the modern pharmaceutical industry, and references specific areas of current development. One commercially attractive development is identified as the repackaging of existing, patient-expired, medications using nanotechnology. Such developments become ‘new’ within the context of the drug delivery vehicle incorporating nanotechnology.

Delivering treatments with nanotechnology overcomes many problems of existing delivery systems

Nanotechnology in Drug Delivery

A major advantage of nanoparticles in drug delivery is their ability to improve drug targeting and consequently the effectiveness of specific drugs. This improvement in effectiveness is to some extent achieved by reducing the size of individual drug particle formulation, to sizes less than 100 microns. This provides an inherent advantage in the context of reaching tissue ‘compartments’ which would otherwise be inaccessible to drugs of normal formulation, though it introduces additional potential risks of the presence of nanoparticles within ‘novel’ tissue structures.

Another benefit of nanoparticles is that their small size favours uptake by cells through the process of endocytosis, where nanoparticles can have a typical diameter of 200nm whilst cells have typical dimensions of several 1,000nm. The size distribution of nanoparticles can be considered to overlap with that of viruses. Sahay et al4, however, indicate the key research within nanotechnology relates to the optimisation of endocytosis which involves an in-depth understanding of surface chemistry of nanoparticles and that of the target cells. Of relevance to developing an understanding of the process of endocytosis and nanoparticles is the study of how viruses can attack and penetrate cells as described by Cossart and Helenius.5 Kompella et al6 also indicate that energy will be communicated to nanoparticles by means of Brownian motion, and that the collision frequency of cells with nanoparticles is likely to be greater than that of larger microparticles.

A natural enthusiasm for nanotechnology in drug delivery has to be contrasted, however, with the somewhat limited evidence of drugs utilising nanotechnology which have come to market. The nanoparticle formulation of paclitaxel, Abraxane, has some level of NICE approval for breast cancer in the UK and has approval for treatment of advanced pancreatic cancer in Scotland and Wales. A feature, however, of the role of drugs such as Abraxane, is that it can act as a ‘catalyst’ in drug combination therapies, and the true benefits of a specific nanoparticle formulation can require additional clinical research to identify.

Drug Delivery Challenges

The eye presents specific challenges in the context of delivery of drugs from topical application into the anterior chamber and particularly onwards to the posterior chamber. A key problem is described by one group of researchers as the layer of mucus on the exterior surface of the cornea which provides protection from toxins, allergens and pathogens. Guzman-Aranguez and Argüeso7 have identified the role of O-glycans at the ocular surface in this protective capacity and also highlighted the option of designing drug delivery systems to overcome such defensive barriers. The ability to overcome this protective barrier has potentially far reaching implications for ophthalmology, where the possibility arises of delivering clinically significant drug concentrations to the posterior chamber by means of topical drug applications. This development could reduce the dependence on intravitreal injections and reduce the level of complications associated with such retinal treatments.8


Mucus Penetrating Particle

Kala Pharmaceuticals of Waltham, Massachusetts, is investigating so called mucus-penetrating particle (MPP) technology, which is used to allow drug carrying nanoparticles to penetrate the corneal mucosal barrier. While investigation of effective drug transmission within the eyes, nose, lungs, gastrointestinal tract and genitourinary tract is just under way, development of the technology for ophthalmic applications is more advanced. The technology is designed to provide a mechanism for encapsulation of existing pharmaceutical agents and improve their pharmacokinetic effectiveness across such mucosal barriers. Kala Pharmaceuticals has demonstrated that a range of pharmaceutical agents can be delivered more effectively by such technology with the inclusion of antibiotics, antifungals, antivirals, carbonic anhydrase inhibitors, kinase inhibitors, loop diuretics, non-steroidal anti-inflammatory drugs, nucleic acids and steroids. Popov et al9 describe how nanoparticles with certain partially hydrolysed polyvinyl alcohol can aid particle mobility in mucus, while fully hydrolysed particles are immobilised.

In initial animal studies utilising such MPP technology, Schopf et al10 investigated the drug delivery effectiveness of two compounds; loterprednol etabonate (formulated as mucus-penetrating particle LE-MPP) and KAL821, a novel receptor tyrosine kinase inhibitor (RTKi). It was identified that enhanced drug delivery levels were observed in anterior components of the eye and with therapeutically relevant drug concentrations being measured in the back of the eye.

Kala Pharmaceuticals recently announced encouraging results of a confirmatory phase 3 trial of KPI-121, which is a nanoparticle formulation of loteprednol etabonate with encapsulation of Kala’s patented mucus-penetrating particle (MPP) technology and where the drug is used for the treatment of inflammation and pain in patients who have undergone cataract surgery. The trial used twice daily medication frequency while products of standard drug formulation are delivered four times per day. Currently Kala Pharmaceuticals is undertaking two phase 3 trials for dry eye disease utilising KPI-121 and which are anticipated to be completed in 2017. This follows on from earlier phase 2 trials for dry eye disease reported in 2015.

Other Drug Developments

Cholkar et al11 describe in a more systematic approach, the various challenges to overcome in the delivery of therapeutic drugs to the anterior and posterior chambers of the eye from topical drug administration. At most around 20% of an initial topical dose may be retained in the pre-corneal pocket and with subsequent drainage through the nasolacrimal duct. Transport of drugs across the corneal epithelium is described as being paracellular in nature and limited to the intercellular space between cells. The secretion of aqueous humour by the ciliary body can also act to dilute the concentration of drugs reaching the anterior chamber. There is, however, no specific mention of the mucosal corneal barrier as a factor limiting the penetration of nanoparticles.

Cholkar et al11 also describe the suitability of nanomicelles as drug transporters within both the anterior and the posterior chamber where lipid molecules self organise into a spherical form depending on their hydrophilic/hydrophobic characteristics and where they can be formulated as a clear aqueous pharmaceutical preparation for hydrophobic drugs.

Poonam et al12 describe in animal studies the delivery of voclosporin (a cyclosporine A analogue) at two different formulations using such nanomicellar formulation techniques. This drug formulation is intended as a treatment for uveitis. It was identified that delivered concentrations in the choroid/retina reached therapeutic concentrations after seven days topical administration, but with low concentrations in the lens, aqueous humour and vitreous, suggesting a reduced likelihood of formation of cataracts and elevation of intraocular pressure as side effects.

There is also the perception that nanoparticle presentation of intravitreal injections could provide improved therapeutic action and potentially reduce the frequency of such injections. Sakurai et al,13 for example, using nanospheres containing a fluorescein derivative injected into the vitreous cavity of pigmented rabbit eyes, demonstrated increasing drug persistence with decreasing size of nanoparticles in sequence 2,000nm, 200nm and 50nm. Another example of the use of nanotechnology to provide improved uptake of an existing drug is described by Natarajan et al,14 where the prostaglandin derivative latanoprost is delivered by means of a nanosized unilamellar vesicle via subconjunctival injection.

Target – the Retina

A key theme, however, within nanotechnology developments in ophthalmology relates to drug delivery to the retina using topical medications, especially anti-VEGF agents, thus avoiding the stress and trauma of intravitreal injections.

Chu et al15 describe the development of topically applied, peptide-modified nanoparticles in the treatment of choroidal neovascularization (CNV). In the specific animal study reported, active agents incorporated into nanoparticles included a peptide (iRGD) selected to target areas of CNV and a peptide (TAT) which facilitates penetration through the ocular barrier by nanoparticles. The representative nanoparticle size was estimated at around 67nm. CNV lesions were formed in animal subjects using a 532nm laser and the active agent iRGD was subsequently detected in the formed lesions using red fluorescence techniques. The authors describe the outcome as a successful demonstration of drug delivery to CNV type lesions through topically applied drugs, but this area of research is some way from clinical evaluation.

Bisht et al16 have described the novel approach of which respond to light and form their desired shape in situ injectable implants (ISFIs) as a mechanism of drug delivery to the posterior chamber with avoidance of frequent intravitreal injections. In this proposed technique, a biodegradable implant containing drug-loaded polymeric nanoparticles (NPs) would initially be introduced and activated by light to release therapeutic doses of active drug agent. The authors suggest this as a possible novel mechanism of drug release/activation but without reference to any proof of concept experimental observations.

Osswald et al17 describe observations of the effectiveness of a microsphere-hydrogel drug delivery system (DDS) for delivery of anti-VEGF agents (ranibizumab or aflibercept) in an animal model. Specific subsets of treatment included one where no treatment was delivered, another where microspheres were not loaded with anti-VEGF agent, another with the drug-activated microspheres and one where the anti-VEGF agent was delivered as a conventional bolus dose. Choroidal neovascularization was triggered in all groups by means of green argon laser radiation. It was found that the anti-VEGF-loaded group developed lesions some 60% smaller than the non-treated group. In addition, it was found that the microspheres loaded with anti-VEGF agent at a concentration an order of magnitude less than the conventional bolus injection demonstrated greater treatment efficacy than the conventional bolus injection. This demonstrates the potential for similar results in human subjects. In addition, the increased period of release of active microsphere anti-VEGF agent raises the possibility of reducing the number of intravitreal injections required.

Senturk et al18 describe the use of nanofibres of LPPR peptide sequence as an inhibitor of VEGF activity using in vitro and in vivo techniques. This formulation of the LPPR peptide is considered to have specific advantages due the ability of the nanofibres to remain at the site of interest for extended periods of time. This again raises the possibility of reducing the number of intravitreal injections required.

You et al19 describe the application of nanotechnology in the treatment of uveal melanoma, where a range of potential drug delivery mechanisms have been identified. Such nanoparticle drug delivery techniques are considered to overcome intrinsic problems of conventional chemotherapy where drugs tend to be retained by other body tissues/organs.

Big Pharma

Without doubt, a key area of development of nanotechnology in ophthalmology is that of topical drug applications for treatment of the retina, with the avoidance of intravitreal injections. It is relevant to note that major drug companies such as Novartis appear to have no significant internal programme for the development of nanotechnology products, including those within ophthalmology. A current conventional drug focus for Novartis in this area is the anti-VEGF agent RTH258 (brolucizumab) where the results of two phase 3 trials are due to be reported later this year. The current policy of Novartis with regard to nanotechnology implies a preference for the development of ‘biodegradable nano-scale drug delivery’.

Novartis has, however, recently teamed up with the Canadian company Parvus Therapeutics for marketing a lead nanomedicine for type 1 diabetes which incorporates the ‘Navacim’ technology. Such nanoparticles selectively alter the behaviour of disease-causing T lymphocyte cells without affecting the general immune system, as described by Tsai et al.20 This treatment mechanism may, however, have relevance for the treatment of ocular presentations of autoimmune disease as is described by Patel and Lundy.21

Discussion

There is no doubt that research into the various implementations of nanotechnology in ophthalmology continues at a brisk pace, though there are few pharmaceuticals incorporating nanotechnology about to come to market. The challenge of the pharmaceutical industry is to be more efficient in research and also in drug manufacture. While there is ample scope for the development of wholly new ranges of pharmaceuticals incorporating nanotechnology delivery mechanisms, products will also emerge as ‘premium’ drugs which replicate characteristics of existing drugs but achieve superior outcomes due to more effective drug delivery mechanisms.

There is every indication, however, that the promise of nanotechnology remains in its infancy, and that the best of nanotechnology within drug technology is yet to emerge. The significant developments, for example, made by Parvus Therapeutics, have been described as ‘serendipitous’, indicating that there may be many more gadgets waiting to be discovered in the nanotechnology ‘toolkit’. 

Dr Douglas Clarkson is development and quality manager at the department of clinical physics and bio-engineering, Coventry and Warwickshire University Hospital Trust.

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