Evaluation of the neuroprotective mechanisms of 7,8-dihydroxyflavone and its structural analogue OPGG-A2 and generation of corresponding sustained release microparticles for improved ocular drug delivery
Retinal and macular degenerations (IRD and AMD) are pathologies of the back of the eye leading to visual impairment and often blindness. The heterogeneity and the complexity of these diseases pose a great challenge in terms of generating therapeutic options to alleviate the burden for patients and caregivers.
Even though AMD and IRD are different in terms of pathophysiology, a communal hallmark is the presence of degeneration due to the direct activation of cell death or as a secondary cause of oxidative stress. In this project, the use of a neuroprotective approach, by inhibiting cell death, is used to slow-down the retinal degeneration1,2.
Recently, in our laboratory, attention has been placed on a natural compound, 7,8-Dihydroxyflavone (7,8-DHF), a brain derived neurotrophic factor (BDNF) mimetic, able to positively stimulate the TrkB pathway with consequent cell survival and proliferation3.
Due to commercial availability, this small molecule has been intensively used in different type of cell lines and animal models, showing positive therapeutic effects in central nervous system disorders, e.g Alzheimer disease, depression, Huntington, and in retinal degeneration4,5.
In contrast, it is interesting to underline that the flavonoids are catechol group-containing compounds, which are subjected to many metabolic modifications including conjugation and oxidation, which are usually responsible for poor bioavailability and pharmacokinetics (PK). Indeed, in recent times, a study showed that 50 mg/kg of 7,8-DHF administrated orally resulted in only 7 ng/g of 7,8-DHF detected in the brain after 4h from the administration and below the quantitative limit after 6h from the administration6. In this scenario, in collaboration with CRESSET, following a computational screening, we discovered a novel 7,8-DHF 3D structural analogue, re-named as OPGG-A2, showing a better efficacy in restoring visual function in a zebrafish model of inherited blindness (unpublished).
Recently, our laboratory generated data suggesting systemic delivery of 7,8-DHF in mice did not result in detectable levels in the retina warranting alternative delivery system for ocular drug availability (unpublished). In ocular therapeutics there are challenges concerning drug delivery to the posterior eye7. The eye is a particularly challenging tissue in terms of drug delivery: various barriers from tear dilutions to blood-aqueous and blood-retinal barrier make the retina a difficult tissue to reach. Several routes can be used to reach the retina, such as topical, systemic and intraocular injections7. In the latter case, the proportion of administered drug reaching the target tissue is greatly increased. To reduce side effects, for ocular disorders, reducing the number of intraocular injections, is necessary. One strategy is to inject biodegradable polymers which allow sustained drug delivery over months, reducing the injection frequency. Among the polymers, Poly D-L(lactide-co-glycolide), PLGA, an FDA approved polymer, is a popular material for ocular drug delivery via microparticles or implants due to its biodegradability and biocompatibility8-11. Indeed, many PLGA implants are currently on the market: Zoladex by AstraZeneca, Ozurdex by Allergan etc.
The main goal of my project is to synthetize and characterize PLGA microspheres encapsulating 7,8-DHF and its novel structural analogue OPGG-A2, evaluating their safety and efficacy in mammalian pre-clinical model of blindness. Furthermore, I am evaluating the mechanism by which the drugs rescue vision using both zebrafish and human ARPE19 cell line. The data collected so far suggest that both the drugs are able to reduce the oxidative stress making them good candidates to treat AMD and IRD conditions.
- Hernández-Zimbrón, L. F. et al. Age-Related Macular Degeneration: New Paradigms for Treatment and Management of AMD. Oxid Med Cell Longev 2018, 1–14 (2018).
- Arbabi, A., Liu, A. & Ameri, H. Gene Therapy for Inherited Retinal Degeneration. J Ocul Pharmacol Th 35, 79–97 (2019).
- Daly C, Shine L, Heffernan T, et al. A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model. Sci Rep-uk. 2017;7(1):11320.
- Chen, C. et al. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proc National Acad Sci 115, 578–583 (2018).
- Du, X. & Hill, R. A. The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia. J Mol Neurosci 60, 336–348 (2016).
- Liu X, Qi Q, Xiao G, Li J, Luo HR, Ye K. O-Methylated Metabolite of 7,8-Dihydroxyflavone Activates TrkB Receptor and Displays Antidepressant Activity. Pharmacology. 2013;91(3-4):185-200
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- García-Caballero, C. et al. Six month delivery of GDNF from PLGA/vitamin E biodegradable microspheres after intravitreal injection in rabbits. Eur J Pharm Sci 103, 19–26 (2017).
- Herrero-Vanrell, R., Bravo-Osuna, I., Andrés-Guerrero, V., Vicario-de-la-Torre, M. & Molina- Martínez, I. T. The potential of using biodegradable microspheres in retinal diseases and other intraocular pathologies. Prog Retin Eye Res 42, 27–43 (2014).