Lutein loaded double-layered polymer nanocarrier modulate H2O2 and CoCl2 induced oxidative and hypoxia damage and angiogenic markers in ARPE-19 cells

Lutein plays a crucial role in the protection of retina by diminishing oxidative stress in diabetic retinopathy (DR). However, its poor aqueous solubility, chemical instability and low bioavailability edge its application. Also, beneficial effects of lutein supplementation and lower lutein levels in the serum and retina of DR patients created an interest in nanopreparation. Hence, lutein-loaded chitosan‑sodium alginate nanocarrier comprising oleic acid core (LNCs) was developed and examined its protective effect on hyperglycemia-mediated changes in oxidative stress and angiogenesis in ARPE-19 cells. Results showed that the LNCs have smaller size and a smooth spherical morphology and did not affect the ARPE-19 cell viability (up to 20 μM) and showed higher cellular uptake in both normal and H 2 O 2 -induced stress conditions. LNCs pre-treatment suppressed the H 2 O 2 -induced oxidative stress and CoCl 2 -induced hypoxia-mediated elevation of intracellular reactive oxygen species , protein carbonyl and malondialdehyde levels by restoring antioxidant enzymes in ARPE-19 cells. Further, LNCs protected H 2 O 2 -mediated down-regulation of Nrf2 and its downstream antioxidant enzymes. LNCs also restored the H 2 O 2 -altered angiogenic (Vascular endothelial growth factor (VEGF), X-box binding protein 1 (XBP-1) and Hypoxia-inducible factor 1-alpha (HIF-1α)), endoplasmic reticulum stress (activating transcription factor-4 (ATF4)) and tight junction (Zona occludens 1 (ZO-1)) markers. To conclude, we could successfully develop biodegradable LNCs to improve the cellular uptake of lutein to treat DR by curtailing oxidative stress in retina. A presumed model for the therapeutic pathway molecules of nanolutein on H 2 O 2 /CoCl 2 mediated oxidative damage in ARPE-19. Nanolutein activates Nrf2 translocation and inhibits the production of VEGF by regulating the HIF-1α and XBP-1 by downregulating the ER stress markers (ATF4) and by downregulating the oxidative stress thereby upregulates protective antioxidant enzymes in H 2 O 2 /CoCl 2 -ARPE-19 cells. • Double layered chitosan-sodium alginate based lutein nanocarrier (LNCs) • Slow and controlled lutein release from LNCs for treatment of diabetic retinopathy • LNCs display anti-angiogenic property in H 2 O 2 exposed ARPE-19 cells. • LNCs improve the cellular efficacy of lutein by curtailing oxidative stress.