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Physicochemical and Biological Evaluation of Curdlan-Poly(Lactic-Co-Glycolic Acid) Nanoparticles as a Host-Directed Therapy Against Mycobacterium Tuberculosis.

ABSTRACT: Nanoparticles (NPs) that can activate macrophages infected with the tuberculosis causative pathogen Mycobacterium tuberculosis, could be an effective host directed therapy for the disease. In this study, curdlan was conjugated to poly(lactic-co-glycolic acid) (PLGA) to produce immunotherapeutic NPs. Various physicochemical characterizations were used to evaluate the curdlan-PLGA copolymer and the NPs. Molecular dynamics and simulation studies were used to characterize the interaction between curdlan, on the polymer and on NPs, with the Dectin-1 macrophage receptor. NPs with varying curdlan densities were evaluated for their effects on the production of pro- and anti-inflammatory cytokines in M. tuberculosis infected RAW264.7 macrophages. The killing efficacy of the NPs against intracellular M. tuberculosis was assessed. Physicochemical characterization of the curdlan-PLGA copolymer and NPs indicated successful formation of curdlan-PLGA copolymer and NPs of varying curdlan density (0-8% w/w) had sizes between 330 and 453 nm. Modelling studies showed curdlan to have a strong affinity for Dectin-1. Cytotoxicity assays showed the NPs to be non-toxic over 72 h. The proinflammatory cytokine TNF-α was found to be significantly upregulated by the NPs. The NPs reduced intracellular M. tuberculosis burden over 72 h. These NPs are a promising host directed therapy for intracellular eradication of M. tuberculosis.

SUBMITTER: D'Souza S

PROVIDER: S-EPMC8792347 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Curcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability.Following oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells.Following in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo.These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future studies should focus on enhancing the resistance to metabolic degradation and conversion of CUR to other metabolites, which may lead to novel discoveries regarding food function and disease prevention.

Dataset Information

Physicochemical and Biological Evaluation of Curdlan-Poly(Lactic-Co-Glycolic Acid) Nanoparticles as a Host-Directed Therapy Against Mycobacterium Tuberculosis.

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