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Visualizing intracellular particles and precise control of drug release using an emissive hydrazone photochrome.

ABSTRACT: The spatiotemporal control over the structure of nanoparticles while monitoring their localization in tumor cells can improve the precision of controlled drug release, thus enhancing the efficiency of drug delivery. Here, we report on a photochromic nanoparticle system (LSNP), assembled from fluorescent bistable hydrazone photoswitch-modified amphiphilic copolymers. The intrinsic emission of the hydrazone switch allows for the visualization of particle uptake, as well as their intracellular distribution. The Z → E photoswitching of the hydrazone switch within the nanoparticle leads to the expansion of the nanoparticles (i.e., drug release) accompanied by emission quenching, the degree of which can function as an internal indicator for the amount of drug released. The bistability of the switch enables the kinetic trapping of particles of different sizes as a function of irradiation time, and allows for the exhibition of light-dependent cell cytotoxicity in MDA-MB-231 cells using LSNP loaded with doxorubicin.

SUBMITTER: Guo X

PROVIDER: S-EPMC8157519 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:N-Acetyl-L-cysteine (NAC) is an antioxidant and anti-inflammatory agent with significant potential in clinical applications including stroke and neuroinflammation. The drug shows high plasma binding upon IV administration, requiring high doses and associated side effects. Through the use of an appropriate delivery vehicle, the stability and efficacy of NAC can be significantly improved. Dendrimers are an emerging class of nanoscale drug delivery vehicles, which enable high drug payloads and intracellular delivery. Poly(amidoamine) (PAMAM) dendrimer-NAC conjugates having cleavable disulfide linkages are designed for intracellular delivery based on glutathione levels. We have successfully synthesized two conjugates with a cationic G4-NH(2) and an anionic G3.5-COOH PAMAM dendrimer with NAC payloads of 16 and 18 per dendrimer, respectively, as confirmed by (1)H NMR and MALDI-TOF analysis. NAC release from the conjugates at intracellular and extracellular glutathione (GSH) concentrations were evaluated by reverse phase HPLC (RP-HPLC) analysis, and approximately 70% of NAC payload was released within one hour at intracellular GSH concentrations (approximately 10 mM), whereas negligible NAC release was observed at extracellular GSH levels (2 microM). FITC-labeled conjugates showed that they enter cells rapidly and localize in the cytoplasm of lipopolysaccharide (LPS)-activated microglial cells (the target cells in vivo). The significantly improved efficacies of dendrimer-NAC conjugates in activated microglial cells was confirmed by measuring the nitrite inhibition in the cell culture medium, which is an indication of the antioxidative property of the drug. Both G4-NH(2) and G3.5-COOH conjugates showed significantly better nitrite inhibition both at 24 and 72 h compared to free NAC, by as much as a factor of 16. The results indicate that PAMAM dendrimer conjugates produce higher local NAC concentration inside the cells, with GSH-sensitive disulfide linker enabling efficient and rapid cellular release of the drug.

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Visualizing intracellular particles and precise control of drug release using an emissive hydrazone photochrome.

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