Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye
Introduction
Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide [1], with the number of people living with AMD expected to reach 196 million by 2020 and an estimated increase to 288 million by 2040 [2]. Effective drug delivery to the back of the eye is still challenging due to the presence of various elimination mechanisms (tear flow, nasolacrimal drainage, systemic absorption, protein binding and enzymatic degradation) and complex barriers (cornea, blood-aqueous barrier and blood-retinal barrier) which limit the entry of drug into the posterior segment following topical application (Fig. 1) [3], [4], [5].
After topical instillation of an eye drop, the majority of the drug is lost due to these elimination mechanisms resulting in low anterior segment bioavailability (2–5%) [6], [7]. Moreover, the long distance between the site of application (cornea) and the target site (retina) make drug delivery to the posterior segment of the eye even more challenging [8]. To overcome these limitations, intravitreal (IVT) injections have become the gold standard for the management of posterior segment diseases. This involves direct administration of the drug solution into the vitreous thus overcoming the majority of the barriers and elimination mechanisms [9], [10]. However, most drugs used in the treatment of posterior segment diseases have relatively short intravitreal half-lives. Therefore, to maintain the required therapeutic drug concentration at the target site, injections are generally required every 4–8 weeks which may be associated with pain, risk of infection and high treatment costs [11]. Two of the currently marketed ocular implants for the management of posterior segment diseases (Vitrasert® and Retisert®) need surgical implantation and removal after the release of the loaded drug. And while they are able to deliver the drug over months to years, their implantation is still a rather invasive procedure that has been associated with various side effects and a high cost burden for patients and health care providers [12], [13], [14].
With recent advancements in the field of drug delivery technologies, formulation scientists and clinicians are looking for safer and more effective ways to deliver drugs to the posterior segment of the eye. To overcome the limitations associated with existing clinical interventions, nanoparticle (NP)-loaded light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retina with great accuracy, safety and minimal invasiveness.
Section snippets
The hypothesis
Considering the impact of sight threatening diseases on a wide population globally, the focus of formulation scientists and clinicians has recently shifted from the anterior to the posterior segment of the eye. Irrespective of the immense development in the field of ocular therapeutics over the last decades, effective drug delivery to the retinal tissues remains challenging. Light-responsive systems are attractive for drug delivery to the back of the eye in a safe and effective manner as light
Evaluation of the hypothesis
For conventional ocular dosage forms, such as topical eye drops, the majority of the instilled drug is immediately lost from the precorneal area due to lacrimal secretion and nasolacrimal drainage. Whatever remains on the ocular surface then has to be absorbed through corneal and non-corneal routes. The corneal route involves the permeation of the drug across the cornea and into the aqueous humor, from where it is distributed to the various intraocular tissues. The non-corneal route involves
Consequences of the hypothesis
Effective delivery of therapeutic molecules such as peptides into the posterior segment of the eye is still challenging due to the presence of various penetration barriers. Current treatment of retinal diseases involves frequent IVT injections which may result in various side effects. We hypothesize that biodegradable and biocompatible PLGA NP-loaded light-responsive ISFIs are able to overcome the majority of the ocular barriers non-invasively and deliver the peptide to the posterior segment of
Sources of support
The proposed work was financially supported by the Health Research Council of New Zealand (14/018). The authors would also like to thank the University of Auckland for providing an International Doctoral Scholarship to Rohit Bisht.
Conflicts 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.
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