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Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport.

ABSTRACT: Bile acid-modified nanomedicine is a promising strategy to improve oral bioavailability. However, the efficiencies of different bile acids have not been clarified. To clarify this issue, deoxycholic acid (DCA) and cholic acid (CA) and glycocholic acid (GCA) were conjugated to carboxylated polystyrene nanoparticle (CPN). The endocytosis, intracellular and transcellular transport among the NPs were compared in Caco-2 cells, and their oral pharmacokinetics profiles were studied in C57BL/6 J mice. It was found that DCPN demonstrated higher uptake and transcytosis rate. With modification by different bile acids, the transport pathways of the NPs were altered. In mice, GCPN showed the highest absorption speed and oral bioavailability. It was found that the synergic effect of hydrophobicity and ASBT affinity might lead to the difference between in vitro and in vivo transport. This study will build a basis for the rational design of bile acid-modified nanomedicines.

SUBMITTER: Deng F

PROVIDER: S-EPMC9918699 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport.

Deng Feiyang F Bae You Han YH

Nanomedicine : nanotechnology, biology, and medicine 20221121

Bile acid-modified nanomedicine is a promising strategy to improve oral bioavailability. However, the efficiencies of different bile acids have not been clarified. To clarify this issue, deoxycholic acid (DCA) and cholic acid (CA) and glycocholic acid (GCA) were conjugated to carboxylated polystyrene nanoparticle (CPN). The endocytosis, intracellular and transcellular transport among the NPs were compared in Caco-2 cells, and their oral pharmacokinetics profiles were studied in C57BL/6 J mice. I ...[more]

PMID: 36410698

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Project description:Diarrhea is one of the most common infirmities affecting international travelers, occurring in 20 to 50% of persons from industrialized countries visiting developing regions. Enterotoxigenic Escherichia coli (ETEC) is the most common causative agent and is isolated from approximately half of the cases of traveler's diarrhea. Rifaximin, a largely water-insoluble, nonabsorbable (<0.4%) antibiotic that inhibits bacterial RNA synthesis, is approved for use for the treatment of traveler's diarrhea caused by diarrheagenic E. coli. However, the drug has minimal effect on the bacterial flora or the infecting E. coli strain in the aqueous environment of the colon. The purpose of the present study was to evaluate the antimicrobial effect and bioavailability of rifaximin in aqueous solution in the presence and absence of physiologic concentrations of bile acids. The methods used included growth measurement of ETEC (strain H10407), rifaximin solubility measurements, total bacterial protein determination, and assessment of the functional activity of rifaximin by monitoring inhibition of bacterial beta-galactosidase expression. Solubility studies showed rifaximin to be 70- to 120-fold more soluble in bile acids (approximately 30% in 4 mM bile acids) than in aqueous solution. Addition of both purified bile acids and human bile to rifaximin at subinhibitory and inhibitory concentrations significantly improved the drug's anti-ETEC effect by 71% and 73%, respectively, after 4 h. This observation was confirmed by showing a decrease in the overall amount of total bacterial protein expressed during incubation of rifaximin plus bile acids. Rifaximin-treated samples containing bile acids inhibited the expression of ETEC beta-galactosidase at a higher magnitude than samples that did not contain bile acids. The study provides data showing that bile acids solubilize rifaximin on a dose-response basis, increasing the drug's bioavailability and antimicrobial effect. These observations suggest that rifaximin may be more effective in the treatment of infections in the small intestine, due to the higher concentration of bile in this region of the gastrointestinal tract than in the colon. The water insolubility of rifaximin is the likely explanation for the drug's minimal effects on colonic flora and fecal pathogens, despite in vitro susceptibility.

Project description:Introduction:An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods:A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n = 3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results:Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4-10% n.d.c.) and high radiochemical purity (>99%); 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion:A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.

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Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport.

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Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport.

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