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Synthesis and Intracellular Uptake of Rhodamine-Nucleolipid Conjugates into a Nanoemulsion Vehicle.

ABSTRACT: Neurodegenerative diseases represent some of the greatest challenges for both basic science and clinical medicine. Due to their prevalence and the lack of known biochemical-based treatments, these complex pathologies result in an increasing societal cost. Increasing genetic and neuropathological evidence indicates that lysosomal impairment may be a common factor linking these diseases, demanding the development of therapeutic strategies aimed at restoring the lysosomal function. Here, we propose the design and synthesis of a nucleolipid conjugate as a nonviral chemical nanovector to specifically target neuronal cells and intracellular organelles. Herein, thymidine, appropriately substituted to increase its lipophilicity, was used as a model nucleoside and a fluorophore moiety, covalently bound to the nucleoside, allowed the monitoring of nucleolipid internalization in vitro. To improve nucleolipid protection and cellular uptake, these conjugates were formulated in nanoemulsions. In vitro biological assays demonstrated cell uptake- and internalization-associated colocalization with lysosomal markers. Overall, this nucleolipid-nanoemulsion-based formulation represents a promising drug-delivery tool to target the central nervous system, able to deliver drugs to restore the impaired lysosomal function.

SUBMITTER: Cunha A

PROVIDER: S-EPMC7097973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Spherical nucleic acid (SNA) nanoparticle conjugates are a class of bionanomaterials that are extremely potent in many biomedical applications. Their unique ability to enter multiple mammalian cell types as single-entity agents arises from their novel three-dimensional architecture, which consists of a dense shell of highly oriented oligonucleotides chemically attached typically to a gold nanoparticle core. This architecture allows SNAs to engage certain cell surface receptors to facilitate entry. Here, we report studies aimed at determining the intracellular fate of SNAs and the trafficking events that occur inside C166 mouse endothelial cells after cellular entry. We show that SNAs traffic through the endocytic pathway into late endosomes and reside there for up to 24 h after incubation. Disassembly of oligonucleotides from the nanoparticle core is observed 16 h after cellular entry, most likely due to degradation by enzymes such as DNase II localized in late endosomes. Our observations point to these events being likely independent of core composition and treatment conditions, and they do not seem to be particularly dependent upon oligonucleotide sequence. Significantly and surprisingly, the SNAs do not enter the lysosomes under the conditions studied. To independently track the fate of the particle core and the fluorophore-labeled oligonucleotides that comprise its shell, we synthesized a novel class of quantum dot SNAs to determine that as the SNA structures are broken down over the 24 h time course of the experiment, the oligonucleotide fragments are recycled out of the cell while the nanoparticle core is not. This mechanistic insight points to the importance of designing and synthesizing next-generation SNAs that can bypass the degradation bottleneck imposed by their residency in late endosomes, and it also suggests that such structures might be extremely useful for endosomal signaling pathways by engaging receptors that are localized within the endosome.

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Synthesis and Intracellular Uptake of Rhodamine-Nucleolipid Conjugates into a Nanoemulsion Vehicle.

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