Abstract
Purpose. The aim of the study was to evaluate the capacity of poly(isohexylcyanoacrylate) nanospheres to concentrate 3′-azido 3′-deoxythymidine (AZT) in the intestinal epithelium and associated immunocompetent cells, which are known to be one of the major reservoirs of the human immunodeficiency virus (HIV).
Methods. The tissue concentration of 3H-radiolabeled AZT in the gastrointestinal (GI) tract was obtained 30 and 90 minutes after intragastric administration to rats at a dose of 0.25 mg AZT/100 g of body weight. The distribution along the intestine was determined. AZT concentrations in the lymph were obtained by lymphatic duct cannulation.
Results. Unlike the solution, nanoparticles did concentrate AZT very efficiently in the intestinal mucosa, as well as in the Peyer's patches, and could simultaneously control the release of free AZT. Concentration in Peyer's patches was 4 times higher for nanoparticles, compared with the control solution. The tissue concentration was 30-45 μM, which was much higher than the reported IC50 of AZT (0.06-1.36 μM) and was regularly distributed along the gastrointestinal tract.
Conclusions. Nanoparticles have been shown to be efficient in concentrating AZT in the intestinal epithelium and gut-associated lymphoid tissues, supporting the view that these particles may represent a promising carrier to treat specifically the GI reservoir of HIV.
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REFERENCES
G. Pantaleo, C. Graziosi, J. F. Demarest, L. Butini, M. Montroni, C. H. Fox, J. M. Orenstein, D. P. Kotler, and A. S. Fauci. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362:355-358 (1993).
J. Embretson, M. Zupancic, J. L. Ribas, A. Burke, P. Racz, K. Tenner-Racz, and A. T. Haase. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362:359-362 (1993).
H. B. Mayer and C. A. Wanke. Diagnostic strategies in HIV-infected patients with diarrhea. Aids 8:1639-1648 (1994).
J. A. Nelson, C. A. Wiley, C. Reynolds-Kohler, C. E. Reese, W. Margaretten, and J. A. Levy. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet 1:259-262 (1988).
M. R. Neutra. Interactions of viruses and microparticles with apical plasma membranes of M cells: Implications for human immunodeficiency virus transmission. J. Infect. Dis. 179:S441-443 (1999).
C. Heise, S. Dandekar, P. Kumar, R. Duplantier, R. M. Donovan, and C. H. Halsted. Human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal mucosa. Gastroenterology 100:1521-1527 (1991).
T. Schneider, H. U. Jahn, W. Schmidt, E. O. Riecken, M. Zeitz, and R. Ullrich. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Berlin Diarrhea/Wasting Syndrome Study Group. Gut 37:524-529 (1995).
X. Li and W. K. Chan. Transport, metabolism and elimination mechanisms of anti-HIV agents. Adv. Drug Deliv. Rev. 39:81-103 (1999).
G. Ponchel, M.-J. Montisci, A. Dembri, C. Durrer, and D. Duchêne. Mucoadhesion of colloidal particulate systems in gastrointestinal tract. Eur. J. Pharm. Biopharm. 44:25-31 (1997).
R. Löbenberg, L. Araujo, H. von Briesen, E. Rodgers, and J. Kreuter. Body distribution of azidothymidine bound to hexyl-cyanoacrylate nanoparticles after i.v. injection to rats. J. Control. Release 50:21-30 (1998).
A. L. Warshaw. A simplified method of cannulating the intestinal lymphatics of the rat. Gut 13:66-67 (1972).
A. T. Haase, K. Henry, M. Zupancic, G. Sedgewick, R. A. Faust, H. Melroe, W. Cavert, K. Gebhard, K. Staskus, Z. Q. Zhang, P. J. Dailey, H. H. J. Balfour, A. Erice, and A. S. Perelson. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274:985-989 (1996).
J. J. Mathewson, Z. D. Jiang, H. L. DuPont, C. Chintu, N. Luo, and A. Zumla. Intestinal secretory IgA immune response against human immunodeficiency virus among infected patients with acute and chronic diarrhea. J. Infect. Dis. 169:614-617 (1994).
C. Durrer, J. M. Irache, F. Puisieux, D. Duchêne and G. Ponchel. Mucoadhesion of latexes. II. Adsorption isotherms and desorption studies. Pharm. Res. 11:680-683 (1994).
M. P. Desai, V. Labhasetwar, E. Walter, R. J. Levy, and G. L. Amidon. The mechanism of uptake of biodegradable microparticles in Caco-2 cells is size dependent. Pharm. Res. 14:1568-1573 (1997).
G. M. Hodges, E. A. Carr, R. A. Hazzard, and K. E. Carr. Uptake and translocation of microparticles in small intestine. Morphology and quantification of particle distribution. Dig. Dis. Sci. 40:967-975 (1995).
M. W. Smith, N. W. Thomas, P. G. Jenkins, N. G. Miller, D. Cremaschi, and C. Porta. Selective transport of microparticles across Peyer's patch follicle-associated M cells from mice and rats. Exp. Physiol. 80:735-743 (1995).
P. G. Jenkins, K. A. Howard, N. W. Blackhall, N. W. Thomas, S. S. Davis, and D. T. O'Hagan. The quantitation of the absorption of microparticles into the intestinal lymph of Wistar rats. Int. J. Pharm. 102:261-266 (1994).
D. T. O'Hagan. The intestinal uptake of particles and the implications for drug and antigen delivery. J. Anat. 189:477-482 (1996).
N. C. Phillips and C. Tsoukas. Liposomal encapsulation of azidothymidine results in decreased hematopoietic toxicity and enhanced activity against murine acquired immunodeficiency syndrome. Blood 79:1137-1143 (1992).
U. Benatti, M. Giovine, G. Damonte, A. Gasparini, S. Scarfi, A. De Flora, A. Fraternale, L. Rossi, and M. Magnani. Azidothymidine homodinucleotide-loaded erythrocytes and bioreactors for slow delivery of the antiretroviral drug azidothymidine. Biochem. Biophys. Res. Commun. 220:20-25 (1996).
R. Löbenberg, L. Araujo, and J. Kreuter. Body distribution of azidothymidine bound to nanoparticles after oral administration. Eur. J. Pharm. Biopharm. 44:127-132 (1997).
D. Scherer, J. R. Robinson, and J. Kreuter. Influence of enzymes on the stability of polybutylcyanoacrylate nanoparticles. Int. J. Pharm. 101:165-168 (1994).
A. Bender, V. Schäfer, A. M. Steffan, C. Royer, J. Kreuter, H. Rubsamen-Waigmann, and H. von Briesen. Inhibition of HIV in vitro by antiviral drug-targeting using nanoparticles. Res. Virol. 145:215-220 (1994).
V. Schäfer, H. von Briesen, R. Andreesen, A. M. Steffan, C. Royer, S. Troster, J. Kreuter, and H. Rubsamen-Waigmann. Phagocytosis of nanoparticles by human immunodeficiency virus (HIV)-infected macrophages: A possibility for antiviral drug targeting. Pharm. Res. 9:541-546 (1992).
G. Pantaleo, C. Graziosi, L. Butini, P. A. Pizzo, S. M. Schnittman, D. P. Kotler, and A. S. Fauci. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 88:9838-9842 (1991).
P. Herdewijn, J. Balzarini, E. De Clercq, R. Pauwels, M. Baba, S. Broder, and H. Vanderhaeghe. 3′-substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J. Med. Chem. 30:1270-1278 (1987).
S. K. Aggarwal, S. R. Gogu, S. R. Rangan, and K. C. Agrawal. Synthesis and biological evaluation of prodrugs of zidovudine. J. Med. Chem. 33:1505-1510 (1990).
B. A. Larder, S. D. Kemp, and P. R. Harrigan. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269:696-699 (1995).
S. M. Daluge, S. S. Good, M. B. Faletto, W. H. Miller, M. H. St. Clair, L. R. Boone, M. Tisdale, N. R. Parry, J. E. Reardon, R. E. Dornsife, D. R. Averett, and T. A. Krenitsky. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob. Agents. Chemother. 41:1082-1093 (1997).
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Dembri, A., Montisci, MJ., Gantier, J.C. et al. Targeting of 3′-Azido 3′-Deoxythymidine (AZT)-Loaded Poly(Isohexylcyanoacrylate) Nanospheres to the Gastrointestinal Mucosa and Associated Lymphoid Tissues. Pharm Res 18, 467–473 (2001). https://doi.org/10.1023/A:1011050209986
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DOI: https://doi.org/10.1023/A:1011050209986