• Sapna Jain Chowdhary Dr. Hari Singh Gour University
  • Amit Chowdhary Dr. Hari Singh Gour University
  • Sushil Kashaw Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A central university), Sagar, India 470003


Leishmaniasis is a vector-borne zoonotic infection caused by an obligate intra macrophage protozoan parasite ‘Leishmania’. Despite of a number of remedies available, leishmaniasis is still a speedy migrating and deadly infection due to the resistance of the parasite to the drugs as well as their toxicity. Hence, there is a need for targeted drug delivery system for enhancing the systematic effect of antileishmanial drugs. Although the number of antileishmanial drugs in a variety of dosage forms is available, there is an urgency to develop more efficient, cost-effective and safe therapy, which can be achieved by macrophage targeting utilizing passive (phagocytosis), and/or active (receptor mediated) strategies utilizing nano-formulations. Positive considerations of various factors like the enhanced permeation and retention (EPR) effect, size, and charge of nano-formulations can facilitate the passive targeting, and various receptors like lectin receptor, mannose receptor, mannosyl-fucosyl receptor, scavenger receptor, etc on the macrophage surface may play an important role in active drug targeting. Also, monoclonal antibody, interferon’s, tufstin are other agents which have been broadly utilized for targeting.

Keywords: Leishmaniasis, Macrophages, Targeting, Receptor, Nano-formulations


Download data is not yet available.


1. Handman E, Bullen DV. Interaction of Leishmania with the host macrophage. Treands Parasitol 2002;18:332-4.
2. Gour JK, Srivastava A, Kumar V, Bajpai S, Kumar H, Mishra M, et al. Nanomedicine and leishmaniasis: future prospects. Digest J Nanomater Biostructures 2009;4:495-9.
3. Guy RA, Belosevic M. Comparison of receptors required for entry of leishmania major amastigotes into macrophages. Infect Immun 1993;4:1553-8.
4. Rittig MH, Bogdan C. Leishmania-host-cell interaction: complexities and alternative views. Parasitol Today 2000;16:292-7.
5. Braunwald E, Fauci AS, Hauser SL. Harrison’s manual of medicine, Mcgraw-Hill, New York; 2001.
6. Chatterjee KD. Parasitology and helminthology, Chatterjee medical publishers, Calcutta; 1976
7. Prasad LS. Kala Azar. Indian J Pediatr 1999;66:539-46.
8. Moll H, Flohe S, Rollinghoff M. Dendritic cells in leishmania major-immune mice harbor persistent parasites and mediate an antigen-specific t cell immune response. Eur J Immunol 1995;25:693-9.
9. Shargel L, Yu BC. Applied biopharmaceutics and pharmacokinetics. Appleton and lange. Connecticut; 1993.
10. WHO. Model prescribing information drugs used in parasitic diseases, Geneva World health organization; 1990. p. 14-8.
11. World health organization. TDR news; 1998;34:1-7.
12. Sundar S, More DK, Singh MK, Singh VP, Sharma S, Makharia A, et al. Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the indian epidemic. Clin Infect Dis 2000;31:1104–7.
13. Sundar S, Chatterjee M. Visceral leishmaniasis-current therapeutic modalities. Indian J Med Res 2006;123:345-52.
14. Fre´zard F, Demicheli C, Ribeiro RR. Pentavalent antimonials: New perspectives for old drugs. Molecules 2009;14:2317-6.
15. Mishra J, Saxena A, Singh S. Chemotherapy of leishmaniasis: the past, present and future. Curr Med Chem 2007;14:1153-69.
16. Fre_zard F, Martins PS, Barbosa MCM. New insights into the chemical structure and composition of the pentavalent antimonial drugs, meglumine antimoniate and sodium stibogluconate. J Inorg Biochem 2008;102:656-65.
17. Chapman JR, Hanson WL, Alving CR, Hendricks LD. Antileishmanial activity of liposome-encapsulated meglumine antimonate in the dog. Am J Vet Res 1984;45:1028-30.
18. Bryceson A. Pentamidine-induced diabetes mellitus. East Afr Med J 1968;45:110-7.
19. Berman JD. Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 y. Clin Infect Dis 1997;24:684-703.
20. Scott JA, Davidson RN, Moody AH. Aminosidine (paromomycin) in the treatment of leishmaniasis imported into the united kingdom. Trans R Soc Trop Med Hyg 1992;86:617-9.
21. Davis AJ, Kedzierski L. Recent advances in antileishmanial drug development. Curr Opin Invest Drugs 2005;6:163-9.
22. Duclos S, Desjardins M. Subversion of a young phagosome: the survival strategies of intracellular pathogens. Cell Microbiol 2000;2:365-77.
23. Gaspar R, Pre´at V, Roland M. Nanoparticles of polyisohexyl-cyanoacrylate (pihca) as carriers of primaquine: formulation, physico-chemical characterization, and acute toxicity. Int J Pharm 1991;68:111-9.
24. Gaspar R, Oppredoes F, Preat V. Drug targeting with poly alkyl cyanoacrylate nanoparticles: In-vitro activity of primaquine-loaded nanoparticles against intracellular leishmania donovani. Ann Trop Med Parasitol 1992;86:41-9.
25. Rodrigues JM JR, Croft SL, Fessi H. The activity and ultrastructural localization of primaquine-loaded poly (d,l-lactide) nanoparticles in leishmania donovani infected mice. Trop Med Parasitol 1994;45:223-8.
26. Rodrigues JM JR, Fessi H, Bories C. Primaquine-loaded polylactide nanoparticles: physicochemical study and acute tolerance in mice. Int J Pharm 1995;126:253-60.
27. Shukla AK, Patra S, Dubey VK. Nanospheres are encapsulating anti-leishmanial drugs for their specific macrophage targeting, reduced toxicity, and deliberate intracellular release. Vector-Borne Zoonotic Diseases 2012;12:11.
28. Croft SL. In-vitro screens in the experimental chemotherapy of leishmaniasis and trypanosomiasis. Parasitol Today 1986;2:64-9.
29. Zhang D, Tan T, Gao L, Zhao W, Wang P. Preparation of azithromycin nanosuspensions by high-pressure homogenization and its physiochemical characterization studies. Drug Dev Ind Pharm 2007;33:569-75.
30. Gaspar R, Preat V, Oppredoes FR, Roland M. Macrophage avtivation by polymeric nanoparticles of polyalkyl-cynoacrylates: activity against intracellular leishmania donovani associated with hydrogen peroxide production. Pharm Res 1992;9:782-7.
31. Fevrier A, Ferreira ME, Fournet A. Acetogenins and other compounds from rollinia emarginate and their antiprotozoal activities. Planta Med 1999;65:47-9.
32. Matsumura Y, Maeda H. "A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs". Cancer Res 1986;46:6387–92.
33. Khattab MA, Farr SJ, Taylor G, Kellaway IW. The In-vitro characterization and biodistribution of some non-ionic surfactant coated liposomes in the rabbit. J Drug Target 1995;3:39-49.
34. Proulx ME, Desormeaux A, Marquis J. Treatment of visceral leishmaniasis with sterically stabilized liposomes containing camptothecin. Antimicrob Agents Chemother 2001;45:2623-7.
35. Lakshmi V, Pandey K, Kapil A. In-vitro and in-vivo leishmanicidal activity of dysoxylum binectariferum and its fractions against leishmania donovani. Phytomedicine 2007;14:36-42.
36. Schettini DA, Ribeiro RR, Demicheli C, Rocha OGF, Melo MN, Michalick MSM, et al. Improved targeting of antimony to the bone marrow of dogs using liposomes of reduced size. Int J Pharm 2006;315:140-7.
37. Das S, Khan W, Mohsin S, Kumar N. Miltefosine loaded albumin microparticles for the treatment of visceral leishmaniasis: formulation development and in vitro evaluation. Polymer Adv Technol 2010;22:172-9.
38. Nahar M, Dubey V, Mishra D, Mishra PK, Dube A, Jain NK. In vitro evaluation of surface functionalized gelatin nanoparticles for macrophage targeting in the therapy of visceral leishmaniasis. J Drug Targeting 2010;18:93-105.
39. Singh P, Gupta A, Jaiswal A, Dube A, Mishra S, Chaurasia MK. Design and development of amphotericin b bearing polycaprolactone microparticles for macrophage targeting. J Biomed Nanotechnol 2011;7:50-1.
40. Dey T, Anam K, Afrin F. Antileishmanial activities of stearyl amine-bearing liposomes. Antimicrob Agents Chemother 2000;44:1739-42.
41. Alving CR, Steck EA, Chapman WL. Therapy of leishmaniasis: superior efficacies of liposome encapsulated drugs (antimonial compounds/phospholipids/model membranes/parasites). Proc Natl Acad Sci 1978;75:2959-63.
42. Banerjee G, Nandi G, Mahato SB. Drug delivery system: targeting of pentamidines to specific sites using sugar grafted liposomes. J Antimicrob Chemother 1996;38:145-50.
43. Veerareddy PR, Vobalaboina V, Nahid A. Formulation and evaluation of oil-in-water emulsions of piperine in visceral leishmaniasis. Pharmazie 2004;59:194-7.
44. Ahsan F, Rivas IP, Khan MA, Torres Suarez AI. Targeting to macrophages: role of physicochemical properties of particulate carriers-liposomes and microspheres on the phagocytosis by macrophages. J Controlled Release 2002;79:29-40.
45. Papagiannaros A, Bories C, Demetzos C. Antileishmanial and trypanocidal activities of new miltefosine liposomal formulations. Biomed Pharmacother 2005;59:545-50.
46. Cauchetier E, Paul M, Rivollet D. Therapeutic evaluation of free and liposome-encapsulated atovaquone in the treatment of murine leishmaniasis. Int J Parasitol 2000;30:777-83.
47. Mullen AB, Carter KC, Baillie AJ. Comparison of the efficacies of various formulations of amphotericin b against murine visceral leishmaniasis. Antimicrob Agents Chemother 1997;41:2089-92.
48. Carter KC, Baillie AJ, Mullen AB. The cured immune phenotype achieved by treatment of visceral leishmaniasis in the balb/c mouse with a nonionic surfactant vesicular formulation of sodium stibogluconate does not protect against reinfection. Clin Diagn Lab Immunol 1999;6:61-5.
49. Hunter CA, Dolan TF, Coombs GH. Vesicular systems (niosomes and liposomes) for delivery of sodium stibogluconate in experimental murine visceral leishmaniasis. J Pharm Pharmacol 1988;40:161-5.
50. Mullen AB, Baillie AJ, Carter KC. Visceral leishmaniasis in the balb/c mouse: a comparison of the efficacy of a nonionic surfactant formulation of sodium stibogluconate with those of three proprietary formulations of amphotericin B. Antimicrob Agent Chemother 1998;42:2722-5.
51. Nieto J, Alvar J, Mullen AB. Pharmacokinetics, toxicities and efficacies of sodium stibogluconate formulations after intravenous administration in animals. Antimicrob Agents Chemother 2003;47:2781-7.
52. Baillie AJ, Coombs GH, Dolan TF. Biodegradable microspheres: polyacrylate starch microparticles as a delivery system for the antileishmanial drug, sodium stibogluconate. J Pharm Pharmacol 1987;39:832-5.
53. Ordonez GL, Espada FR, Dea MA. In vitro effect of new formulations of amphotericin B on amastigote and promastigote forms of leishmania infantum. Int J Antimicrob Agents 2007;30:325-9.
54. Sanchez-brunete JA, Dea MA, Rama S. Treatment of experimental visceral leishmaniasis with amphotericin b in stable albumin microspheres. Antimicrob Agents Chemother 2004;48:3246-52.
55. Kunjachan S, Gupta S, Dwivedi AK, Dube A, Chourasia MK. Chitosan-based macrophage-mediated drug targeting for the treatment of experimental visceral leishmaniasis. Informa Health Care 2011;28:301-10.
56. Venier-julienne MC, Vouldoukis I, Monjour L. In vitro study of the anti-leishmanial activity of biodegradable nanoparticles. J Drug Target 1995;3:23-9.
57. Durand R, Paul M, Rivollet D. Activity of pentamidine loaded methacrylate nanoparticles against leishmania infantum in a mouse model. Int J Parasitol 1997;27:1361-7.
58. Rodrigues JM, Croft SL, Fessi H. The activity and ultrastructural localization of primaquine-loaded poly (d, llactide) nanoparticles in leishmania donovani infected mice. Trop Med Parasitol 1994;45:223-8.
59. Kayser O, Olbrich C, Yardley V. Formulation of amphotericin B as nanosuspension for oral administration. Int J Pharm 2003;254:73-5.
60. Kayser O. Nanosuspensions for the formulation of aphidicolin to improve drug targeting effects against leishmania-infected macrophages. Int J Pharm 2000;196:253-6.
61. Veerareddy PR, Vobalaboina V, Ali N. Antileishmanial activity, pharmacokinetics and tissue distribution studies of mannose-grafted amphotericin B lipid nanospheres. J Drug Target 2009;17:140-7.
62. Gupta S, Moulik SP, Lala S. Designing and testing of an effective oil-in-water microemulsion drug delivery system for in vivo application. Drug delivery 2005;12:267-73.
63. Cortadellas O. Initial and long-term efficacy of a lipid emulsion of amphotericin B desoxycholate in the management of canine leishmaniasis. J Vet Intern Med 2003;17:808-12.
64. Lamothe J. Activity of amphotericin B in lipid emulsion in the initial treatment of canine leishmaniasis. J Small Anim Pract 2001;42:170-5.
65. Gupta S, Vyas SP. Development and characterization of amphotericin B bearing emulsomes for passive and active macrophage targeting. J Drug Target 2007;15:206-17.
66. Carter KC, Mullen AB, Sundar S. Efficacies of vesicular and free sodium stibogluconate formulations against clinical isolates of leishmania donovani. Antimicrob Agents Chemother 2001;45:3555-9.
67. Garnier T, Brown MB, Lawrence MJ. In-vitro and in vivo studies on a topical formulation of sitamaquine dihydrochloride for cutaneous leishmaniasis. J Pharm Pharmacol 2006;58:1043-54.
68. Roberts WL, Hariprashad J, Rainey PM. Pentavalent antimony-mannan conjugate therapy of experimental visceral leishmaniasis. Am J Trop Med Hyg 1996;55:444-6.
69. Golenser J, Frankenburg S, Ehrenfreund T. Efficacious treatment of experimental leishmaniasis with amphotericin b-arabinogalactan water-soluble derivatives. Antimicrob Agents Chemother 1999;43:2209-14.
70. Nan A, Croft SL, Yardley V, Ghandehari H. Targetable water-soluble polymer-drug conjugates for the treatment of visceral leishmaniasis. J Controlled Release 2004;94:115-27.
71. Alexander J, Russell DG. The interaction of leishmania species with macrophages. Adv Parasitol 1992;31:175-254.
72. Mosser DM, Vlassara H, Edelson PJ, Cerami A. Leishmania promastigotes are recognized by the macrophage receptor for advanced glycosylation end products. J Exp Med 1987;165:140-5.
73. Mosser DM, Edelson PJ. The third component of complement (c3) is responsible for the intracellular survival of leishmania major. Nature 1987;327:329-31.
74. Ilgoutz SC, Mcconville MJ. Function and assembly of the leishmania surface coat. Int J Parasitol 2001;31:899-908.
75. Kansa S, Tandon R, Dwivedi P. Development of nanocapsules bearing doxorubicin for macrophage targeting through h the phosphatidylserine ligand: a system for intervention in visceral leishmaniasis J Antimicrob Chemother 2012;67:2650-60.
76. Roy P, Das S, Auddy RG, Mukherjee A. Biological targeting and drug delivery in control of leishmaniasis. J Cell Anim Biol 2012;6:6:73-87.
77. Mitra M, Mandal AK, Chatterjee TK, Das N. Targeting of mannosylated liposome incorporated benzyl derivative of penicillium nigricans derived compound mt81 to reticuloendothelial systems for the treatment of visceral leishmaniasis. J Drug Target 2005;13:285-93.
78. Barratt G, Tenu JP, Yapo A, Peti JF. Preparation and characterization of liposomes containing mannosylated phospholipids capable of targeting drugs to macrophages. Biochim Biophys Acta 1986;862:153-64.
79. Muller CD, Schuber F. Neo-mannosylated liposomes: synthesis and interaction with mouse kupffer cells and resident peritoneal macrophages. Biochim Biophys Acta 1989;986:97-105.
80. Harashima H, Kiwada H. Liposomal targeting and drug delivery: kinetic consideration. Adv Drug Delivery Rev 1996;19:425.
81. Fiani ML, Beitz J, Turvy D, Blum JS, Stahl PD. Regulation of mannose receptor synthesis and turnover in mouse j774 macrophages. J Leukoc Biol 1998;64:85–91.
82. Datta N, Mukherjee S, Das L, Das P. Targeting of immunostimulatory DNA cures experimental visceral leishmaniasis through nitric oxide up-regulation and T cell activation. Eur J Immunol 2003;33:1508–18.
83. Kole L, Das L, Das PK. Synergistic effect of interferon-g and mannosylated liposome incorporated doxorubicin in the therapy of experimental visceral leishmaniasis. J Infect Dis 1999;180:811-20.
84. Amselem S, Yogev A, Zawoznik E. Emulsomes, a novel drug delivery Technology. Proc Int Symp Controlled Release Bioact Mater 1994;21:1368-9.
85. Amselem S, Friedman D. Solid fat nanoemulsions. Us5662932; 1997.
86. Negre E, Michael I, Chance, Hanboula SY, Monsigny M, Roche AC, et al. Antileishmanial drug targeting through glycosylated polymers specifically internalized by macrophage membrane lectins. Antimicrob Agents Chemother 1992;36:2228-32.
87. Arkar K, Sarkar HS, Kole L. Receptor-mediated endocytosis of fucosylated neoglycoprotein by macrophages. Mol Cell Biochem 1996;156:109-16.
88. Chakraborty P, Bhaduri AN, Das PK. Neoglycoproteins as carriers for receptor-mediated drug targeting in the treatment of experimental visceral leishmaniasis”. J Eukaryotic Microbiol 1990;37:358-64.
89. Schottelius J. Neoglycoproteins as tools for the detection of carbohydrate-specific receptors on the cell surface of Leishmania. Parasitol Res 1991;78:309-15.
90. Sarkar K, Das PK. Rotective effect of neoglycoprotein-conjugated muramyl dipeptide against leishmania donovani infection: the role of cytokines” J Immunonol 1997;158:5357-65.
91. Tempone AG, Perez D, That S, Vilanrinho AL, Mortara RA, Andrade HF. Targeting Leishmania (L.) chagasi amastigotes through macrophage scavenger receptor: the use of drugs entrapped in liposomes containing phosphatidylserine. J Antimicrob Chemother 2004;54:60-8.
92. Mukhopadhyay A, Basu SK. Scavenger receptor-mediated drug delivery: a versatile approach for modulation of macrophage metabolism. Proc Natl Acad Sci India 2002;B68:4:361-70.
93. Solaro R, Chiellini F, Battisti A. Targeted delivery of protein drugs by nanocarriers. Materials 2010;3:1928-80.
94. Mukherjee S, Das L, Kole L. Targeting of parasite-specific immuno- liposome-encapsulated doxorubicin in the treatment of experimental visceral leishmaniasis. J Infect Dis 2004;189:1024-34.
95. Dasgupta D, Chakraborty P, Basu MK. Ligation of fc receptor of macrophages Stimulates protein kinase c and anti-leishmanial activity. Mol Cell Biochem 2000;209:1-8.
96. Kumara R, Sahoo GC, Pandeya K, Dasa VNR, Ansaria Y, Ranaa S, et al. PLGA-PEG Encapsulated sitamaquine nanoparticles drug delivery system against Leishmania donovani. Am J Sci Ind Res 2014;3:85-90.
97. Kole L, Das AL, Das PK. Synergistic effect of interferon-g and mannosylated liposome-incorporated doxorubicin in the therapy of experimental visceral leishmaniasis. J Infect Dis 1999;180:811–20.
98. Najjar VA. Biological and biochemical characteristics of the tetrapeptide tuftsin, Thr-lys-pro-arg. Adv Exp Med Biol 1979;121:131-47.
99. Fridkin M, Gottlieb P. Tuftsin, thr-lys-pro-arg. Anatomy of an immunologically active peptide. Mol Cell Biochem 1981;41:73-97.
100. Nishioka K, Constantopoulos A, Satoh PS. The characteristics, isolation, and synthesis of the phagocytosis stimulating peptide tuftsin. Biochem Biophys Res Commun 1972;47:172-9.
101. Fridkin M, Stabinsky Y, Zakuth V, Spirer Z. Tuftsin and some analogs: synthesis and interaction with human polymorphonuclear leukocytes. Biochim Biophys Acta 1977;496:203-11.
102. Bar-shavit Z, Stabinsky Y, Fridkin M, Goldman R. Tuftsin-macrophage interaction: specific binding and augmentation of phagocytosis. J Cell Physiol 1979;100:55-62.
103. Gupta CM, Haq W. Tuftsin-bearing liposomes as antibiotic carriers in the treatment of macrophage infections. Methods Enzymol 2005;391:291-304.
104. Guru PY, Agarwal AK, Singha UK. Drug targeting in leishmania donovani infections using tuftsin-bearing liposomes as drug vehicles. Febs Lett 1989;254:204-8.
105. Agrawal AK, Agrawal A, Pal A. Superior chemotherapeutic efficacy of Amphotericin b in tuftsin-bearing liposomes against leishmania donovani infection in hamsters. J Drug Target 2002;10:41-5.
106. Schettini DA, Costa Val Ap, Souza LF. Pharmacokinetic and parasitological evaluation of the bone marrow of dogs with visceral leishmaniasis submitted to multiple dose treatment with liposome-encapsulated meglumine antimoniate. Braz J Med Biol Res 2005;38:1879-83.
107. Brajtburg J, Bolard J. Carrier effects on biological activity of amphotericin B. Clin Microbiol Rev 1996;9:512-31.
108. Nicoletti S, Seifert K, Gilbert IH. N-(2-hydroxypropyl)meth acrylamide–amphotericin b (hpma–amb) copolymer conjugates as antileishmanial agents. Int J Antimicrob Agents 2009;33:441-8.
109. Koczan G, Ghose AC, Mookerjee A, Hudecz F. Methotrexate conjugate with branched polypeptide influences leishmania donovani infection in-vitro and in experimental animals. Bioconjug Chem 2002;13:518-24.
578 Views | 7370 Downloads
How to Cite
Chowdhary, S. J., A. Chowdhary, and S. Kashaw. “MACROPHAGE TARGETING: A STRATEGY FOR LEISHMANIASIS SPECIFIC DELIVERY”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 8, no. 2, Feb. 2016, pp. 16-26,
Review Article(s)