Liquid crystalline lipid nanoparticles for combined delivery of curcumin, fish oil and BDNF: In vitro neuroprotective potential in a cellular model of tunicamycin-induced endoplasmic reticulum stress
Miora Rakotoarisoa, Borislav Angelov, Markus Drechsler, Valérie Nicolas, Thomas Bizien, Yu. E. Gorshkova, Yuru Deng, Angelina Angelova
Abstract
We develop multidrug-loaded cubosome and spongosome lipid nanoparticles for targeting of endoplasmic reticulum stress as a potential emerging therapeutic strategy against neuronal degeneration. The multicompartment organization of the liquid crystalline nanoparticles (LCNPs), fabricated by self-assembly, was characterized by cryogenic transmission electron microscopy (cryo-TEM) and small-angle X-ray scattering (SAXS). Monoolein-based cubosome and spongosome LCNPs co-encapsulated the natural plant-derived antioxidant curcumin, fish oil rich in ω-3 polyunsaturated fatty acids (PUFA), and the neurotrophin brain-derived neurotrophic factor (BDNF), which is of vital need for neurogenesis. The neuroprotective properties of the nanoparticles were in vitro investigated in a cellular model of tunicamycin-induced endoplasmic reticulum (ER) stress using differentiated human neuroblastoma SH-SY5Y cells deprieved from serum. The intracellular accumulation of aggregates of misfolded proteins, typical for the ER stress process, was analyzed by fluorescence microscopy co-localization imaging and ER staining. The performed cellular bioassays established that the BDNF-loaded LCNPs enhanced the neuronal cell survival. The diminution of the tunicamycin-induced ER stress upon internalization of neuroprotective nanoparticles was quantified via the changes in the Thioflavin T fluorescence, which is a sensitive marker of protein aggregation. LCNPs with multi-drug loading appear to be promising candidates to face the challenges in neuroprotective nanomedicine development by exploiting ER-stress targeting mechanisms.