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Junsung Lee, Ji Ho Park; Bioengineered Delivery of Hydrophobic and Hydrophilic Compounds to Whole Retinal Layers. Invest. Ophthalmol. Vis. Sci. 2014;55(13):467.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal injection is a simple method to deliver drugs and nanoparticles specifically to the retina. However, deep penetration of drugs and nanoparticles in the retina has been challenging because the internal limiting membrane and intervening cells hamper their diffusion through multiple layers of retina. Here, we demonstrated that liposomal compounds injected into the vitreous were delivered to cells of inner retinal layers, where they were incorporated into cell-derived membrane vesicles(MVs), and subsequently, the compound-loaded MVs were transmigrated through multiple cell layers of retina.
Various PEGylated liposomes with different surface charges (- 5 ~ 20 mV) were prepared to find an optimal formulation for retinal delivery. For all formulations, DiI (hydrophobic compound) was embedded in the liposomal membrane, while carboxyfluorescein (CF, hydrophilic compound) was loaded in the aqueous core of liposomes or conjugated to the phospholipids of liposomes. Distribution of both compounds in the vitreous and retina were observed over 48 h after 1.5 μL of each liposome was injected intravitreally into murine eyes. To verify MVs-mediated retinal delivery, Brefeldin A was co-injected to inhibit production of cell-derived MVs.
Highly cationic PEGylated liposomes (20 mV) remained aggregated in the vitreous humor over 48 h after injection because of anionic charge of vitreous. Although the rest PEGylated formulations were uniformly distributed over the entire vitreous over 48 h after injection, only hydrophobic compounds delivered by moderate cationic PEGylated liposomes (15 mV) were transmigrated into the deep layers of retina. Hydrophilic CF was delivered to deep retinal layers when conjugated to phospholipids of liposomes, but was not delivered when loaded in the aqueous core of liposomes. Importantly, retinal delivery of hydrophobic and phospholipid-conjugated hydrophilic compounds was significantly reduced in the brefeldin A-treated retina, implying that the MVs indeed mediate transmigration of these compounds in the retina layers.
In this study, we found that the intravitreal delivery of optimized liposomal compounds enabled their penetration into the deep layers of retina via cell-derived MVs, which are one of the natural transport systems. We believe that this work offers a promising pathway for efficient retinal delivery of poorly-penetratable drugs.
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