Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

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Drug resistance is complicating the treatment of parasitic diseases including African trypanosomiasis, a fatal disease if left untreated. Development of a vaccine is unlikely due to parasite antigenic variation. Current chemotherapy relies primarily on four drugs. Three of these drugs access the cell’s interior through surface transporters and resistance mechanisms are largely associated with loss-of-function mutations in the involved surface drug transporters. We reasoned that using an alternative drug entrance would circumvent parasite resistance due to mutation in a surface transporter. We have developed a drug nanocarrier that consists of polymeric nanoparticles coated with a single domain antibody that targets the trypanosome surface. This new formulation reduces the minimal curative dose and, most importantly, circumvents drug resistance in a resistant cell line as a result of mutations in the surface transporter that mediate drug uptake. This study presents a proof-of-concept of a novel technology for reversing transporter-related drug resistance with applications to other infectious diseases.

Vyšlo v časopise: Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004942
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004942

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1. Barrett MP, Burchmore RJ, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, et al. The trypanosomiases. Lancet. 2003;362(9394):1469–80. Epub 2003/11/07. S0140-6736(03)14694-6 [pii]; doi: 10.1016/S0140-6736(03)14694-6 14602444.

2. Brun R, Blum J. Human african trypanosomiasis. Infect Dis Clin North Am. 2012;26(2):261–73. Epub 2012/05/29. S0891-5520(12)00012-8 [pii] doi: 10.1016/j.idc.2012.03.003 22632638.

3. Glover L, Hutchinson S, Alsford S, McCulloch R, Field MC, Horn D. Antigenic variation in African trypanosomes: the importance of chromosomal and nuclear context in VSG expression control. Cell Microbiol. 2013. Epub 2013/09/21. doi: 10.1111/cmi.12215 24047558.

4. Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009;374(9683):56–64. Epub 2009/06/30. S0140-6736(09)61117-X [pii] doi: 10.1016/S0140-6736(09)61117-X 19559476.

5. Delespaux V, de Koning HP. Drugs and drug resistance in African trypanosomiasis. Drug Resist Updat. 2007;10(1–2):30–50. Epub 2007/04/06. S1368-7646(07)00021-0 [pii] doi: 10.1016/j.drup.2007.02.004 17409013.

6. Arias JL. Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems. Molecules. 2008;13(10):2340–69. Epub 2008/10/03. 13102340 [pii]. 18830159.

7. Unciti-Broceta JD, Del Castillo T, Soriano M, Magez S, Garcia-Salcedo JA. Novel therapy based on camelid nanobodies. Therapeutic delivery. 2013;4(10):1321–36. Epub 2013/10/15. doi: 10.4155/tde.13.87 24116915.

8. Stijlemans B, Conrath K, Cortez-Retamozo V, Van Xong H, Wyns L, Senter P, et al. Efficient targeting of conserved cryptic epitopes of infectious agents by single domain antibodies. African trypanosomes as paradigm. J Biol Chem. 2004;279(2):1256–61. Epub 2003/10/07. doi: 10.1074/jbc.M307341200 M307341200 [pii]. 14527957.

9. Baral TN, Magez S, Stijlemans B, Conrath K, Vanhollebeke B, Pays E, et al. Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor. Nat Med. 2006;12(5):580–4. Epub 2006/04/11. nm1395 [pii] doi: 10.1038/nm1395 16604085.

10. Magez S, Radwanska M, Stijlemans B, Xong HV, Pays E, De Baetselier P. A conserved flagellar pocket exposed high mannose moiety is used by African trypanosomes as a host cytokine binding molecule. J Biol Chem. 2001;276(36):33458–64. Epub 2001/06/19. doi: 10.1074/jbc.M103412200 M103412200 [pii]. 11404356.

11. Arias JL, Unciti-Broceta JD, Maceira J, Del Castillo T, Hernandez-Quero J, Magez S, et al. Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis. J Control Release. 2015;197:190–8. Epub 2014/12/03. S0168-3659(14)00739-1 [pii] doi: 10.1016/j.jconrel.2014.11.002 25445702.

12. Arias JL. Advanced methodologies to formulate nanotheragnostic agents for combined drug delivery and imaging. Expert Opin Drug Deliv. 2011;8(12):1589–608. Epub 2011/11/22. doi: 10.1517/17425247.2012.634794 22097904.

13. Arias JL, Reddy LH, Couvreur P. Superior preclinical efficacy of gemcitabine developed as chitosan nanoparticulate system. Biomacromolecules. 2011;12(1):97–104. Epub 2010/12/02. doi: 10.1021/bm101044h 21117615.

14. Malhotra M, Tomaro-Duchesneau C, Prakash S. Synthesis of TAT peptide-tagged PEGylated chitosan nanoparticles for siRNA delivery targeting neurodegenerative diseases. Biomaterials. 2013;34(4):1270–80. doi: 10.1016/j.biomaterials.2012.10.013 23140978

15. Torrecilla D, Lozano MV, Lallana E, Neissa JI, Novoa-Carballal R, Vidal A, et al. Anti-tumor efficacy of chitosan-g-poly(ethylene glycol) nanocapsules containing docetaxel: Anti-TMEFF-2 functionalized nanocapsules vs. non-functionalized nanocapsules. European Journal of Pharmaceutics and Biopharmaceutics. 2013;83(3):330–7. doi: 10.1016/j.ejpb.2012.10.017 23262164

16. Thuita JK, Karanja SM, Wenzler T, Mdachi RE, Ngotho JM, Kagira JM, et al. Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis. Acta Trop. 2008;108(1):6–10. Epub 2008/08/30. S0001-706X(08)00210-6 [pii] doi: 10.1016/j.actatropica.2008.07.006 18722336.

17. Frearson JA, Brand S, McElroy SP, Cleghorn LA, Smid O, Stojanovski L, et al. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature. 2010;464(7289):728–32. Epub 2010/04/03. nature08893 [pii] doi: 10.1038/nature08893 20360736; PubMed Central PMCID: PMC2917743.

18. Stijlemans B, Caljon G, Natesan SK, Saerens D, Conrath K, Perez-Morga D, et al. High affinity nanobodies against the Trypanosome brucei VSG are potent trypanolytic agents that block endocytosis. PLoS Pathog. 2011;7(6):e1002072. Epub 2011/06/24. doi: 10.1371/journal.ppat.1002072 10-PLPA-RA-4101 [pii]. 21698216; PubMed Central PMCID: PMC3116811.

19. Caljon G, Stijlemans B, Saerens D, Van Den Abbeele J, Muyldermans S, Magez S, et al. Affinity is an important determinant of the anti-trypanosome activity of nanobodies. PLoS Negl Trop Dis. 2012;6(11):e1902. Epub 2012/11/21. doi: 10.1371/journal.pntd.0001902 PNTD-D-12-00780 [pii]. 23166849; PubMed Central PMCID: PMC3499403.

20. De Vooght L, Caljon G, Stijlemans B, De Baetselier P, Coosemans M, Van den Abbeele J. Expression and extracellular release of a functional anti-trypanosome Nanobody(R) in Sodalis glossinidius, a bacterial symbiont of the tsetse fly. Microb Cell Fact. 2012;11:23. Epub 2012/02/18. 1475-2859-11-23 [pii] doi: 10.1186/1475-2859-11-23 22335892; PubMed Central PMCID: PMC3311065.

21. Nolan DP, Geuskens M, Pays E. N-linked glycans containing linear poly-N-acetyllactosamine as sorting signals in endocytosis in Trypanosoma brucei. Curr Biol. 1999;9(20):1169–72. Epub 1999/10/26. S0960-9822(00)80018-4 [pii] doi: 10.1016/S0960-9822(00)80018-4 10531030.

22. Alsford S, Eckert S, Baker N, Glover L, Sanchez-Flores A, Leung KF, et al. High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature. 2012;482(7384):232–6. Epub 2012/01/27. nature10771 [pii] doi: 10.1038/nature10771 22278056; PubMed Central PMCID: PMC3303116.

23. Bernhard SC, Nerima B, Maser P, Brun R. Melarsoprol- and pentamidine-resistant Trypanosoma brucei rhodesiense populations and their cross-resistance. Int J Parasitol. 2007;37(13):1443–8. Epub 2007/07/03. S0020-7519(07)00180-4 [pii] doi: 10.1016/j.ijpara.2007.05.007 17602691.

24. Carter NS, Berger BJ, Fairlamb AH. Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and-resistant Trypanosoma brucei brucei. J Biol Chem. 1995;270(47):28153–7. Epub 1995/11/24. 7499305.

25. Baker N, Glover L, Munday JC, Aguinaga Andres D, Barrett MP, de Koning HP, et al. Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes. Proc Natl Acad Sci U S A. 2012. Epub 2012/06/20. 1202885109 [pii] doi: 10.1073/pnas.1202885109 22711816.

26. Bridges DJ, Gould MK, Nerima B, Maser P, Burchmore RJ, de Koning HP. Loss of the high-affinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in African trypanosomes. Mol Pharmacol. 2007;71(4):1098–108. Epub 2007/01/20. mol.106.031351 [pii] doi: 10.1124/mol.106.031351 17234896.

27. Graf FE, Ludin P, Wenzler T, Kaiser M, Brun R, Pyana PP, et al. Aquaporin 2 Mutations in Trypanosoma brucei gambiense Field Isolates Correlate with Decreased Susceptibility to Pentamidine and Melarsoprol. PLoS Negl Trop Dis. 2013;7(10):e2475. doi: 10.1371/journal.pntd.0002475 24130910

28. Munday JC, Eze AA, Baker N, Glover L, Clucas C, Aguinaga Andres D, et al. Trypanosoma brucei aquaglyceroporin 2 is a high-affinity transporter for pentamidine and melaminophenyl arsenic drugs and the main genetic determinant of resistance to these drugs. The Journal of antimicrobial chemotherapy. 2013. Epub 2013/11/16. doi: 10.1093/jac/dkt442 24235095.

29. de Koning HP, Anderson LF, Stewart M, Burchmore RJ, Wallace LJ, Barrett MP. The trypanocide diminazene aceturate is accumulated predominantly through the TbAT1 purine transporter: additional insights on diamidine resistance in african trypanosomes. Antimicrob Agents Chemother. 2004;48(5):1515–9. Epub 2004/04/24. 15105099; PubMed Central PMCID: PMC400564.

30. Munday JC, Rojas Lopez KE, Eze AA, Delespaux V, Van Den Abbeele J, Rowan T, et al. Functional expression of TcoAT1 reveals it to be a P1-type nucleoside transporter with no capacity for diminazene uptake. Int J Parasitol Drugs Drug Resist. 2013;3:69–76. Epub 2014/02/18. doi: 10.1016/j.ijpddr.2013.01.004 S2211-3207(13)00005-5 [pii]. 24533295; PubMed Central PMCID: PMC3862423.

31. Munday JC, Tagoe DN, Eze AA, Krezdorn JA, Rojas Lopez KE, Alkhaldi AA, et al. Functional analysis of drug resistance-associated mutations in the Trypanosoma brucei adenosine transporter 1 (TbAT1) and the proposal of a structural model for the protein. Mol Microbiol. 2015. Epub 2015/02/25. doi: 10.1111/mmi.12979 25708978.

32. Munday JC, Settimo L, de Koning HP. Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei. Front Pharmacol. 2015;6:32. Epub 2015/03/31. doi: 10.3389/fphar.2015.00032 25814953; PubMed Central PMCID: PMC4356943.

33. Barrett MP, Vincent IM, Burchmore RJS, Kazibwe AJN, Matovu E. Drug resistance in human African trypanosomiasis. Future Microbiology. 2011;6(9):1037–47. doi: 10.2217/fmb.11.88 21958143

34. Garcia-Salcedo J, Munday J, Unciti-Broceta J, Koning H. Progress Towards New Treatments for Human African Trypanosomiasis. In: Magez S, Radwanska M, editors. Trypanosomes and Trypanosomiasis: Springer Vienna; 2014. p. 217–38.

35. Mäser P, Wittlin S, Rottmann M, Wenzler T, Kaiser M, Brun R. Antiparasitic agents: new drugs on the horizon. Current Opinion in Pharmacology. 2012;12(5):562–6. doi: 10.1016/j.coph.2012.05.001 22652215

36. Vanaerschot M, Huijben S, Van den Broeck F, Dujardin JC. Drug resistance in vectorborne parasites: multiple actors and scenarios for an evolutionary arms race. FEMS Microbiol Rev. 2013. Epub 2013/07/03. doi: 10.1111/1574-6976.12032 23815683.

37. Vincent IM, Creek D, Watson DG, Kamleh MA, Woods DJ, Wong PE, et al. A molecular mechanism for eflornithine resistance in African trypanosomes. PLoS Pathog. 2010;6(11):e1001204. Epub 2010/12/03. doi: 10.1371/journal.ppat.1001204 21124824; PubMed Central PMCID: PMC2991269.

38. Schumann Burkard G, Jutzi P, Roditi I. Genome-wide RNAi screens in bloodstream form trypanosomes identify drug transporters. Mol Biochem Parasitol. 2011;175(1):91–4. Epub 2010/09/21. S0166-6851(10)00233-1 [pii] doi: 10.1016/j.molbiopara.2010.09.002 20851719.

39. Carter NS, Fairlamb AH. Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature. 1993;361(6408):173–6. Epub 1993/01/14. doi: 10.1038/361173a0 8421523.

40. Maser P, Sutterlin C, Kralli A, Kaminsky R. A nucleoside transporter from Trypanosoma brucei involved in drug resistance. Science. 1999;285(5425):242–4. Epub 1999/07/10. 7645 [pii]. 10398598.

41. Matovu E, Stewart ML, Geiser F, Brun R, Maser P, Wallace LJ, et al. Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei. Eukaryot Cell. 2003;2(5):1003–8. Epub 2003/10/14. 14555482; PubMed Central PMCID: PMC219364.

42. Park JH, Saravanakumar G, Kim K, Kwon IC. Targeted delivery of low molecular drugs using chitosan and its derivatives. Advanced Drug Delivery Reviews. 2010;62(1):28–41. doi: 10.1016/j.addr.2009.10.003 19874862

43. Sinha VR, Singla AK, Wadhawan S, Kaushik R, Kumria R, Bansal K, et al. Chitosan microspheres as a potential carrier for drugs. International Journal of Pharmaceutics. 2004;274(1–2):1–33. doi: 10.1016/j.ijpharm.2003.12.026 15072800

44. Manca ML, Loy G, Zaru M, Fadda AM, Antimisiaris SG. Release of rifampicin from chitosan, PLGA and chitosan-coated PLGA microparticles. Colloids and Surfaces B: Biointerfaces. 2008;67(2):166–70. doi: 10.1016/j.colsurfb.2008.08.010 18835764

45. Durand R, Paul M, Rivollet D, Houin R, Astier A, Deniau M. Activity of pentamidine-loaded methacrylate nanoparticles against Leishmania infantum in a mouse model. International Journal for Parasitology. 1997;27(11):1361–7. doi: 10.1016/S0020-7519(97)00124-0 9421724

46. Fusai T, Deniau M, Durand R, Bories C, Paul M, Rivollet D, et al. Action of pentamidine-bound nanoparticles against Leishmania on an in vivo model. Parasite (Paris, France). 1994;1(4):319–24. 9140499

47. Durand R, Paul M, Rivollet D, Fessi H, Houin R, Astier A, et al. Activity of pentamidine-loaded poly (D,L-lactide) nanoparticles against Leishmania infantum in a murine model. Parasite. 1997;4(4):331–6. 9587601

48. Hirumi H, Hirumi K. Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. The Journal of parasitology. 1989;75(6):985–9. Epub 1989/12/01. 2614608.

49. Dash BC, Réthoré G, Monaghan M, Fitzgerald K, Gallagher W, Pandit A. The influence of size and charge of chitosan/polyglutamic acid hollow spheres on cellular internalization, viability and blood compatibility. Biomaterials. 2010;31(32):8188–97. doi: 10.1016/j.biomaterials.2010.07.067 20701967

50. Unciti-Broceta JD, Maceira J, Morales S, Garcia-Perez A, Munoz-Torres ME, Garcia-Salcedo JA. Nicotinamide inhibits the lysosomal cathepsin b-like protease and kills African trypanosomes. J Biol Chem. 2013. Epub 2013/02/28. M112.449207 [pii] doi: 10.1074/jbc.M112.449207 23443665.

51. Kourtis IC, Hirosue S, de Titta A, Kontos S, Stegmann T, Hubbell JA, et al. Peripherally Administered Nanoparticles Target Monocytic Myeloid Cells, Secondary Lymphoid Organs and Tumors in Mice. PLoS ONE. 2013;8(4):e61646. doi: 10.1371/journal.pone.0061646 23626707

52. Stewart ML, Burchmore RJ, Clucas C, Hertz-Fowler C, Brooks K, Tait A, et al. Multiple genetic mechanisms lead to loss of functional TbAT1 expression in drug-resistant trypanosomes. Eukaryot Cell. 2010;9(2):336–43. Epub 2009/12/08. EC.00200-09 [pii] doi: 10.1128/EC.00200-09 19966032; PubMed Central PMCID: PMC2823006.

53. Spitznagel D, Ebikeme C, Biran M, Nic a' Bhaird N, Bringaud F, Henehan GT, et al. Alanine aminotransferase of Trypanosoma brucei—a key role in proline metabolism in procyclic life forms. FEBS J. 2009;276(23):7187–99. Epub 2009/11/10. EJB7432 [pii] doi: 10.1111/j.1742-4658.2009.07432.x 19895576.