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Characterization of Toxicological Properties of L-Lysine Polymers in CD-1 Mice

  • Titlow, William B. (Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky) ;
  • Lee, Chul-Hoon (Department of Pharmacy, College of Pharmacy, Hanyang University) ;
  • Ryou, Chongsuk (Department of Pharmacy, College of Pharmacy, Hanyang University)
  • Received : 2013.02.25
  • Accepted : 2013.03.11
  • Published : 2013.07.28

Abstract

We recently showed that polylysine, the polymer of lysines, retains anti-prion activity. Although the effectiveness of prion inhibition by polylysine was demonstrated with the regimen tolerated in mice, a determination of quantitative polylysine toxicity is necessary to precisely address the in vivo toxicity level of polylysine. In this communication, we report the results of body weight monitoring and hematologic tests performed in CD-1 mice that received two different tolerable dosages of polylysine for an either 5-day or 4-week period. We found that there was no significant alteration in overall serum chemistry, blood cell count, and body weight gain compared with controls. The only notable quantitative change with statistical significance was the decrease of platelet numbers in mice subchronically administered with polylysine. Our results suggest that polylysine is harmless in mice if administered for a short period, but administrations of polylysine in mice may require considerate attention for safety in future investigations as mice chronically receive tolerable doses of polylysine.

Keywords

References

  1. Arnold LJJ, Dagan A, Gutheil J, Kaplan NO. 1979. Antineoplastic activity of poly(L-lysine) with some ascites tumor cells. Proc. Natl. Acad. Sci. USA 76: 3246-3250. https://doi.org/10.1073/pnas.76.7.3246
  2. Bae Y, Fukushima S, Harada A, Kataoka K. 2003. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: Polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Ed. Engl. 42: 4640-4643. https://doi.org/10.1002/anie.200250653
  3. De Vries A, Feldman JD, Stein O, Stein Y, Katchalski E. 1953. Effects of intravenously administered poly-DL-lysine in rats. Proc. Soc. Exp. Biol. Med. 76: 237-240.
  4. Donovan J, Brown P. 2006. Blood collection. Curr. Protoc. Immunol. DOI: 10.1002/0471142735.im0107a73.
  5. Harada-Shiba M, Yamauchi K, Harada A, Takamisawa I, Shimokado K, Kataoka K. 2002. Polyion complex micelles as vectors in gene therapy - pharmacokinetics and in vivo gene transfer. Gene Ther. 9: 407-414. https://doi.org/10.1038/sj.gt.3301665
  6. Hatton MW, Regoeczi E. 1975. The relevance of the structure of lysine bound to Sepharose for the affinity of rabbit plasminogen. Biochim. Biophys. Acta 379: 504-511. https://doi.org/10.1016/0005-2795(75)90157-9
  7. Jackson KS, Yeom J, Han Y, Bae Y, Ryou C. 2013. Preference toward a polylysine enantiomer in inhibiting prions. Amino Acids 44: 993-1000. https://doi.org/10.1007/s00726-012-1430-8
  8. Johnston TP, Kuchimanchi KR, Alur H, Chittchang M, Mitra AK. 2003. Inducing a change in the pharmacokinetics and biodistribution of poly-L-lysine in rats by complexation with heparin. J. Pharm. Pharmacol. 55: 1083-1090. https://doi.org/10.1211/0022357021530
  9. Langeland N, Moore LJ, Holmsen H, Haarr L. 1988. Interaction of polylysine with the cellular receptor for herpes simplex virus type 1. J. Gen. Virol. 69: 1137-1145. https://doi.org/10.1099/0022-1317-69-6-1137
  10. Mays CE, Ryou C. 2010. Plasminogen stimulates propagation of protease-resistant prion protein in vitro. FASEB J. 24: 5102-5112. https://doi.org/10.1096/fj.10-163600
  11. Mays CE, Ryou C. 2011. Plasminogen: A cellular protein cofactor for PrPSc propagation. Prion 5: 22-27. https://doi.org/10.4161/pri.5.1.14460
  12. Moreau E, Domurado M, Chapon P, Vert M, Domurado D. 2002. Biocompatibility of polycations: In vitro agglutination and lysis of red blood cells and in vivo toxicity. J. Drug Target. 10: 161-173. https://doi.org/10.1080/10611860290016766
  13. Nicholas Delihas LWR, Loo W, Berkowitz J, Poltoratskaia N. 1995. High sensitivity of mycobacterium species to the bactericidal activity by polylysine. FEMS Microbiol. Lett. 132: 233-237. https://doi.org/10.1111/j.1574-6968.1995.tb07839.x
  14. Okuda T, Kawakami S, Maeie T, Niidome T, Yamashita F, Hashida M. 2006. Biodistribution characteristics of amino acid dendrimers and their PEGylated derivatives after intravenous administration. J. Control. Release 114: 69-77. https://doi.org/10.1016/j.jconrel.2006.05.009
  15. Park SH, Raines RT. 2004. Fluorescence gel retardation assay to detect protein-protein interactions. Methods Mol. Biol. 261: 155-160.
  16. Ryou C. 2010. Transmissible spongiform encephalopathy, pp. 151-172. In Saleh M (ed.). Molecular Aspects of Infectious Diseases. Nova Science Publisher, Hauppauge, New York.
  17. Ryou C. 2011. Prion diseases. In Harper D (ed.). Encyclopedia of Life Sciences. John Wiley & Sons Inc, Chichester, UK.
  18. Ryou C, Titlow WB, Mays CE, Bae Y, Kim S. 2011. The suppression of prion propagation using poly-L-lysine by targeting plasminogen that stimulates prion protein conversion. Biomaterials 32: 3141-3149. https://doi.org/10.1016/j.biomaterials.2011.01.017
  19. Sakharov DV, Jie AFH, Bekkers MEA, Emeis JJ, Rijken DC. 2001. Polylysine as a vehicle for extracellular matrix-targeted local drug delivery, providing high accumulation and longterm retention within the vascular wall. Arterioscler. Thromb. Vasc. Biol. 21: 943-948. https://doi.org/10.1161/01.ATV.21.6.943
  20. Schmaier AH, Lazarus HM. 2011. Acquired thrombocytopenia, pp. 154-173. In Warkentin TE, Warkentin AE (eds.). Concise Guide to Hematology. Wiley-Blackwell.
  21. Sela M, Katchalski E. 1959. Biological properties of poly-aamino acids, pp. 391-478. In Anfinsen CB, et al. (eds.). Advances in Protein Chemistry, Vol. 14. Academic Press, New York.
  22. Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O'Neill LAJ, et al. 2007. Resolution of inflammation: State of the art, definitions and terms. FASEB J. 21: 325-332. https://doi.org/10.1096/fj.06-7227rev
  23. Sodetz JM, Brockway WJ, Castellino FJ. 1972. Multiplicity of rabbit plasminogen. Physical characterization. Biochemistry 11: 4451-4458.
  24. Ward CM, Read ML, Seymour LW. 2001. Systemic circulation of poly(L-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA: differential circulation in mice and rats and the implications for human gene therapy. Blood 97: 2221-2229. https://doi.org/10.1182/blood.V97.8.2221
  25. Xu Z, Adrover M, Pastore A, Prigent S, Mouthon F, Comoy E, et al. 2011. Mechanistic insights into cellular alteration of prion by poly-D-lysine: The role of H2H3 domain. FASEB J. 25: 3426-3435. https://doi.org/10.1096/fj.11-187534

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