Rosmarinic Acid Intravitreal Implants: A New Therapeutic Approach for Ocular Neovascularization

Abstract

Rosmarinic acid, a plant-derived compound with antiangiogenic activity, can be applied for the treatment of ocular diseases related to neovascularization, such as diabetic retinopathy, macular edema, and age-related macular degeneration. These diseases represent the leading causes of blindness worldwide if they are not properly treated. Intravitreal devices allow for localized drug delivery to the posterior segment, increasing the drug bioavailability and promoting extended release, thus, reducing side effects and enhancing the patientʼs compliance to the treatment. In this work, rosmarinic acid-loaded poly lactic-co-glycolic acid intraocular implants were developed with a view for the treatment of ocular neovascularization. Physical-chemical, biocompatibility, and safety studies of the implants were carried out in vitro and in vivo as well as an evaluation of the antiangiogenic activity in a chorioallantoic membrane assay. Data obtained showed that rosmarinic acid released from the implants was quantified in the vitreous for 6 weeks, while when it was in the solution formulation, after 24 h, no drug was found in the vitreous. The delivery device did not show any sign of toxicity after clinical evaluation and in electroretinographic findings. Histological analysis showed normal eye tissue. Rosmarinic acid released from implants reduced 30% of new vesselʼs formation. The intravitreal implant successfully allowed for the prolonged release of rosmarinic acid, was safe to rabbits eyes, and demonstrated activity in vessel reduction, thus demonstrating potential in preventing neovascularization in ophthalmic diseases.

Low-dose melittin is safe for intravitreal administration and ameliorates inflammation in an experimental model of uveitis

“…Antiangiogenic activity of MEL was assessed by the chicken embryo CAM assay, as previously described by Vieira et al. (2020) .…”

Molecular mechanisms of neuroprotective offerings by rosmarinic acid against neurodegenerative and other CNS pathologies

“…In concurrence with these results, placebo‐controlled randomized clinical trials in human subjects diagnosed with aging‐associated memory impairments reported no significant side‐effects of an aqueous spearmint extract containing RA on multiple tolerability parameters indicative of toxicity; including vital signs, endocrine and hematological and biochemical assessment of blood, and subjective gastrointestinal assessment (Lasrado et al, 2017; Nieman et al, 2015). Lastly, studies have also confirmed inconsequential detrimental effects of different nanoformulations loaded with RA on multiple parameters indicative of gut microbiome dysbiosis, and liver and kidney dysfunction, and hematological, biochemical, genotoxic, cytotoxic and oxidative damage (Reis et al, 2016; Vieira et al, 2020).…”

Discovering the Potential of Natural Antioxidants in Age-Related Macular Degeneration: A Review

“…Numerous compounds, namely, artemisinin (a lactone isolated from Artemisia annua) [64], astragaloside (a cycloartane-type glycoside isolated from Astragalus membranaceus) [65], celastrol (a quinone methide triterpene) [70], carnosic acid (a phenolic diterpene isolated from rosemary extract) [69], diarylheptanoids isolated from Curcuma comosa [75], diphlorethohydroxycarmalol (a phlorotannin isolated from brown macroalga Ishige okamurae) [76], FLZ (a novel synthetic cyclic analogue of natural squamosamide isolated from Annona glabra) [77,78], glycyrrhizin (a glycoside isolated from licorice roots (Glycyrrhiza glabra)) [81], GPETAFLR (a biopeptide isolated from Lupinus angustifolius) [82], gypenosides (dammaranetype triterpene saponins isolated from Gynostemma pentaphyllum) [83], kinsenoside isolated from Anoectochilus roxburghii [84], phillyrin (a lignan isolated from dried fruit of Forsythia suspense) [85], rosmarinic acid isolated from Rosmarinus officinalis [86] and total saponins isolated from rhizomes of Paris polyphylla [87] also demonstrated promising protective effects against oxidative damage in preclinical models.…”

“…A recent, remarkable trial on New Zealand white rabbits demonstrated the efficacy of therapeutically designed rosmarinic acid-poly lactic-co-glycolic acid (PLGA) implants in impeding ocular neovascularization. This strategy takes a long-term view toward the possible use of PLGA, a biodegradable polymer as an implantable intravitreal device to promote prolonged and controlled release of rosmarinic acid in vitreous humor [86].…”