Successful drug therapies for treating ocular diseases require effective concentrations of neuroprotective compounds maintained over time at the site of action. The purpose of this work was to assess the efficacy of intravitreal controlled delivery of tauroursodeoxycholic acid (TUDCA) encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres for the treatment of the retina in a rat model of retinitis pigmentosa. PLGA microspheres (MSs) containing TUDCA were produced by the O/W emulsion-solvent evaporation technique. Particle size and morphology were assessed by light scattering and scanning electronic microscopy, respectively. Homozygous P23H line 3 rats received a treatment of intravitreal injections of TUDCA-PLGA MSs. Retinal function was assessed by electroretinography at P30, P60, P90 and P120. The density, structure and synaptic contacts of retinal neurons were analyzed using immunofluorescence and confocal microscopy at P90 and P120. TUDCA-loaded PLGA MSs were spherical, with a smooth surface. The production yield was 78%, the MSs mean particle size was 23 μm and the drug loading resulted 12.5 ± 0.8 μg TUDCA/mg MSs. MSs were able to deliver the loaded active compound in a gradual and progressive manner over the 28-day in vitro release study. Scotopic electroretinografic responses showed increased ERG a- and b-wave amplitudes in TUDCA-PLGA-MSs-treated eyes as compared to those injected with unloaded PLGA particles. TUDCA-PLGA-MSs-treated eyes showed more photoreceptor rows than controls. The synaptic contacts of photoreceptors with bipolar and horizontal cells were also preserved in P23H rats treated with TUDCA-PLGA MSs. This work indicates that the slow and continuous delivery of TUDCA from PLGA-MSs has potential neuroprotective effects that could constitute a suitable therapy to prevent neurodegeneration and visual loss in retinitis pigmentosa.
Pathologies affecting the optic nerve and the retina are one of the major causes of blindness. These diseases include age-related macular degeneration (AMD), diabetic retinopathy (DR) and glaucoma, among others. Also, there are genetic disorders that affect the retina causing visual impairment. The prevalence of neurodegenerative diseases of the posterior segment is increased as most of them are related with the elderly. Even with the access to different treatments, there are some challenges in managing patients suffering retinal diseases. One of them is the need for frequent interventions. Also, an unpredictable response to therapy has suggested that different pathways may be playing a role in the development of these diseases. The management of these pathologies requires the development of controlled drug delivery systems able to slow the progression of the disease without the need of frequent invasive interventions, typically related with endophthalmitis, retinal detachment, ocular hypertension, cataract, inflammation, and floaters, among other. Biodegradable microspheres are able to encapsulate low molecular weight substances and large molecules such as biotechnological products. Over the last years, a large variety of active substances has been encapsulated in microspheres with the intention of providing neuroprotection of the optic nerve and the retina. The purpose of the present review is to describe the use of microspheres in chronic neurodegenerative diseases affecting the retina and the optic nerve. The advantage of microencapsulation of low molecular weight drugs as well as therapeutic peptides and proteins to be used as neuroprotective strategy is discussed. Also, a new use of the microspheres in the development of animal models of neurodegeneration of the posterior segment is described.
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