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. 1990 Nov;34(11):2055–2060. doi: 10.1128/aac.34.11.2055

Improvement of amphotericin B activity during experimental cryptococcosis by incorporation into specific immunoliposomes.

F Dromer 1, J Barbet 1, J Bolard 1, J Charreire 1, P Yeni 1
PMCID: PMC171998  PMID: 2073097

Abstract

Cryptococcosis is an opportunistic infection that is responsible for increased morbidity and mortality in patients with the acquired immunodeficiency syndrome. The high toxicity of the antifungal agent that is mainly used against cryptococcosis, amphotericin B (AMB), accounts for the need for new treatments, especially in patients with the acquired immunodeficiency syndrome because of the high relapse rate of cryptococcosis. Drug targeting may be one of these alternate treatments. Since we have demonstrated that an immunoglobulin G1 (IgG1) anti-Cryptococcus neoformans serotype A monoclonal antibody (E1) was protective during experimental cryptococcosis in mice, we investigated whether specific targeting of AMB with liposomes that bear E1 would improve the therapeutic index of the drug. For that purpose, in vitro and in vivo experiments were designed to compare the specificities and activities of these liposomes with those of control immunoliposomes bearing a nonrelated IgG1 monoclonal antibody (CY34). The immunoliposomes were prepared by covalently linking E1 or CY34 and small unilamellar vesicles. When immunoliposomes were incubated with yeast cells, only E1-bearing liposomes recognized C. neoformans. In vivo, mice that were treated 24 h after infection with one injection of AMB (0.12 mg/kg of body weight) intercalated into E1-bearing liposomes survived significantly longer than did those given the same dose of AMB alone or AMB intercalated into nontargeted liposomes or control immunoliposomes. None of the mice that were given control treatments did statistically better than those that were given AMB. Keeping in mind that this kind of therapy requires knowledge of the antigenic type of the infecting organism, the results suggest that specific targeting of small doses of AMB improve the efficacy of AMB and might be an alternative to the use of larger doses of AMB.

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Selected References

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  1. Barbet J., Machy P., Leserman L. D. Monoclonal antibody covalently coupled to liposomes: specific targeting to cells. J Supramol Struct Cell Biochem. 1981;16(3):243–258. doi: 10.1002/jsscb.1981.380160305. [DOI] [PubMed] [Google Scholar]
  2. Dismukes W. E. Cryptococcal meningitis in patients with AIDS. J Infect Dis. 1988 Apr;157(4):624–628. doi: 10.1093/infdis/157.4.624. [DOI] [PubMed] [Google Scholar]
  3. Dromer F., Charreire J., Contrepois A., Carbon C., Yeni P. Protection of mice against experimental cryptococcosis by anti-Cryptococcus neoformans monoclonal antibody. Infect Immun. 1987 Mar;55(3):749–752. doi: 10.1128/iai.55.3.749-752.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dromer F., Perronne C., Barge J., Vilde J. L., Yeni P. Role of IgG and complement component C5 in the initial course of experimental cryptococcosis. Clin Exp Immunol. 1989 Dec;78(3):412–417. [PMC free article] [PubMed] [Google Scholar]
  5. Dromer F., Salamero J., Contrepois A., Carbon C., Yeni P. Production, characterization, and antibody specificity of a mouse monoclonal antibody reactive with Cryptococcus neoformans capsular polysaccharide. Infect Immun. 1987 Mar;55(3):742–748. doi: 10.1128/iai.55.3.742-748.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dromer F., Yeni P., Charreire J. Genetic control of the humoral response to cryptococcal capsular polysaccharide in mice. Immunogenetics. 1988;28(6):417–424. doi: 10.1007/BF00355373. [DOI] [PubMed] [Google Scholar]
  7. Dupont B., Drouhet E. Cryptococcal meningitis and fluconazole. Ann Intern Med. 1987 May;106(5):778–778. doi: 10.7326/0003-4819-106-5-778_2. [DOI] [PubMed] [Google Scholar]
  8. Graybill J. R., Craven P. C., Taylor R. L., Williams D. M., Magee W. E. Treatment of murine cryptococcosis with liposome-associated amphotericin B. J Infect Dis. 1982 May;145(5):748–752. doi: 10.1093/infdis/145.2.748. [DOI] [PubMed] [Google Scholar]
  9. Hopfer R. L., Mills K., Mehta R., Lopez-Berestein G., Fainstein V., Juliano R. L. In vitro antifungal activities of amphotericin B and liposome-encapsulated amphotericin B. Antimicrob Agents Chemother. 1984 Mar;25(3):387–389. doi: 10.1128/aac.25.3.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hospenthal D. R., Rogers A. L., Beneke E. S. Effect of attachment of anticandidal antibody to the surfaces of liposomes encapsulating amphotericin B in the treatment of murine candidiasis. Antimicrob Agents Chemother. 1989 Jan;33(1):16–18. doi: 10.1128/aac.33.1.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hospenthal D. R., Rogers A. L., Mills G. L. Development of amphotericin B liposomes bearing antibody specific to Candida albicans. Mycopathologia. 1988 Jan;101(1):37–45. doi: 10.1007/BF00455667. [DOI] [PubMed] [Google Scholar]
  12. Hospenthal D., Gretzinger K., Rogers A. Treatment of a murine model of systemic candidiasis with liposomal amphotericin B bearing antibody to Candida albicans. J Med Microbiol. 1989 Nov;30(3):193–197. doi: 10.1099/00222615-30-3-193. [DOI] [PubMed] [Google Scholar]
  13. Joly V., Dromer F., Barge J., Yeni P., Seta N., Molas G., Carbon C. Incorporation of amphotericin B (AMB) into liposomes alters AMB-induced acute nephrotoxicity in rabbits. J Pharmacol Exp Ther. 1989 Oct;251(1):311–316. [PubMed] [Google Scholar]
  14. Jullien S., Contrepois A., Sligh J. E., Domart Y., Yeni P., Brajtburg J., Medoff G., Bolard J. Study of the effects of liposomal amphotericin B on Candida albicans, Cryptococcus neoformans, and erythrocytes by using small unilamellar vesicles prepared from saturated phospholipids. Antimicrob Agents Chemother. 1989 Mar;33(3):345–349. doi: 10.1128/aac.33.3.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jullien S., Vertut-Croquin A., Brajtburg J., Bolard J. Circular dichroism for the determination of amphotericin B binding to liposomes. Anal Biochem. 1988 Jul;172(1):197–202. doi: 10.1016/0003-2697(88)90432-0. [DOI] [PubMed] [Google Scholar]
  16. Kovacs J. A., Kovacs A. A., Polis M., Wright W. C., Gill V. J., Tuazon C. U., Gelmann E. P., Lane H. C., Longfield R., Overturf G. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med. 1985 Oct;103(4):533–538. doi: 10.7326/0003-4819-103-4-533. [DOI] [PubMed] [Google Scholar]
  17. Leserman L. D., Barbet J., Kourilsky F., Weinstein J. N. Targeting to cells of fluorescent liposomes covalently coupled with monoclonal antibody or protein A. Nature. 1980 Dec 11;288(5791):602–604. doi: 10.1038/288602a0. [DOI] [PubMed] [Google Scholar]
  18. Leserman L. D., Machy P., Barbet J. Cell-specific drug transfer from liposomes bearing monoclonal antibodies. Nature. 1981 Sep 17;293(5829):226–228. doi: 10.1038/293226a0. [DOI] [PubMed] [Google Scholar]
  19. Lopez-Berestein G., Fainstein V., Hopfer R., Mehta K., Sullivan M. P., Keating M., Rosenblum M. G., Mehta R., Luna M., Hersh E. M. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study. J Infect Dis. 1985 Apr;151(4):704–710. doi: 10.1093/infdis/151.4.704. [DOI] [PubMed] [Google Scholar]
  20. Lopez-Berestein G., Hopfer R. L., Mehta R., Mehta K., Hersh E. M., Juliano R. L. Liposome-encapsulated amphotericin B for treatment of disseminated candidiasis in neutropenic mice. J Infect Dis. 1984 Aug;150(2):278–283. doi: 10.1093/infdis/150.2.278. [DOI] [PubMed] [Google Scholar]
  21. Lopez-Berestein G. Liposomal amphotericin B in the treatment of fungal infections. Ann Intern Med. 1986 Jul;105(1):130–131. doi: 10.7326/0003-4819-105-1-130. [DOI] [PubMed] [Google Scholar]
  22. Lopez-Berestein G., Mehta R., Hopfer R. L., Mills K., Kasi L., Mehta K., Fainstein V., Luna M., Hersh E. M., Juliano R. Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin B. J Infect Dis. 1983 May;147(5):939–945. doi: 10.1093/infdis/147.5.939. [DOI] [PubMed] [Google Scholar]
  23. Lopez-Berestein G., Rosenblum M. G., Mehta R. Altered tissue distribution of amphotericin B by liposomal encapsulation: comparison of normal mice to mice infected with Candida albicans. Cancer Drug Deliv. 1984 Summer;1(3):199–205. doi: 10.1089/cdd.1984.1.199. [DOI] [PubMed] [Google Scholar]
  24. Machy P., Barbet J., Leserman L. D. Differential endocytosis of T and B lymphocyte surface molecules evaluated with antibody-bearing fluorescent liposomes containing methotrexate. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4148–4152. doi: 10.1073/pnas.79.13.4148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McGaw T. G., Kozel T. R. Opsonization of Cryptococcus neoformans by human immunoglobulin G: masking of immunoglobulin G by cryptococcal polysaccharide. Infect Immun. 1979 Jul;25(1):262–267. doi: 10.1128/iai.25.1.262-267.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mehta R. T., Mehta K., Lopez-Berestein G., Juliano R. L. Effect of liposomal amphotericin B on murine macrophages and lymphocytes. Infect Immun. 1985 Feb;47(2):429–433. doi: 10.1128/iai.47.2.429-433.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Norley S. G., Huang L., Rouse B. T. Targeting of drug loaded immunoliposomes to herpes simplex virus infected corneal cells: an effective means of inhibiting virus replication in vitro. J Immunol. 1986 Jan;136(2):681–685. [PubMed] [Google Scholar]
  28. Perfect J. R., Durack D. T., Hamilton J. D., Gallis H. A. Failure of ketoconazole in cryptococcal meningitis. JAMA. 1982 Jun 25;247(24):3349–3351. [PubMed] [Google Scholar]
  29. Perfect J. R., Granger D. L., Durack D. T. Effects of antifungal agents and gamma interferon on macrophage cytotoxicity for fungi and tumor cells. J Infect Dis. 1987 Aug;156(2):316–323. doi: 10.1093/infdis/156.2.316. [DOI] [PubMed] [Google Scholar]
  30. Rhodes J. C. Contribution of complement component C5 to the pathogenesis of experimental murine cryptococcosis. Sabouraudia. 1985 Jun;23(3):225–234. doi: 10.1080/00362178585380331. [DOI] [PubMed] [Google Scholar]
  31. Stamm A. M., Diasio R. B., Dismukes W. E., Shadomy S., Cloud G. A., Bowles C. A., Karam G. H., Espinel-Ingroff A. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med. 1987 Aug;83(2):236–242. doi: 10.1016/0002-9343(87)90691-7. [DOI] [PubMed] [Google Scholar]
  32. Symington F. W., Subbarao B., Mosier D. E., Sprent J. Lyb-8.2: A new B cell antigen defined and characterized with a monoclonal antibody. Immunogenetics. 1982;16(5):381–391. doi: 10.1007/BF00372098. [DOI] [PubMed] [Google Scholar]
  33. Szoka F. C., Jr, Milholland D., Barza M. Effect of lipid composition and liposome size on toxicity and in vitro fungicidal activity of liposome-intercalated amphotericin B. Antimicrob Agents Chemother. 1987 Mar;31(3):421–429. doi: 10.1128/aac.31.3.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tremblay C., Barza M., Fiore C., Szoka F. Efficacy of liposome-intercalated amphotericin B in the treatment of systemic candidiasis in mice. Antimicrob Agents Chemother. 1984 Aug;26(2):170–173. doi: 10.1128/aac.26.2.170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Viviani M. A., Tortorano A. M., Giani P. C., Arici C., Goglio A., Crocchiolo P., Almaviva M. Itraconazole for cryptococcal infection in the acquired immunodeficiency syndrome. Ann Intern Med. 1987 Jan;106(1):166–166. doi: 10.7326/0003-4819-106-1-166_1. [DOI] [PubMed] [Google Scholar]
  36. Weinstein J. N., Leserman L. D. Liposomes as drug carriers in cancer chemotherapy. Pharmacol Ther. 1984;24(2):207–233. doi: 10.1016/0163-7258(84)90035-4. [DOI] [PubMed] [Google Scholar]
  37. Wiebe V. J., DeGregorio M. W. Liposome-encapsulated amphotericin B: a promising new treatment for disseminated fungal infections. Rev Infect Dis. 1988 Nov-Dec;10(6):1097–1101. doi: 10.1093/clinids/10.6.1097. [DOI] [PubMed] [Google Scholar]
  38. Zuger A., Louie E., Holzman R. S., Simberkoff M. S., Rahal J. J. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med. 1986 Feb;104(2):234–240. doi: 10.7326/0003-4819-104-2-234. [DOI] [PubMed] [Google Scholar]

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