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Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye
Medical Hypotheses 103 (2017) 5–9
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye Rohit Bisht, Jagdish K. Jaiswal, Ilva D. Rupenthal ⇑ a Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand b Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand
a r t i c l e
i n f o
Article history: Received 12 December 2016 Accepted 30 March 2017
Keywords: Ocular drug delivery Injectable implants Light-responsive systems Photocrosslinking PLGA nanoparticles
a b s t r a c t 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. Ó 2017 Elsevier Ltd. All rights reserved.
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 ⇑ Corresponding author at: Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. E-mail address: [email protected] (I.D. Rupenthal). http://dx.doi.org/10.1016/j.mehy.2017.03.033 0306-9877/Ó 2017 Elsevier Ltd. All rights reserved.
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) [3–5]. 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
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sol-to-gel transformation would also result in improved physical properties helpful in maintaining the structural integrity of the system over longer durations, thus enhancing drug retention and bioavailability. In addition, the biodegradable nature of the ISFIs would avoid the need for surgical removal of the system after the drug release is completed. It is anticipated that incorporation of NPs into the light-responsive ISFIs will further reduce any burst release resulting in an even better safety profile. Due to the sustained release properties of this dual system the need for frequent IVT injections would be reduced. Therefore, biodegradable NP-loaded light-responsive ISFIs could have great potential as a sustained ophthalmic drug delivery platform for safe and effective management of posterior segment diseases.
Evaluation of the hypothesis
Fig. 1. Barriers to ocular drug delivery. (A) Corneal barrier; (B) Blood-aqueous barrier and (C) Blood-retinal barrier. RPE-Retinal-pigment epithelium.
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 (VitrasertÒ and RetisertÒ) 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 [12–14]. 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. 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. Lightresponsive systems are attractive for drug delivery to the back of the eye in a safe and effective manner as light of a certain wavelength can easily pass the transparent cornea and lens in a noninvasive manner. Thus, light can be used for site specific photocrosslinking of the system in the vitreous resulting in in situ implant formation and thus avoiding the need for surgical implantation. Here, we propose NP-loaded light-responsive ISFIs as a platform for safe and effective drug delivery to the posterior segment of the eye. ISFIs are basically light-responsive liquids which can be injected into the vitreous in a minimally invasive manner and form a clear gel or solid depot quickly upon non-invasive photoirradiation through the cornea. Compared to other stimuli (pH, ions and temperature), light may result in more rapid sol-to-gel transformation lowering the diffusion rate of both the polymer and the entrapped drug. This would reduce the drug burst release from the polymer matrix and thus avoid any cytotoxicity related to free drug concentrations higher than the safety margins. The rapid
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 the absorption of the drug through the conjunctiva, from where it reaches the choroid and retinal pigment epithelium through the sclera [6,15]. The long distance between the site of drug administration and the retinal tissues including several complex barriers further limit the entry of drug into the posterior segment of the eye. Thus, conventional eye drops generally fail to deliver sufficient drug concentrations to the retinal tissues [16]. At present, the treatment of posterior segment diseases involves frequent IVT injections which have been associated with some side effects and high treatment costs. NPloaded light-responsive ISFIs would therefore bring great benefit and innovation as advanced ocular drug delivery platform. To date, various systems, such as colloidal formulations (polymeric nanocapsules, microparticles, liposomes and micelles) and polymeric implants have been developed or are under investigation for effective drug delivery to the posterior segment of the eye [17–21]. Hydrogels have been successfully marketed as artificial tears, corrective soft contact lenses [22] and foldable intraocular lenses [23]. Moreover, a few in situ gelling vehicles for topical administration, including Timoptic-XEÒ, have also made it onto the market with many more currently being investigated [24– 27]. In situ gelling systems are three dimensional networks of soft materials containing a high percentage of water. They are free flowing liquids which transform into a gel or semi-sold depot in the presence of certain stimuli including pH, ions, temperature, light or specific biomolecules. Such systems have wide biomedical applications, such as tissue engineering, medical device development and drug delivery, mainly due to their structural similarities to body tissues [28–32]. Stimuli-responsive ISFIs offer various benefits for ophthalmic applications including (i) direct injection into the vitreous circumventing the majority of the penetration barriers (ii) ease of manufacturing; (iii) biodegradability avoiding the need for surgical removal; (iv) transparency and clarity important for unhindered vision; (v) ability to protect the incorporated therapeutics from degradation in the vitreous body, (vi) biocompatibility and (vii) ability to release drug in a sustained manner over prolonged periods of time thus avoiding the need for frequent IVT injections [33,34]. To date, various injectable stimuli-responsive in situ forming systems have been developed for drug delivery to the posterior segment of the eye [25,35–37]. However, many have suffered from a high initial drug burst release from the polymeric matrix due to
R. Bisht et al. / Medical Hypotheses 103 (2017) 5–9
the relatively slow sol-to-gel transformation. This may result in the majority of the drug diffusing out of the polymer matrix before proper implant formation is achieved thus potentially leading to side effects due to drug concentrations higher than the safety margins. In addition, slow sol-to-gel transformation also affects the overall performance of the system and may result in inadequate physical properties of the formed implant with regards to hardness, porosity and rate of degradation [38]. To date, in situ gelling systems have been extensively studied for effective drug delivery to the anterior and posterior segments of the eye. However, irrespective of the advancements, active, time-dependent, high-resolution control of the in situ gel formation process has been lacking. We will address this issue by developing ISFIs that respond to ultraviolet light (UV, 365 nm) resulting in rapid sol-to-gel transformation. Over the past decade, lightresponsive systems for the management of posterior eye diseases have attracted the attention of formulation scientists and clinicians [37]. Currently, VisudyneÒ (Verteporfin) is the only light-activated liposomal medication available commercially for the management of AMD, with PhotrexÒ (Rostaporfin), another liposomal lightactivated formulation with a shorter duration of photosensitivity after systemic administration, currently awaiting Food and Drug Administration (FDA) approval [39]. Light as an external stimulus offers various benefits, such as (i) light of a certain wavelength can easily pass through the transparent cornea and lens in a non-invasive manner to reach the back of the eye; (ii) light as an external stimulus can be applied easily and in a controlled manner; (iii) the rapid sol-to-gel transformation upon photoirradiation results in improved mechanical strength, a low drug burst and more controlled drug release; and (iv) lightresponsive systems are less affected by patient- or diseasedependent stimuli such as temperature, ions or specific biomarkers as the gelling reaction is controlled solely by the wavelength, intensity and duration of photoirradiation. Fig. 2 schematically outlines implant formation upon photoirradiation in the posterior segment of the eye. Light settings and photoinitiator are among the most important factors deciding the overall performance of the system. To date, different light sources (UV, visible and near infra-red (NIR)) have been used for the development of light-responsive in situ gelling systems for various applications [40]. Most photoreactions involving NIR-responsive chromophores are generally slow and require longer irradiation times again resulting in a higher burst release. In the proposed system we will use long wavelength UV light
Fig. 2. Schematic illustration of the formation of ISFIs in the posterior segment of the eye upon photoirradiation; (A) PLGA NPs suspended in the polymeric solution before crosslinking and (B) Formation of PLGA NP-loaded photocrosslinked gel upon photoirradiation (UV, 365 nm) through the cornea.
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(365 nm) as the external stimulus. Compared to UV-B (280– 315 nm) and UV-C (100–280 nm), UV-A (315–400 nm) is more suitable for the development of light-responsive ISFIs as it is less absorbed by biological components and is able to penetrate the entire cornea and lens to reach the vitreous without causing any significant damage. Recently, Almutairi et al. [41] developed light-responsive polymeric NPs for drug delivery to the back of the eye using UV-A as the light trigger. The study revealed that applying UV-A light on human retinal pigment epithelium cells (ARPE-19) for 8–10 min caused no cytotoxic effect and was thus deemed safe for ocular use. Besides drug delivery applications, UV light is currently also used for corneal crosslinking. The FDA just recently approved Avedro’s corneal crosslinking system (Photrexa ViscousÒ (0.146% riboflavin 50 -phosphate in 20% dextran ophthalmic solution), PhotrexaÒ (0.146% riboflavin 50 -phosphate ophthalmic solution) and the KXLÒ system) for the management of progressive keratoconus and corneal ectasia following refractive surgery. This procedure involves application of the photosensitizer (riboflavin) to the cornea and subsequent exposure to UV-A light (360–370 nm) with an accumulated irradiance of 5.4 J/cm2 for 30 min found to be safe for ocular use [42,43]. Already having the relevant equipment available in ophthalmological practice, renders the development of UV-A light-responsive formulations for sustained intravitreal drug delivery more clinically relevant. As seen with corneal crosslinking, the choice of the photoinitiator (chromophore), which absorbs the light and initiates the photopolymerization reaction/sol-to-gel transformation, plays an important role. To date, various photoinitiators, such as IrgacureÒ variants, o-nitrobenzyl and anthracene have been used for the development of in situ gelling systems for ocular and other applications [44–46]. Williams et al. [47] evaluated the possible cytotoxicity of different photoinitiators including 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959), 1-hydroxycyclohexyl-1-phenyl ketone (Irgacure 184), and 2,2-dimethoxy-2-phenylacetophenone (Irgacure 651) on bovine chondrocytes, goat bone marrow-derived mesenchymal stem cells, human bone marrow-derived mesenchymal stem cells, rabbit corneal epithelial cells, human fetal osteoblasts and human embryonic germ cells. Results showed that compared to other photoinitiators, Irgacure 2959 was well tolerated at a wide range of concentrations by many cell lines. We therefore suggest Irgacure 2959 as a suitable photoinitiator for ocular drug delivery applications. For the proposed system, we are incorporating peptide-loaded biodegradable poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs) into the ISFIs to further reduce the high initial burst release seen for NPs or the polymeric matrix alone [48]. Moreover, most drugs used in the treatment of posterior eye diseases, including peptides, have short vitreous half-lives and are prone to degradation. Incorporation of such therapeutic molecules into NPs will improve their vitreal half-life and release the drug in a sustained manner, which will be further controlled by incorporating the NPs into the ISFIs. Fig. 3 depicts different phases by which drug release can be controlled through incorporation of NPs into ISFIs. The peptide-loaded NPs will be engulfed by the crosslinked gel which will inhibit NP movement in the vitreous and will thus prevent their rapid elimination [49]. This will increases the residence time of the NPs in the vitreous maintaining therapeutic drug concentrations at the target site for prolonged periods of time thus reducing the need for frequent injections.
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
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Fig. 3. Mechanisms involved in drug release from NP-loaded light-responsive ISFIs. (A) Entrapment of peptide-loaded PLGA NPs in the photocrosslinked gel; (B) Gel absorbs water from the surrounding vitreous and swells; PLGA NPs start to degrade and release peptide into the gel matrix; (C) Peptide diffusion and release is further sustained by the surrounding gel; (D) The remaining NPs are released upon gel degradation; (E) PLGA NPs and gel are biodegraded and safely eliminate from the posterior segment of the eye.
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 the eye in a sustained manner. Light as an external stimulus will hereby result in rapid sol-to-gel transformation and better physical properties that will enhance the overall performance of the in situ formed implant. We envisage that this will result in a creative and promising intravitreal drug delivery platform in the future. 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 [1] Thakur SS, Barnett NL, Donaldson MJ, Parekh HS. Intravitreal drug delivery in retinal disease: are we out of our depth? Expert Opin Drug Deliv 2014;11:1575–90. [2] Bharadwaj AS, Appukuttan B, Wilmarth PA, Pan Y, et al. Role of the retinal vascular endothelial cell in ocular disease. Prog Retin Eye Res 2013;32:102–80. [3] Chen M-S, Hou PK, Tai TY, Lin BJ. Blood-ocular barriers. Tzu Chi Med J 2008;20:25–34. [4] Cholkar K, Dasari SR, Pal D, Mitra AK. 1 - Eye: anatomy, physiology and barriers to drug delivery. In: Ocular transporters and receptors. Woodhead Publishing; 2013. p. 1–36. [5] Leong YY, Tong L. Barrier function in the ocular surface: from conventional paradigms to new opportunities. Ocul Surf 2015;13:103–9. [6] Kim YC, Chiang B, Wu X, Prausnitz MR. Ocular delivery of macromolecules. J Control Release 2014;190:172–81. [7] Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev 2006;58:1258–68.
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[34] Balakrishnan B, Jayakrishnan A. Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. Biomaterials 2005;26:3941–51. [35] Thrimawithana TR, Rupenthal ID, Young SA, Alany RG. Environmentsensitive polymers for ophthalmic drug delivery. J Drug Deliv Sci Tech 2012;22:117–24. [36] Shastri D, Patel L, Parikh R. Studies on In situ hydrogel: a smart way for safe and sustained ocular drug delivery. J Young Pharm 2010;2:116–20. [37] Bisht R, Jaiswal JK, Chen YS, Jin J, et al. Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye. Expert Opin Drug Deliv 2016;13:953–62. [38] Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer 2008;49:1993–2007. [39] Hongwen MR, Patrick MH. Protein drug delivery to retina and choroid. In: Ocular drug delivery systems. CRC Press; 2012. p. 191–214. [40] Tomatsu I, Peng K, Kros A. Photoresponsive hydrogels for biomedical applications. 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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye Rohit Bisht, Jagdish K. Jaiswal, Ilva D. Rupenthal ⇑ a Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand b Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand
a r t i c l e
i n f o
Article history: Received 12 December 2016 Accepted 30 March 2017
Keywords: Ocular drug delivery Injectable implants Light-responsive systems Photocrosslinking PLGA nanoparticles
a b s t r a c t 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. Ó 2017 Elsevier Ltd. All rights reserved.
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 ⇑ Corresponding author at: Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. E-mail address: [email protected] (I.D. Rupenthal). http://dx.doi.org/10.1016/j.mehy.2017.03.033 0306-9877/Ó 2017 Elsevier Ltd. All rights reserved.
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) [3–5]. 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
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sol-to-gel transformation would also result in improved physical properties helpful in maintaining the structural integrity of the system over longer durations, thus enhancing drug retention and bioavailability. In addition, the biodegradable nature of the ISFIs would avoid the need for surgical removal of the system after the drug release is completed. It is anticipated that incorporation of NPs into the light-responsive ISFIs will further reduce any burst release resulting in an even better safety profile. Due to the sustained release properties of this dual system the need for frequent IVT injections would be reduced. Therefore, biodegradable NP-loaded light-responsive ISFIs could have great potential as a sustained ophthalmic drug delivery platform for safe and effective management of posterior segment diseases.
Evaluation of the hypothesis
Fig. 1. Barriers to ocular drug delivery. (A) Corneal barrier; (B) Blood-aqueous barrier and (C) Blood-retinal barrier. RPE-Retinal-pigment epithelium.
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 (VitrasertÒ and RetisertÒ) 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 [12–14]. 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. 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. Lightresponsive systems are attractive for drug delivery to the back of the eye in a safe and effective manner as light of a certain wavelength can easily pass the transparent cornea and lens in a noninvasive manner. Thus, light can be used for site specific photocrosslinking of the system in the vitreous resulting in in situ implant formation and thus avoiding the need for surgical implantation. Here, we propose NP-loaded light-responsive ISFIs as a platform for safe and effective drug delivery to the posterior segment of the eye. ISFIs are basically light-responsive liquids which can be injected into the vitreous in a minimally invasive manner and form a clear gel or solid depot quickly upon non-invasive photoirradiation through the cornea. Compared to other stimuli (pH, ions and temperature), light may result in more rapid sol-to-gel transformation lowering the diffusion rate of both the polymer and the entrapped drug. This would reduce the drug burst release from the polymer matrix and thus avoid any cytotoxicity related to free drug concentrations higher than the safety margins. The rapid
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 the absorption of the drug through the conjunctiva, from where it reaches the choroid and retinal pigment epithelium through the sclera [6,15]. The long distance between the site of drug administration and the retinal tissues including several complex barriers further limit the entry of drug into the posterior segment of the eye. Thus, conventional eye drops generally fail to deliver sufficient drug concentrations to the retinal tissues [16]. At present, the treatment of posterior segment diseases involves frequent IVT injections which have been associated with some side effects and high treatment costs. NPloaded light-responsive ISFIs would therefore bring great benefit and innovation as advanced ocular drug delivery platform. To date, various systems, such as colloidal formulations (polymeric nanocapsules, microparticles, liposomes and micelles) and polymeric implants have been developed or are under investigation for effective drug delivery to the posterior segment of the eye [17–21]. Hydrogels have been successfully marketed as artificial tears, corrective soft contact lenses [22] and foldable intraocular lenses [23]. Moreover, a few in situ gelling vehicles for topical administration, including Timoptic-XEÒ, have also made it onto the market with many more currently being investigated [24– 27]. In situ gelling systems are three dimensional networks of soft materials containing a high percentage of water. They are free flowing liquids which transform into a gel or semi-sold depot in the presence of certain stimuli including pH, ions, temperature, light or specific biomolecules. Such systems have wide biomedical applications, such as tissue engineering, medical device development and drug delivery, mainly due to their structural similarities to body tissues [28–32]. Stimuli-responsive ISFIs offer various benefits for ophthalmic applications including (i) direct injection into the vitreous circumventing the majority of the penetration barriers (ii) ease of manufacturing; (iii) biodegradability avoiding the need for surgical removal; (iv) transparency and clarity important for unhindered vision; (v) ability to protect the incorporated therapeutics from degradation in the vitreous body, (vi) biocompatibility and (vii) ability to release drug in a sustained manner over prolonged periods of time thus avoiding the need for frequent IVT injections [33,34]. To date, various injectable stimuli-responsive in situ forming systems have been developed for drug delivery to the posterior segment of the eye [25,35–37]. However, many have suffered from a high initial drug burst release from the polymeric matrix due to
R. Bisht et al. / Medical Hypotheses 103 (2017) 5–9
the relatively slow sol-to-gel transformation. This may result in the majority of the drug diffusing out of the polymer matrix before proper implant formation is achieved thus potentially leading to side effects due to drug concentrations higher than the safety margins. In addition, slow sol-to-gel transformation also affects the overall performance of the system and may result in inadequate physical properties of the formed implant with regards to hardness, porosity and rate of degradation [38]. To date, in situ gelling systems have been extensively studied for effective drug delivery to the anterior and posterior segments of the eye. However, irrespective of the advancements, active, time-dependent, high-resolution control of the in situ gel formation process has been lacking. We will address this issue by developing ISFIs that respond to ultraviolet light (UV, 365 nm) resulting in rapid sol-to-gel transformation. Over the past decade, lightresponsive systems for the management of posterior eye diseases have attracted the attention of formulation scientists and clinicians [37]. Currently, VisudyneÒ (Verteporfin) is the only light-activated liposomal medication available commercially for the management of AMD, with PhotrexÒ (Rostaporfin), another liposomal lightactivated formulation with a shorter duration of photosensitivity after systemic administration, currently awaiting Food and Drug Administration (FDA) approval [39]. Light as an external stimulus offers various benefits, such as (i) light of a certain wavelength can easily pass through the transparent cornea and lens in a non-invasive manner to reach the back of the eye; (ii) light as an external stimulus can be applied easily and in a controlled manner; (iii) the rapid sol-to-gel transformation upon photoirradiation results in improved mechanical strength, a low drug burst and more controlled drug release; and (iv) lightresponsive systems are less affected by patient- or diseasedependent stimuli such as temperature, ions or specific biomarkers as the gelling reaction is controlled solely by the wavelength, intensity and duration of photoirradiation. Fig. 2 schematically outlines implant formation upon photoirradiation in the posterior segment of the eye. Light settings and photoinitiator are among the most important factors deciding the overall performance of the system. To date, different light sources (UV, visible and near infra-red (NIR)) have been used for the development of light-responsive in situ gelling systems for various applications [40]. Most photoreactions involving NIR-responsive chromophores are generally slow and require longer irradiation times again resulting in a higher burst release. In the proposed system we will use long wavelength UV light
Fig. 2. Schematic illustration of the formation of ISFIs in the posterior segment of the eye upon photoirradiation; (A) PLGA NPs suspended in the polymeric solution before crosslinking and (B) Formation of PLGA NP-loaded photocrosslinked gel upon photoirradiation (UV, 365 nm) through the cornea.
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(365 nm) as the external stimulus. Compared to UV-B (280– 315 nm) and UV-C (100–280 nm), UV-A (315–400 nm) is more suitable for the development of light-responsive ISFIs as it is less absorbed by biological components and is able to penetrate the entire cornea and lens to reach the vitreous without causing any significant damage. Recently, Almutairi et al. [41] developed light-responsive polymeric NPs for drug delivery to the back of the eye using UV-A as the light trigger. The study revealed that applying UV-A light on human retinal pigment epithelium cells (ARPE-19) for 8–10 min caused no cytotoxic effect and was thus deemed safe for ocular use. Besides drug delivery applications, UV light is currently also used for corneal crosslinking. The FDA just recently approved Avedro’s corneal crosslinking system (Photrexa ViscousÒ (0.146% riboflavin 50 -phosphate in 20% dextran ophthalmic solution), PhotrexaÒ (0.146% riboflavin 50 -phosphate ophthalmic solution) and the KXLÒ system) for the management of progressive keratoconus and corneal ectasia following refractive surgery. This procedure involves application of the photosensitizer (riboflavin) to the cornea and subsequent exposure to UV-A light (360–370 nm) with an accumulated irradiance of 5.4 J/cm2 for 30 min found to be safe for ocular use [42,43]. Already having the relevant equipment available in ophthalmological practice, renders the development of UV-A light-responsive formulations for sustained intravitreal drug delivery more clinically relevant. As seen with corneal crosslinking, the choice of the photoinitiator (chromophore), which absorbs the light and initiates the photopolymerization reaction/sol-to-gel transformation, plays an important role. To date, various photoinitiators, such as IrgacureÒ variants, o-nitrobenzyl and anthracene have been used for the development of in situ gelling systems for ocular and other applications [44–46]. Williams et al. [47] evaluated the possible cytotoxicity of different photoinitiators including 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959), 1-hydroxycyclohexyl-1-phenyl ketone (Irgacure 184), and 2,2-dimethoxy-2-phenylacetophenone (Irgacure 651) on bovine chondrocytes, goat bone marrow-derived mesenchymal stem cells, human bone marrow-derived mesenchymal stem cells, rabbit corneal epithelial cells, human fetal osteoblasts and human embryonic germ cells. Results showed that compared to other photoinitiators, Irgacure 2959 was well tolerated at a wide range of concentrations by many cell lines. We therefore suggest Irgacure 2959 as a suitable photoinitiator for ocular drug delivery applications. For the proposed system, we are incorporating peptide-loaded biodegradable poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs) into the ISFIs to further reduce the high initial burst release seen for NPs or the polymeric matrix alone [48]. Moreover, most drugs used in the treatment of posterior eye diseases, including peptides, have short vitreous half-lives and are prone to degradation. Incorporation of such therapeutic molecules into NPs will improve their vitreal half-life and release the drug in a sustained manner, which will be further controlled by incorporating the NPs into the ISFIs. Fig. 3 depicts different phases by which drug release can be controlled through incorporation of NPs into ISFIs. The peptide-loaded NPs will be engulfed by the crosslinked gel which will inhibit NP movement in the vitreous and will thus prevent their rapid elimination [49]. This will increases the residence time of the NPs in the vitreous maintaining therapeutic drug concentrations at the target site for prolonged periods of time thus reducing the need for frequent injections.
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
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Fig. 3. Mechanisms involved in drug release from NP-loaded light-responsive ISFIs. (A) Entrapment of peptide-loaded PLGA NPs in the photocrosslinked gel; (B) Gel absorbs water from the surrounding vitreous and swells; PLGA NPs start to degrade and release peptide into the gel matrix; (C) Peptide diffusion and release is further sustained by the surrounding gel; (D) The remaining NPs are released upon gel degradation; (E) PLGA NPs and gel are biodegraded and safely eliminate from the posterior segment of the eye.
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 the eye in a sustained manner. Light as an external stimulus will hereby result in rapid sol-to-gel transformation and better physical properties that will enhance the overall performance of the in situ formed implant. We envisage that this will result in a creative and promising intravitreal drug delivery platform in the future. 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 [1] Thakur SS, Barnett NL, Donaldson MJ, Parekh HS. Intravitreal drug delivery in retinal disease: are we out of our depth? Expert Opin Drug Deliv 2014;11:1575–90. [2] Bharadwaj AS, Appukuttan B, Wilmarth PA, Pan Y, et al. Role of the retinal vascular endothelial cell in ocular disease. Prog Retin Eye Res 2013;32:102–80. [3] Chen M-S, Hou PK, Tai TY, Lin BJ. Blood-ocular barriers. Tzu Chi Med J 2008;20:25–34. [4] Cholkar K, Dasari SR, Pal D, Mitra AK. 1 - Eye: anatomy, physiology and barriers to drug delivery. In: Ocular transporters and receptors. Woodhead Publishing; 2013. p. 1–36. [5] Leong YY, Tong L. Barrier function in the ocular surface: from conventional paradigms to new opportunities. Ocul Surf 2015;13:103–9. [6] Kim YC, Chiang B, Wu X, Prausnitz MR. Ocular delivery of macromolecules. J Control Release 2014;190:172–81. [7] Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev 2006;58:1258–68.
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