Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

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

References

  1. WHO. Global tuberculosis report 2016. 19 November 2016. Available from: http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1.

  2. Kusner DJ. Mechanisms of mycobacterial persistence in tuberculosis. Clin Immunol (Orlando, Fla). 2005;114(3):239–47.

    Article  CAS  Google Scholar 

  3. Verma RK, Kaur J, Kumar K, Yadav AB, Misra A. Intracellular time course, pharmacokinetics, and Biodistribution of isoniazid and Rifabutin following pulmonary delivery of inhalable microparticles to mice. Antimicrob Agents Chemother. 2008;52(9):3195–201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Xie S, Tao Y, Pan Y, Qu W, Cheng G, Huang L, et al. Biodegradable nanoparticles for intracellular delivery of antimicrobial agents. J Control Release. 2014;187:101–17.

    Article  PubMed  CAS  Google Scholar 

  5. Kumar PV, Asthana A, Dutta T, Jain NK. Intracellular macrophage uptake of rifampicin loaded mannosylated dendrimers. J Drug Target. 2006;14(8):546–56.

    Article  PubMed  CAS  Google Scholar 

  6. Dube A, Reynolds JL, Law W-C, Maponga CC, Prasad PN, Morse GD. Multimodal nanoparticles that provide immunomodulation and intracellular drug delivery for infectious diseases. Nanomedicine. 2014;10(4):831–8.

    Article  PubMed  CAS  Google Scholar 

  7. Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, et al. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother. 2007;51(11):3781–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Sundaramurthi JC, Hanna LE, Selvaraju S, Brindha S, Joel Gnanadoss J, Vincent S, et al. TBDRUGS – database of drugs for tuberculosis. Tuberculosis. 2016;100:69–71.

    Article  PubMed  Google Scholar 

  9. Dube A, Lemmer Y, Hayeshi R, Balogun M, Labuschagne P, Swai H, et al. State of the art and future directions in nanomedicine for tuberculosis. Expert Opinion on Drug Delivery. 2013;10(12):1725–34.

    Article  PubMed  CAS  Google Scholar 

  10. Chono S, Tanino T, Seki T, Morimoto K. Uptake characteristics of liposomes by rat alveolar macrophages: influence of particle size and surface mannose modification. J Pharm Pharmacol. 2007;59(1):75–80.

    Article  PubMed  CAS  Google Scholar 

  11. Chono S, Tanino T, Seki T, Morimoto K. Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections. J Control Release. 2008;127(1):50–8.

    Article  PubMed  CAS  Google Scholar 

  12. Tukulula M, Hayeshi R, Fonteh P, Meyer D, Ndamase A, Madziva MT, et al. Curdlan-conjugated PLGA nanoparticles possess macrophage stimulant activity and drug delivery capabilities. Pharm Res. 2015;32(8):2713–26.

    PubMed  CAS  Google Scholar 

  13. Brown GD, Taylor PR, Reid DM, Willment JA, Williams DL, Martinez-Pomares L, et al. Dectin-1 is a major β-glucan receptor on macrophages. J Exp Med. 2002;196(3):407–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Goodridge HS, Wolf AJ, Underhill DM. β-glucan recognition by the innate immune system. Immunol Rev. 2009;230(1):38–50.

    Article  PubMed  CAS  Google Scholar 

  15. Chan GC, Chan WK, Sze DM. The effects of beta-glucan on human immune and cancer cells. J Hematol Oncol. 2009;2:25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Adamczyk M, Grote J. Efficient synthesis of rhodamine conjugates through the 2′-position. Bioorg Med Chem Lett. 2000;10(14):1539–41.

    Article  PubMed  CAS  Google Scholar 

  17. Li M, Czyszczon EA, Reineke JJ. Delineating intracellular pharmacokinetics of paclitaxel delivered by PLGA nanoparticles. Drug Deliv Trans Res. 2013;3(6):551–61.

    Article  CAS  Google Scholar 

  18. Jiang L, He L, Fountoulakis M. Comparison of protein precipitation methods for sample preparation prior to proteomic analysis. J Chromatogr A. 2004;1023(2):317–20.

    Article  PubMed  CAS  Google Scholar 

  19. Ece Gamsiz D, Shah LK, Devalapally H, Amiji MM, Carrier RL. A model predicting delivery of saquinavir in nanoparticles to human monocyte/macrophage (Mo/Mac) cells. Biotechnol Bioeng. 2008;101(5):1072–82.

    Article  PubMed  CAS  Google Scholar 

  20. D’Argenio D, Schumitzky A, Wang XADAPT. 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. USA: Biomedical Simulations Resource, CA; 2009.

    Google Scholar 

  21. Ramos SS, Vilhena AF, Santos L, Almeida P. 1H and 13C NMR spectra of commercial rhodamine ester derivatives. Magn Reson Chem. 2000;38(6):475–8.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Matshawandile Tukulula and Luis Gouveia contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Tshwane University of Technology, Pretoria, South Africa

    Matshawandile Tukulula

  2. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa,, Lisbon, Portugal

    Luis Gouveia & Paulo Paixao

  3. DST/NWU Preclinical Drug Development Platform, North-West University,, Potchefstroom, South Africa

    Rose Hayeshi

  4. Council for Scientific and Industrial Research, Polymers and Composites, Pretoria, South Africa

    Brendon Naicker

  5. Discipline of Pharmaceutics, School of Pharmacy, University of the Western Cape,, Bellville, 7535, South Africa

    Admire Dube

Authors
  1. Matshawandile Tukulula
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis Gouveia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paulo Paixao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rose Hayeshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brendon Naicker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Admire Dube
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Admire Dube.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-018-2391-8

Key words

Search

Navigation