Elsevier

Medical Hypotheses

Volume 103, June 2017, Pages 5-9
Medical Hypotheses

Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye

https://doi.org/10.1016/j.mehy.2017.03.033Get rights and content

Abstract

Diseases affecting the posterior segment the eye, such as age-related macular degeneration (AMD), are the leading cause of blindness worldwide. Conventional dosage forms, such as eye drops, have to surmount several elimination mechanisms and complex barriers to achieve therapeutic concentrations at the target site often resulting in low anterior segment bioavailability (ca. 2–5%) with generally none of the drug reaching posterior segment tissues. Thus, frequent intravitreal injections are currently required to treat retinal conditions which have been associated with poor patient compliance due to pain, risk of infection, hemorrhages, retinal detachment and high treatment related costs. To partially overcome these issues, ocular implants have been developed for some posterior segment indications; however, the majority require surgical implantation and removal at the end of the intended treatment period. The transparent nature of the cornea and lens render light-responsive systems an attractive strategy for the management of diseases affecting the back of the eye. Light-responsive in situ forming injectable implants (ISFIs) offer various benefits such as ease of application in a minimally invasive manner and more site specific control over drug release. Moreover, the biodegradable nature of such implants avoids the need for surgical removal after release of the payload. Incorporating drug-loaded polymeric nanoparticles (NPs) into these implants may reduce the high initial burst release from the polymeric matrix and further sustain drug release thus avoiding the need for frequent injections as well as minimizing associated side effects. However, light-responsive systems for ophthalmic application are still in their early stages of development with limited reports on their safety and effectiveness. We hypothesize that the innovative design and properties of NP-containing light-responsive ISFIs can serve as a platform for effective management of ocular diseases requiring long term treatment.

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.

References (49)

  • U.B. Kompella et al.

    Nanomedicines for back of the eye drug delivery, gene delivery, and imaging

    Prog Retin Eye Res

    (2013)
  • Y. Ogura

    Drug delivery to the posterior segments of the eye

    Adv Drug Deliv Rev

    (2001)
  • E.M. Del Amo et al.

    Current and future ophthalmic drug delivery systems. A shift to the posterior segment

    Drug Discov Today

    (2008)
  • P.C. Nicolson et al.

    Soft contact lens polymers: an evolution

    Biomaterials

    (2001)
  • O. Findl et al.

    Meta-analysis of accommodating intraocular lenses

    J Cataract Refract Surg

    (2007)
  • M. Zignani et al.

    Topical semi-solid drug delivery: kinetics and tolerance of ophthalmic hydrogels

    Adv Drug Deliv Rev

    (1995)
  • I.D. Rupenthal et al.

    Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 1: physicochemical characterisation and in vitro release

    Int J Pharm

    (2011)
  • I.D. Rupenthal et al.

    Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 2: Precorneal retention and in vivo pharmacodynamic study

    Int J Pharm

    (2011)
  • A. Fakhari et al.

    Engineered in-situ depot-forming hydrogels for intratumoral drug delivery

    J Control Release

    (2015)
  • S. Ma et al.

    Structural hydrogels

    Polymer

    (2016)
  • A. Sivashanmugam et al.

    An overview of injectable polymeric hydrogels for tissue engineering

    Euro Poly J

    (2015)
  • Y Ohya

    2.3 – Injectable Hydrogels A2 – Ebara, Mitsuhiro

  • J.A. Yang et al.

    In situ-forming injectable hydrogels for regenerative medicine

    Prog Poly Sci

    (2014)
  • P. Agarwal et al.

    Injectable implants for the sustained release of protein and peptide drugs

    Drug Discov Today

    (2013)
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