Skip to main content
SpringerLink
Log in

Receptor-mediated hepatocyte-targeted delivery of primaquine phosphate nanocarboplex using a carbohydrate ligand

  • Research Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Primaquine phosphate is a drug of choice for the treatment of malarial relapse. However, poor drug concentration in the hepatocytes and dose-related toxicity pose severe limitations. We report a nanocarboplex of primaquine phosphate by a simple in situ process using dextran sulphate as a carbohydrate polymer and pullulan as an asialoglycoprotein receptor ligand. Our aim was to preferentially enhance accumulation of the nanocarboplex in the hepatocytes. The in situ pullulan-anchored primaquine nanocarboplex was prepared by simple addition of a solution of dextran sulphate and pullulan with stabilizer to a measured quantity of primaquine phosphate in a vial, followed by shaking to obtain the primaquine phosphate nanocarboplex ready for injection. The nanocarboplex was characterized and evaluated in vivo for pharmacokinetics and biodistribution in the rat model. Specific uptake by hepatocytes in the liver was also quantified. Increase in t ½ with significant uptake in the RES organ was observed. More importantly, anchoring pullulan favored high liver uptake and preferential accumulation in the hepatocytes with a hepatocytes/nonparenchymal cells ratio of 75:25. The in situ primaquine phosphate nanocarboplex anchored with pullulan provides both a significant technological advantage and the desired targeting to the hepatocytes.

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
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18
Fig. 19

Similar content being viewed by others

Abbreviations

PQ:

Primaquine phosphate

DS:

Dextran sulphate

ASGP-R:

Asialoglycoprotein receptor

PU:

Pullulan

HIP:

Hydrophobic ion pair

References

  1. World Malaria Report 2011. http://www.who.int/entity/malaria/world_malaria_report_2011/9789241564403_eng.pdf

  2. Lena H, Larry H. Activation of the hypnozoite: a part of Plasmodium vivax life cycle and survival. Malar J. 2011. doi:10.1186/1475-2875-10-90.

    Google Scholar 

  3. Shanks GD, White NJ. The activation of vivax malaria hypnozoites by infectious diseases. Lancet Infect Dis. 2013;13(10):900–6.

    Article  PubMed  Google Scholar 

  4. Shanks GD. Control and elimination of Plasmodium vivax. Adv Parasitol. 2012;80:301–41.

    Article  PubMed  Google Scholar 

  5. Timothy NCW, Jeremy NB, Baird JK. Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. Trends Parasitol. 2010;26(3):145–51.

    Article  Google Scholar 

  6. John GK, Douglas NM, von Seidlein L, Nosten F, Baird JK, White NJ, et al. Primaquine radical cure of Plasmodium vivax: a critical review of the literature. Malar J. 2012. doi:10.1186/1475-2875-11-280.

    Google Scholar 

  7. Pirson P, Steiger RF, Trouet A, Gillet J, Herman F. Primaquine liposomes in the chemotherapy of experimental murine malaria. Ann Trop Med Parasitol. 1980;74:383–91.

    CAS  PubMed  Google Scholar 

  8. Pirson P, Steiger R, Trouet A. The disposition of free and liposomally encapsulated antimalarial primaquine in mice. Biochem Pharmacol. 1982;31:3501–7.

    Article  CAS  PubMed  Google Scholar 

  9. Labhasetwar VD, Dorle AK. Nanoparticles—a colloidal drug delivery system for primaquine and metronidazole. J Control Rel. 1990;12:113–9.

    Article  CAS  Google Scholar 

  10. Singh KK, Vingkar SK. Formulation, antimalarial activity and biodistribution of oral lipid nanoemulsion of primaquine. Int J Pharm. 2008;347:136–43.

    Article  CAS  PubMed  Google Scholar 

  11. Dierling AM, Cui Z. Targeting primaquine into liver using chylomicron emulsions for potential vivax malaria therapy. Int J Pharm. 2005;33:148–52.

    Google Scholar 

  12. Murao A, Nishikawa M, Managit C, Wong J, Kawakami S, Yamastuta F, et al. Targeting efficiency of galactosylated liposomes to hepatocytes in vivo: effect of lipid composition. Pharm Res. 2002;19:1808–13.

    Article  CAS  PubMed  Google Scholar 

  13. Bhadra D, Yadav AK, Bhadra S, Jain NK. Glycodendrimeric nanoparticulate carriers of primaquine phosphate for liver targeting. Int J Pharm. 2005;295:221–33.

    Article  CAS  PubMed  Google Scholar 

  14. Benjamin GD, Robinson MA. Drug delivery systems based on sugar macromolecule conjugates. Curr Opin Drug Discov Dev. 2002;5(2):279–88.

    Google Scholar 

  15. Kaneo Y, Tanaka T, Nakano T, Yamaguchi Y. Evidence for receptor-mediated hepatic uptake of pullulan in rats. J Control Release. 2001;70:365–73.

    Article  CAS  PubMed  Google Scholar 

  16. Devarajan PV, Joshi VM (2013) Scale up of doxycycline hydrochloride lipomer by nanoprecipitation using an air atomization technique. Am J PharmTech Res 3(4)

  17. Guhagarkar SA, Gaikwad RV, Samad A, Malshe VC, Devarajan PV. Polyethylene sebacate–doxorubicin nanoparticles for hepatic targeting. Int J Pharm. 2010;401:113–22.

    Article  CAS  PubMed  Google Scholar 

  18. Bock TK, Muller BW. A novel assay to determine the hemolytic activity of drugs incorporated in colloidal carrier systems. Pharm Res. 1994;11(4):589.

    Article  CAS  PubMed  Google Scholar 

  19. Guhagarkar SA, Majee SB, Samad A, Devarajan PV. Evaluation of pullulan-functionalized doxorubicin nanoparticles for asialoglycoprotein receptor-mediated uptake in Hep G2 cell line. Cancer Nano. 2011;2:49–55.

    Article  CAS  Google Scholar 

  20. D'Souza AA, Jain P, Galdhar CN, Samad A, Degani MS, Devarajan PV. Comparative in silico-in vivo evaluation of ASGP-R ligands for hepatic targeting of curcumin Gantrez nanoparticles. AAPS J. 2013;15(3):696–706.

    Article  PubMed Central  PubMed  Google Scholar 

  21. La-Scalea MA, Chin CM, Cruz ML, Serrano SH, Ferreira EI. Dissociation and electrooxidation of primaquine diphosphate as an approach to the study of anti-chagas prodrugs mechanism of action. Bioelectrochemistry. 2001;53(1):55–9.

    Article  CAS  PubMed  Google Scholar 

  22. Gaudana R, Khurana V, Parenky A, Mitra AK (2011) Encapsulation of protein-polysaccharide HIP complex in polymeric nanoparticles. J Drug Deliv 458128

  23. Kitaeva MV, Melik-Nubarov NS, Menger FM, Yaroslavov AA. Doxorubicin-poly(acrylic acid) complexes: interaction with liposomes. Langmuir. 2004;20(16):6575–9.

    Article  CAS  PubMed  Google Scholar 

  24. Tian Y, Bromberg L, Lin SN, Alan Hatton T, Tam KC. Complexation and release of doxorubicin from its complexes with pluronic P85-b-poly(acrylic acid) block copolymers. J Control Release. 2007;121(3):137–45.

    Article  CAS  PubMed  Google Scholar 

  25. Margaritis A, Manocha B (2010) Controlled release of doxorubicin from doxorubicin/γ-polyglutamic acid ionic complex. J Nanomater 1–8

  26. Ehtezazi T, Govender T, Stolnik S. Hydrogen bonding and electrostatic interaction contributions to the interaction of a cationic drug with polyaspartic acid. Pharm Res. 2000;17(7):871–7.

    Article  CAS  PubMed  Google Scholar 

  27. Bogush T, Smirnova G, Shubina I, Syrkin A, Robert J. Direct evaluation of intracellular accumulation of free and polymer-bound anthracyclines. Cancer Chemother Pharmacol. 1995;35(6):501–5.

    Article  CAS  PubMed  Google Scholar 

  28. Shaoping S, Liang NA, Kawashima Y, Xia D, Cui F. Hydrophobic ion pairing of an insulin-sodium deoxycholate complex for oral delivery of insulin. Int J Nanomedicine. 2011;6:3049–56.

    Google Scholar 

  29. Kapse SV, Gaikwad RV, Samad A, Devarajan PV. Self nanoprecipitating preconcentrate of tamoxifen citrate for enhanced bioavailability. Int J Pharm. 2012;429:104–12.

    Article  CAS  PubMed  Google Scholar 

  30. Boer F. Drug handling by the lungs. Br J Anaesth. 2003;91:50–60.

    Article  CAS  PubMed  Google Scholar 

  31. Clark AM, Baker JK, McChesney JD. Excretion, distribution, and metabolism of primaquine in rats. J Pharm Sci. 1984;73(4):502–6.

    Article  CAS  PubMed  Google Scholar 

  32. Foye O, William Thomas LL, David WA. Principles of medicinal chemistry. 4th ed. New Delhi: Wavley; 1995. p. 563–4.

    Google Scholar 

Download references

Acknowledgments

The authors are thankful to Phoenix Pharmaceutical LLC, Ohio, USA for providing senior research fellowship; Tata Institute of Fundamental Research, Mumbai, India for powder X-ray diffraction study; and the Sophisticated Analytical Instrument Facility (SAIF) of Indian Institute of Technology (IIT), Mumbai, India for scanning electron microscopy study. The authors are also thankful to Mr. Nyaneshwar Nagmoti and Mr. Jayesh B. Dhodi for their valuable support for in vivo study on rats.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga (E), Mumbai, 400019, India

    Vishvesh M. Joshi & Padma V. Devarajan

Authors
  1. Vishvesh M. Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Padma V. Devarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Padma V. Devarajan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Joshi, V.M., Devarajan, P.V. Receptor-mediated hepatocyte-targeted delivery of primaquine phosphate nanocarboplex using a carbohydrate ligand. Drug Deliv. and Transl. Res. 4, 353–364 (2014). https://doi.org/10.1007/s13346-014-0200-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-014-0200-4

Keywords

Search

Navigation