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General structure and the principal of activity of the conjugate

Targeted delivery of anti-tubercular antibiotics into macrophages infected with Mycobacteria tuberculosis.

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General structure and the principal of activity of the conjugate

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  1. Targeted delivery of anti-tubercular antibiotics into macrophages infected with Mycobacteria tuberculosis Dushkin, M.I.(1), Schwartz, Ya. S.(1), Sennikov, S.V.(1),.Vavilin, V.A.(1), Melnikova, E.V.(1), Kozlov, V.A.(1), Agafonov, A.P.(2), Alekseev, A.Yu.(2), Rassadkin Yu.N.(2), Shestopalov, A.M.(2), Ivankina, T.Yu.(2), Saraev, D.V.(2), Azaev, M.S.(2), Freidin, M.B.(3), Rudko A.V.(3), Puzyrev, V.P.(3), Kurunov, Yu.N.(4), Krasnov, V.A.(4), Reynolds, R.(5), Morris, S.(6), Blinov, V.M.(2) (1) Institute of Clinical Immunology, Siberian Division of Russian Academy of Medical Sciences, Novosibirsk, Russia (2) Institute of Molecular Biology, State Research Center of Virology and Biotechnology Vector, Russian Ministry of Health, Koltsovo, Russia (3) Institute of Medical Genetics, Siberian Division of Russian Academy of Medical Sciences, Tomsk, Russia (4) Novosibirsk Institute of Tuberculosis of Russian Ministry of Public Health, Novosibirsk, Russia (5) Southern Research Institute, Birmingham, Alabama, USA (6) Laboratory of Mycobacteria, Center for Biologics Evaluation and Research of the FDA, Bethesda, MD USA

  2. General structure and the principal of activity of the conjugate Moxifloxacin Dansylcadaverine Carboxymethylated glucan MacrophageScavenger Receptors type A

  3. Light and fluorescent mycroscopy of the impact of ligands to ScR-A upon accumulation the conjugate by macrophage cells J774 Control M-DCMG M-DCMG +CMG M-DCMG +DSO4

  4. Concentration dependency of uptake of the conjugate by cultured macrophages J774(fluorescence photometry)

  5. Uptake of the conjugate by J774 macrophages in the presence or absence of non-labeled ligands to ScR-A (fluorescence photometry)

  6. Light and fluorescent mycroscopy of accumulation of the conjugate by alveolar macrophages of control or conjugate-treated mice Alveolar macrophages of M-DCMG-administered animals Non-adherent cells of broncho-alveolar lavage of control animals Non-adherent cells of broncho-alveolar lavage of M-DCMG-injected animals Alveolar macrophages of control animals

  7. Accumulation of moxifloxacin and the conjugate (M-DCMG) in alveolar Mfs and in non-adherent broncho-alveolar cells in vivo(fluorescence photometry)

  8. Drugs Pharmacokinetic parameters kα (min-1) kβ (min-1) AUC0-∞ Clt(ml/min) t1/2 (min) Vd (ml) M-DCMG 0,11±0,04 0,01±0,01 192,9±119,7 4±2 75,1±43,75 42±43 moxi 0,02±0,01 0,02±0,01 212,2±120,1 0,47±0,38 31,35±5,0 18,97±18,2 р 0,02 0,24 0,85 0,02 0,16 0,44 Drugs Pharmacokinetic parameters kβ (min-1) Cll(ml/min) t1/2 (min) M-DCMG 0,02±0,01 3,83±1,7 46,85±33,88 moxifloxacin 0,02±0,11 0,20±0,11 39,78±10,77 р 0,77 0,021 0,74 Pharmacokinetic parameters of redistribution and elimination of M-DCMG and moxifloxacin Blood serum Liver

  9. Experimental group Concentration of preparation (µg/ml) CFU number Incubation time (h) 1 2 4 moxifloxacin 0.25 71+21 28+14 18+7 1.0 58+11 32+20 16+11 4.0 38+18 25+18 18+19 8.0 22+16 12+10 7+6 M-DCMG 2.5 50+26 40+18 6+6* 10.0 32+22 21+22 5+11* 40.0 24+14 21+12 9+4* 80.0 20+17 14+15 3+1* CMG 40.0 >100 >100 >100 80.0 >100 >100 >100 Infected Mf - >100 >100 >100 Non-infected Mf - 0 0 0 Mycobacteria - >100 >100 >100 The number of CFU of M.tuberculosis strain Erdman grown after incubation of infected cells J774 with conjugates, moxifloxacin, or carboxymethylated beta 1,3-glucan (M  SE)

  10. The dynamics of volume density (%) of mononuclear infiltrates in the LIVER of mice infected with M. tuberculosis and treated/non-treated with different doses of moxifloxacin or M-DMCMG

  11. The dynamics of volume density (%) of mononuclear infiltrates in the LUNGS of mice infected with M. tuberculosis and treated/non-treated with different doses of moxifloxacin or M-DMCMG

  12. The effect of moxifloxacin or conjugate treatment on the number of bacteria in the LIVER at the 21st day of TB infection (15th day of treatment)

  13. The effect of moxifloxacin or conjugate treatment on the number of bacteria in the SPLEEN at the 21st day of TB infection (15th day of treatment)

  14. The effect of moxifloxacin or conjugate treatment on the number of bacteria in the lungs at the 21st day of TB infection (15th day of treatment)

  15. CONCLUSIONS 1. The conjugate of moxifloxacin with carboxymethylglucan is dose-dependently (1-50 µg/ml) accumulated in macrophages through ScR-A. 2. After iv administration of the conjugate into C57Bl/6 mice the conjugate is concentrated in macrophages of lungs and spleen 3. The conjugate is eliminated from the blood by far more rapidly and persists in the tissues much longer than free moxifloxacin 4. The conjugate exerts much more pronounced anti-TB effectthan free moxifloxacin Acknowledgment This work was supported by a grant of BTEP/ISTC 39/2174p.

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