Functionalization of PLGA Nanoparticles with 1,3-β-glucan Enhances the Intracellular Pharmacokinetics of Rifampicin in Macrophages

Abstract

Purpose

Mycobacterium tuberculosis which causes tuberculosis, is primarily resident within macrophages. 1,3-β-glucan has been proposed as a ligand to target drug loaded nanoparticles (NPs) to macrophages. In this study we characterized the intracellular pharmacokinetics of the anti-tubercular drug rifampicin delivered by 1,3-β-glucan functionalized PLGA NPs (Glu-PLGA). We hypothesized that Glu-PLGA NPs would be taken up at a faster rate than PLGA NPs, and consequently deliver higher amounts of rifampicin into the macrophages.

Methods

Carbodiimide chemistry was employed to conjugate 1,3-β-glucan and rhodamine to PLGA. Rifampicin loaded PLGA and Glu-PLGA NPs as well as rhodamine functionalized PLGA and Glu-PLGA NPs were synthesized using an emulsion solvent evaporation technique. Intracellular pharmacokinetics of rifampicin and NPs were evaluated in THP-1 derived macrophages. A pharmacokinetic model was developed to describe uptake, and modelling was performed using ADAPT 5 software.

Results

The NPs increased the rate of uptake of rifampicin by a factor of 17 and 62 in case of PLGA and Glu-PLGA, respectively. Expulsion of NPs from the macrophages was also observed, which was 3 fold greater for Glu-PLGA NPs than for PLGA NPs. However, the ratio of uptake to expulsion was similar for both NPs. After 24 h, the amount of rifampicin delivered by the PLGA and Glu-PLGA NPs was similar. The NPs resulted in at least a 10-fold increase in the uptake of rifampicin.

Conclusions

Functionalization of PLGA NPs with 1,3-β-glucan resulted in faster uptake of rifampicin into macrophages. These NPs may be useful to achieve rapid intracellular eradication of Mycobacterium tuberculosis.

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Abbreviations

DIEA:

N,N-Diisopropylethylamine

DMF:

Dimethylformamide

EDC:

1-Ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride

LC-MS:

Liquid chromatography mass spectrometry

M.tb:

Mycobacterium tuberculosis

NHS:

N-Hydroxysuccinimide

NMR:

Nuclear magnetic resonance spectroscopy

NP:

Nanoparticle

PLGA:

Poly(D,L-lactide-co-glycolide)

PMA:

Phorbol myristate acetate

RIF:

Rifampicin

TB:

Tuberculosis

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Acknowledgments and Disclosures

Author AD wishes to acknowledge financial support from the Council for Scientific and Industrial Research (CSIR) South Africa (YREF 2013 011) and the University of the Western Cape. This work is based on research supported in part by the National Research Foundation of South Africa (Grant Number 109059) awarded to AD.

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Correspondence to Admire Dube.

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Tukulula, M., Gouveia, L., Paixao, P. et al. Functionalization of PLGA Nanoparticles with 1,3-β-glucan Enhances the Intracellular Pharmacokinetics of Rifampicin in Macrophages. Pharm Res 35, 111 (2018). https://doi.org/10.1007/s11095-018-2391-8

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Key words

  • 1,3-β-glucan
  • nanoparticle drug delivery
  • pharmacokinetic modelling
  • PLGA nanoparticles
  • rifampicin intracellular concentrations