Hyaluronic acid coated albumin nanoparticles for targeted peptide delivery in the treatment of retinal ischaemia

Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease

“…Tonabersat did not continue through clinical trials because it only benefited patients suffering migraine with aura [1], suggesting that its mode of action was misunderstood and an inappropriate clinical indication was targeted. Subsequently however, tonabersat has been shown to be a connexin43 hemichannel blocker [9,21], this being a different mode of action than assumed when used for migraine. In the bright light model of dry AMD, similar findings with respect to protecting the retina and its function were observed with tonabersat compared to the mimetic peptide [9,17,19].…”

“…The trigger is ATP release via the pathologic pore, resulting in ATP moving into the extracellular space acting as an inflammasome signal 2 activator [13]. In the eye, Connexin43 hemichannel block has been demonstrated to reduce inflammation and improve functional outcomes in both short-and long-term animal models of ocular disease [9,[15][16][17][18][19][20][21] and a reduction in Connexin43 protein levels in human ocular surface burns [22]. Connexin43 hemichannel block is a potential therapeutic target, acting upstream of current treatment modalities and enabling treatment at an earlier stage, including for dry age-related macular degeneration (AMD) and diabetic retinopathy (DR) [23,24].…”

Polysaccharides in Ocular Drug Delivery

“…Intravitreal drug administration requires control of system parameters, such as the size, surface charge, lipophilicity, and shape of drug carriers [137][138][139][140][141], as these parameters affect drug release and retention of the delivery system within the vitreal cavity. The retention of the delivery system and its components within the vitreal cavity depend, in turn, on the physical barriers between the eye and blood circulation and the chemical composition of the vitreous humor [133,[141][142][143][144][145][146][147]. The main factors defining the elimination of drug delivery materials from the vitreous humour include: (1) the vitreous humor, (2) the inner limiting membrane (ILM), (3) the blood-retina barrier (including the RPE and blood vessel walls in the retina and ciliary body), and (4) the degradation rate of polymer materials in the vitreous humor [147].…”

“…The vitreous humor has a volume of 4 mL in the human eye [137], and it consists of a negatively charged 3D matrix based on collagen and HA [2,137,143]. The mobility of large particles is hindered due to steric effects, because the limiting mesh size of the vitreous is 550 nm [137,144,150,151]. Large drug molecules diffuse through the vitreous humor slightly slower than small molecules do [2], but the differences in diffusion rate among particles are much greater.…”

“…Huang et al [144,163] developed a technology for manufacturing HA-coated (MW 120 kDa) albumin nanoparticles. These nanoparticles were used to deliver Connexin43 mimetic peptide to prevent secondary damage after ischemic and inflammatory diseases of the retina.…”