Skip to main content

Advertisement

SpringerLink
Log in

Pyrimethamine-loaded lipid-core nanocapsules to improve drug efficacy for the treatment of toxoplasmosis

  • Original Paper
  • Published:
Parasitology Research Aims and scope Submit manuscript

Abstract

We propose an innovative product based on the nanoencapsulation of pyrimethamine (PYR), aiming an improvement of drug efficacy for the treatment of toxoplasmosis. The in vitro cytotoxicity effect of encapsulated PYR and PYR-colloidal suspension was concomitantly evaluated against LLC-MK2 lineage and mouse peritoneal macrophage showing that the cells had similar tolerance for both PYR encapsulated or in the aqueous suspension. CF1 mice acutely infected with tachyzoites of Toxoplasma gondii RH strain treated with different doses (5.0–10 mg/kg/day) of PYR-nanocapsules had survival rate higher than the animals treated with the same doses of non-encapsulated PYR. Thus, encapsulation of PYR improved the efficacy of this drug against an acute model of toxoplasmosis in mice and can be considered an alternative for reducing the dose of PYR, which, in turn, could also reduce the side effects associated to the treatment.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Anderson AC (2005) Targeting DHFR in parasitic protozoa. Drug Discov Today 10:121–128

    Article  CAS  PubMed  Google Scholar 

  • Bernardi A, Braganhol E, Jäger E, Figueiró F, Edelweiss MI, Pohlmann AR, Guterres SS, Battastini AM (2009) Indomethacin-loaded nanocapsules treatment reduces in vivo glioblastoma growth in a rat glioma model. Cancer Lett 281:53–63

    Article  CAS  PubMed  Google Scholar 

  • Bernardi A, Frozza RL, Meneghetti A, Hoppe JB, Battastini AM, Pohlmann AR, Guterres SS, Salbego CG (2012) Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer's disease models. Int J Nanomedicine 7:4927–42

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boca MB, Apostolides Z, Pretorius E (2005) A validated HPLC method for determining residues of a dual active ingredient anti-malarial drug on manufacturing equipment surfaces. J Pharm Biomed Anal 37:461–468

    Article  CAS  PubMed  Google Scholar 

  • Bordes C, Snabre P, Frances C, Biscans B (2002) Optical investigation of shear- and time-dependent microstructural changes to stabilize and depletion-flocculated concentrated latex sphere suspensions. Powder Technol 128:218–228

    Article  CAS  Google Scholar 

  • Chio LC, Queener SF (1993) Identification of highly potent and selective inhibitors of Toxoplasma gondii dihydrofolate reductase. Antimicrob Agents Chemother 37:1914–1923

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Couvreur P, Barrat G, Fattal E, Legrand P, Vauthier C (2002) Nanocapsule technology: a review. Crit Rev Ther Drug 19:99–134

    Article  CAS  Google Scholar 

  • De Araújo MGV, Vieira EKB, Lázaro GS, Conegero LS, Ferreira OP, Almeida LE, Barreto LS, da Costa NB, Jr GIF (2007) Inclusion complexes of pyrimethamine in 2-ydroxypropyl-b-cyclodextrin: characterization, phase solubility and molecular modeling. Bioorg Med Chem 15:5752–5759

    Article  PubMed  Google Scholar 

  • Friedrich RB, Fontana MC, Beck RCR, Pohlmann AR, Guterres SS (2008) Development and physicochemical characterization of dexamethasone-loaded polymeric nanocapsule suspensions. Quim Nova 31(5):1131–36

    Article  CAS  Google Scholar 

  • Gangjee A, Jain HD, Queener SF, Kisliuk RL (2008) The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents. J Med Chem 51:4589–600

    Article  CAS  PubMed  Google Scholar 

  • Giannini EG, Testa R, Savarino V (2005) Liver enzyme alteration; a guide for clinicians. CMAJ 172:367–79

    Article  PubMed Central  PubMed  Google Scholar 

  • Goldsmith M, Mizrahy S, Peer D (2011) Grand challenges in modulating the immune response with RNAi nanomedicines. Nanomedicine 6:1771–1785

    Article  CAS  PubMed  Google Scholar 

  • Jornada DS, Fiel LA, Bueno K, Gerent JF, Petzhold CL, Beck RCR, Guterres SS, Pohlmann AR (2012) Lipid-core nanocapsules: mechanism of self-assembly, control of size and loading capacity. Soft Matter 8:6646–6655

    Article  CAS  Google Scholar 

  • Keck CM, Muller RH (2008) Size analysis of submicron particles by laser diffractometry—90% of the published measurements are false. Int J Pharm 355:150–163

    Article  CAS  PubMed  Google Scholar 

  • Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet 363:1965–1976

    Article  CAS  PubMed  Google Scholar 

  • Mora-Huertas CE, Fessi H, Elaissari A (2010) Polymer-based nanocapsules for drug delivery. Int J Pharm 385:113–142

    Article  CAS  PubMed  Google Scholar 

  • Müller RH, Petersen RD, Hommoss A, Pardeike J (2007) Nanostructured lipid carriers (NLC) in cosmetic dermal products. Adv Drug Deliv Rev 59:522–530

    Article  PubMed  Google Scholar 

  • Nissapatorn V, Sawangjaroen N (2011) Parasitic infections in HIV infected individuals: diagnostic & therapeutic challenges. Indian J Med Res 134:878–97

    Article  PubMed  Google Scholar 

  • Oliveira CP, Venturini CG, Donida B, Poletto FS, Guterres SS, Pohlmann AR (2012) An algorithm to determine the mechanism of drug distribution in lipid-core nanocapsule formulations. Soft Matter 9:1141–2012

    Article  Google Scholar 

  • Pohlmann AR, Fonseca FN, Paese K, Detoni CB, Coradini K, Beck RCR, Guterres SS (2013) Poly(ε-caprolactone) microcapsules and nanocapsules in drug delivery. Expert Opin Drug Deliv. doi:10.1517/17425247.2013.769956

  • Poletto FS, Fiel LA, Lopes MV, Schaab G, Gomes AMO, Guterres SS, Rossi-Bergmann B, Pohlmann AR (2012) Fluorescent-labeled poly(ε-caprolactone) lipid-core nanocapsules: synthesis, physicochemical properties and macrophage uptake. J Colloid Sci Biotechnol 1:89–98

    Article  Google Scholar 

  • Poletto FS, Jäger E, Cruz L, Pohlmann AR, Guterres SS (2008) The effect of polymeric wall on the permeability of drug-loaded nanocapsules. Mater Sci Eng C Mater Biol Appl 28:472

    Article  CAS  Google Scholar 

  • Prieto MJ, Bacigalupe D, Pardini O, Amalvy JI, Venturini C, Morilla MJ, Romero EL (2006) Nanomolar cationic dendrimeric sulfadiazine as potential antitoxoplasmic agent. Int J Pharm 326:160–168

    Article  CAS  PubMed  Google Scholar 

  • Sahay G, Alakhova DY, Kabanov AV (2010) Endocytosis of nanomedicines. J Control Release 145:182–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schnell JR, Dyson HJ, Wright PE (2004) Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct 33:119–140

    Article  CAS  PubMed  Google Scholar 

  • Shubar HM, Lachenmaier S, Heimesaat MM, Lohman U, Mauludin R, Mueller RH, Fitzner R, Borner K, Liesenfeld O (2011) SDS-coated atovaquone nanosuspensions show improved therapeutic efficacy against experimental acquired and reactivated toxoplasmosis by improving passage of gastrointestinal and blood–brain barriers. J Drug Target 19:114–124

    Article  CAS  PubMed  Google Scholar 

  • Sordet F, Aumjaud Y, Fessi H, Derouin F (1998) Assessment of the activity of atovaquone-loaded nanocapsules in the treatment of acute and chronic murine toxoplasmosis. Parasite 5:223–9

    CAS  PubMed  Google Scholar 

  • Venturini CG, Jäger E, Oliveira CP, Bernardi A, Battastini AMO, Guterres SS (2011) Formulation of lipid core nanocapsules. Colloid Surf A 375:200–208

    Article  CAS  Google Scholar 

  • Weniger H (1979) Review of side effects and toxicity of pyrimethamine. Geneva: World health Organization; WHO/MAL/79907

Download references

Acknowledgments

The authors thank Mr. Helcio Evangelista da Silva for technical assistance with animal care, Dr. Daniel Gonçalves for technical assistance with FESEM and Dr. Eduardo José Torres and Dr. Kildare Miranda for helpful discussions. The authors would like to thank Perstorp for kindly providing the CAPA® 6500 product. This work was supported by Rede Nanobiotec-Brazil CAPES, Grants CNPq/MCT, and Fellows CAPES. Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Programa de Núcleos de Excelência-Pronex-FAPERJ-CNPq and Pronex FAPERGS-CNPq (#10/0048-4).

Author information

Authors and Affiliations

  1. Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Kenia Pissinate, Érica dos Santos Martins-Duarte, Scheila Rezende Schaffazick, Rossiane Cláudia Vommaro & Wanderley de Souza

  2. Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Érica dos Santos Martins-Duarte, Rossiane Cláudia Vommaro & Wanderley de Souza

  3. Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Scheila Rezende Schaffazick, Catiúscia Padilha de Oliveira, Sílvia Stanisçuaski Guterres & Adriana Raffin Pohlmann

  4. Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Caixa Postal 15003, Av. Bento Gonçalves, 9500, Porto Alegre, 91501-970, Brazil

    Kenia Pissinate & Adriana Raffin Pohlmann

  5. Instituto Nacional de Metrologia e Qualidade Industrial—Inmetro, Rio de Janeiro, Brazil

    Wanderley de Souza

Authors
  1. Kenia Pissinate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Érica dos Santos Martins-Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scheila Rezende Schaffazick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Catiúscia Padilha de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rossiane Cláudia Vommaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sílvia Stanisçuaski Guterres
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adriana Raffin Pohlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wanderley de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenia Pissinate.

Additional information

Kenia Pissinate and Érica dos Santos Martins-Duarte contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pissinate, K., dos Santos Martins-Duarte, É., Schaffazick, S.R. et al. Pyrimethamine-loaded lipid-core nanocapsules to improve drug efficacy for the treatment of toxoplasmosis. Parasitol Res 113, 555–564 (2014). https://doi.org/10.1007/s00436-013-3715-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00436-013-3715-6

Keywords

Search

Navigation