Skip to main content Accessibility help

Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis

  • A. J. SOUSA-BATISTA (a1), F. S. POLETTO (a2), C. I. M. S. PHILIPON (a1), S. S. GUTERRES (a3), A. R. POHLMANN (a2) and B. ROSSI-BERGMANN (a1)...


New oral treatments are needed for all forms of leishmaniasis. Here, the improved oral efficacy of quercetin (Qc) and its penta-acetylated derivative (PQc) was evaluated in cutaneous leishmaniasis after encapsulation in lipid-core nanocapsules (LNCs) of poly(ε-caprolactone). Leishmania amazonensis-infected BALB/c mice were given 51 daily oral doses of free drugs (16 mg kg−1) or LNC-loaded drugs (0·4 mg kg−1). While treatment with free Qc reduced the lesion sizes and parasite loads by 38 and 71%, respectively, LNC-Qc produced 64 and 91% reduction, respectively. The antileishmanial efficacy of PQc was similar but not as potently improved by encapsulation as Qc. None of the treatments increased aspartate aminotransferase, alanine aminotransferase or creatinine serum levels. These findings indicate that when encapsulated in LNC, Qc and, to a lesser extent, PQc can safely produce an enhanced antileishmanial effect even at a 40-fold lower dose, with implications for the development of a new oral drug for cutaneous leishmaniasis.


Corresponding author

*Corresponding author: Instituto de Biofísica Carlos Chagas Filho, Av Carlos Chagas Filho 373, 21·9410901 Rio de Janeiro, RJ, Brazil. E-mail:


Hide All
Ben Salah, A., Ben Messaoud, N., Guedri, E., Zaatour, A., Ben Alaya, N., Bettaieb, J., Gharbi, A., Belhadj Hamida, N., Boukthir, A., Chlif, S., Abdelhamid, K., El Ahmadi, Z., Louzir, H., Mokni, M., Morizot, G., Buffet, P., Smith, P. L., Kopydlowski, K. M., Kreishman-Deitrick, M., Smith, K. S., Nielsen, C. J., Ullman, D. R., Norwood, J. A., Thorne, G. D., McCarthy, W. F., Adams, R. C., Rice, R. M., Tang, D., Berman, J., Ransom, J. et al. (2013). Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. New England Journal of Medicine 368, 524532.
Boeck, P., Bandeira Falcão, C. A., Leal, P. C., Yunes, R. A., Filho, V. C., Torres-Santos, E. C. and Rossi-Bergmann, B. (2006). Synthesis of chalcone analogues with increased antileishmanial activity. Bioorganic and Medicinal Chemistry 14, 15381545.
Bulcão, R. P., Freitas, F. A., Venturini, C. G., Dallegrave, E., Durgante, J., Göethel, G., Cerski, C. T. S., Zielinsky, P., Pohlmann, A. R., Guterres, S. S. and Garcia, S. C. (2013). Acute and subchronic toxicity evaluation of poly(e-caprolactone) lipid-core nanocapsules in rats. Toxicological Sciences 132, 162176.
Crespy, V., Morand, C., Manach, C., Besson, C., Demigne, C. and Remesy, C. (1999). Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. American Journal of Physiology 277, G120G126.
da Cunha-Júnior, E. F., Pacienza-Lima, W., Ribeiro, G. A., Netto, C. D., do Canto-Cavalheiro, M. M., da Silva, A. J. M., Costa, P. R. R., Rossi-Bergmann, B. and Torres-Santos, E. C. (2011). Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis. Journal of Antimicrobial Chemotherapy 66, 15551559.
Demicheli, C., Ochoa, R., da Silva, J. B. B., Falcão, C. A. B., Rossi-Bergmann, B., de Melo, A. L., Sinisterra, R. D. and Frézard, F. (2004). Oral delivery of meglumine antimoniate-beta-cyclodextrin complex for treatment of leishmaniasis. Antimicrobial Agents and Chemotherapy 48, 100103.
Dunnick, J. and Hailey, J. (1992). Toxicity and carcinogenicity studies of quercetin, a natural component of foods. Fundamental and Applied Toxicology 19, 423431.
Fonseca-Silva, F., Inacio, J. D. F., Canto-Cavalheiro, M. M. and Almeida-Amaral, E. E. (2011). Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis . PLoS ONE 6, e14666.
Frozza, R., Bernardi, A., Paese, K., Hoppe, J., da Silva, T., Battastini, A., Pohlmann, A., Guterres, S. and Salbego, C. (2010). Characterization of trans-resveratrol-loaded lipid-core nanocapsules and tissue distribution studies in rats. Journal of Biomedical Nanotechnology 6, 694703.
Gibellini, L., Pinti, M., Nasi, M., Montagna, J. P., De Biasi, S., Roat, E., Bertoncelli, L., Cooper, E. L. and Cossarizza, A. (2010). Quercetin and cancer chemoprevention. Evidence-based Complementary and Alternative Medicine 2011, 115.
Graf, B. A., Ameho, C., Dolnikowski, G. G., Milbury, P. E., Chen, C.-Y. and Blumberg, J. B. (2006). Rat gastrointestinal tissues metabolize quercetin. Journal of Nutrition 136, 3944.
Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M. T., Wang, S., Liu, H. and Yin, Y. (2016 a). Quercetin, inflammation and immunity. Nutrients 8, 114.
Li, H., Chen, M., Su, Z., Sun, M. and Ping, Q. (2016 b). Size-exclusive effect of nanostructured lipid carriers on oral drug delivery. International Journal of Pharmaceutics 511, 524537.
Li, H., Zhao, X., Ma, Y., Zhai, G., Li, L. and Lou, H. (2009). Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. Journal of Controlled Release 133, 238244.
Lima, H. C., Bleyenberg, J. A. and Titus, R. G. (1997). A simple method for quantifying Leishmania in tissues of infected animals. Parasitology Today 13, 8082.
Lopes, M., Abrahim, B., Cabral, L., Rodrigues, C., Seiça, R., de Baptista, F. and Ribeiro, A. (2014). Intestinal absorption of insulin nanoparticles: contribution of M cells. Nanomedicine 10, 11391151.
López, L., Robayo, M., Vargas, M. and Vélez, I. D. (2012). Thermotherapy. An alternative for the treatment of American cutaneous leishmaniasis. Trials 13, 17.
Marín, C., Boutaleb-Charki, S., Díaz, J. G., Huertas, O., Rosales, M. J., Pérez-Cordon, G., Guitierrez-Sánchez, R. and Sánchez-Moreno, M. (2009). Antileishmaniasis activity of flavonoids from Consolida oliveriana . Journal of Natural Products 72, 10691074.
Mlcek, J., Jurikova, T., Skrovankova, S. and Sochor, J. (2016). Quercetin and its anti-allergic immune response. Molecules 21, 115.
Monge-Maillo, B. and López-Vélez, R. (2015). Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations. Clinical Infectious Diseases 60, 13981404.
Muzitano, M. F., Tinoco, L. W., Guette, C., Kaiser, C. R., Rossi-Bergmann, B. and Costa, S. S. (2006). The antileishmanial activity assessment of unusual flavonoids from Kalanchoe pinnata . Phytochemistry 67, 20712077.
Muzitano, M. F., Falcão, C. A. B., Cruz, E. A., Bergonzi, M. C., Bilia, A. R., Vincieri, F. F., Rossi-Bergmann, B. and Costa, S. S. (2009). Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Medica 75, 307311.
Navin, T. R., Arana, B. A., Arana, F. E., de Mérida, A. M., Castillo, A. L. and Pozuelos, J. L. (1990). Placebo controlled clinical trial of meglumine antimonate (glucantime) vs. localized controlled heat in the treatment of cutaneous leishmaniasis in Guatemala. American Journal of Tropical Medicine and Hygiene 42, 4350.
Otsuka, T., Takagi, H., Horiguchi, N., Toyoda, M., Sato, K., Takayama, H. and Mori, M. (2002). CCl4-induced acute liver injury in mice is inhibited by hepatocyte growth factor overexpression but stimulated by NK2 overexpression. FEBS Letters 532, 391395.
Pohlmann, A. R., Fonseca, F. N., Paese, K., Detoni, C. B., Coradini, K., Beck, R. C. R. and Guterres, S. S. (2013). Poly (e-caprolactone) microcapsules and nanocapsules in drug delivery. Expert Opinion on Drug Delivery 10, 623638.
Poletto, F. S., Fiel, L. A., Lopes, M. V., Schaab, G., Gomes, A. M. O., Guterres, S. S., Rossi-Bergmann, B. and Pohlmann, A. R. (2012). Fluorescent-labeled poly(ε-caprolactone) lipid-core nanocapsules: synthesis, physicochemical properties and macrophage uptake. Journal of Colloid Science and Biotechnology 1, 8998.
Poletto, F. S., De Oliveira, C. P., Wender, H., Regent, D., Donida, B., Teixeira, S. R., Guterres, S. S., Rossi-Bergmann, B. and Pohlmann, A. R. (2015). How sorbitan monostearate can increase drug-loading capacity of lipid-core polymeric nanocapsules. Journal of Nanoscience and Nanotechnology 15, 827837.
Rodrigues, S. F., Fiel, L. A., Shimada, A. L., Pereira, N. R., Guterres, S. S., Pohlmann, A. R. and Farsky, S. H. (2016). Lipid-core nanocapsules act as a drug shuttle through the blood brain barrier and reduce glioblastoma after intravenous or oral administration. Journal of Biomedical Nanotechnology 12, 9861000.
Rossi-Bergmann, B., Lenglet, A., Bezerra-Santos, C., Costa-Pinto, D. and Traub-Czeko, Y. (1999). Use of fluorescent Leishmania for faster quantification of parasite growth in vitro and in vivo. Memorias do Instituto Oswaldo Cruz 94, 74.
Sen, R. and Chatterjee, M. (2011). Plant derived therapeutics for the treatment of leishmaniasis. Phytomedicine 18, 10561069.
Sen, G., Mandal, S., Roy, S. S., Mukhopadhyay, S. and Biswas, T. (2005). Therapeutic use of quercetin in the control of infection and anemia associated with visceral leishmaniasis. Free Radical Biology and Medicine 38, 12571264.
Sosa, N., Capitán, Z., Nieto, J., Nieto, M., Calzada, J., Paz, H., Spadafora, C., Kreishman-Deitrick, M., Kopydlowski, K., Ullman, D., McCarthy, W. F., Ransom, J., Berman, J., Scott, C. and Grogl, M. (2013). Randomized, double-blinded, phase 2 trial of WR 279,396 (paromomycin and gentamicin) for cutaneous leishmaniasis in Panama. American Journal of Tropical Medicine and Hygiene 89, 557563.
Srivastava, S., Shankar, P., Mishra, J. and Singh, S. (2016). Possibilities and challenges for developing a successful vaccine for leishmaniasis. Parasites & Vectors 9, 277292.
Sun, M., Gao, Y., Pei, Y., Guo, C., Li, H., Cao, F., Yu, A. and Zhai, G. (2010). Development of nanosuspension formulation for oral delivery of quercetin. Journal of Biomedical Nanotechnology 6, 325332.
Sundar, S. and Chakravarty, J. (2015). An update on pharmacotherapy for leishmaniasis. Expert Opinion on Pharmacotherapy 2, 237252.
Torres-Santos, E. C., Rodrigues, J. M., Moreira, D. L., Kaplan, M. A. C. and Rossi-Bergmann, B. (1999). Improvement of in vitro and in vivo antileishmanial activities of 2′,6′-dihydroxy-4′-methoxychalcone by entrapment in poly(D,L-lactide) nanoparticles. Antimicrobial Agents and Chemotherapy 43, 17761778.
Tran, T. H., Guo, Y., Song, D., Bruno, R. S. and Lu, X. (2014). Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability. Journal of Pharmaceutical Sciences 103, 840852.
Venturini, C. G., Jäger, E., Oliveira, C. P., Bernardi, A., Battastini, A. M. O., Guterres, S. S. and Pohlmann, A. R. (2011). Formulation of lipid core nanocapsules. Colloids and Surfaces A: Physicochemical and Engineering Aspects 375, 200208.
Weiss-Angeli, V., Poletto, F. S., De Marco, S. L., Salvador, M., Da Silveira, N. P., Guterres, S. S. and Pohlmann, A. R. (2012). Sustained antioxidant activity of quercetin-loaded lipid-core nanocapsules. Journal of Nanoscience and Nanotechnology 12, 28742880.
World Health Organization (2015). Investing to Overcome the Global Impact of Neglected Tropical Diseases: Third WHO Report on Neglected Tropical Diseases. World Health Organization, Geneva, Switzerland.


Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis

  • A. J. SOUSA-BATISTA (a1), F. S. POLETTO (a2), C. I. M. S. PHILIPON (a1), S. S. GUTERRES (a3), A. R. POHLMANN (a2) and B. ROSSI-BERGMANN (a1)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed