Pharmaceutics

Body distribution and in situ evading of phagocytic uptake by macrophages of long-circulating poly (ethylene glycol) cyanoacrylate-co-n-hexadecyl cyanoacrylate nanoparticles

Abstract

Aim:

To investigate the body distribution in mice of [14C]-labeled poly methoxyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate (PEG-PHDCA) nanoparticles and in situ evading of phagocytic uptake by mouse peritoneal macrophages.

Methods:

PEG-PHDCA copolymers were synthesized by condensation of methoxypolyethylene glycol cyanoacetate with [14C]-hexadecylcyanoacetate. [14C]-nanoparticles were prepared using the nanoprecipitation/solvent diffusion method, while fluorescent nanoparticles were prepared by incorporating rhodamine B. In situ phagocytic uptake was evaluated by flow cytometry. Body distribution in mice was evaluated by determining radioactivity in tissues using a scintillation method.

Results:

Phagocytic uptake by macrophages can be efficiently evaded by fluorescent PEG-PHDCA nanoparticles. After 48 h, 31% of the radioactivity of the stealth [14C]-PEG-PHDCA nanoparticles after iv injection was still found in blood, whereas non-stealth PHDCA nanoparticles were cleaned up from the bloodstream in a short time. The distribution of stealth PEG-PHDCA nanoparticles and non-stealth PHDCA nanoparticals in mice was poor in lung, kidney, and brain, and a little higher in hearts. Lymphatic accumulation was unusually high for both stealth and non-stealth nanoparticles, typical of lymphatic capture. The accumulation of stealth PEG-PHDCA nanoparticles in the spleen was 1.7 times as much as that of non-stealth PHDCA (P<0.01). But the accumulation of stealth PEG-PHDCA nanoparticles in the liver was 0.8 times as much as that of non-stealth PHDCA (P<0.05).

Conclusion:

PEGylation leads to long-circulation of nanoparticles in the bloodstream, and splenotropic accumulation opens up the potential for further development of spleen-targeted drug delivery.

References

  1. 1

    Makino K, Yamamoto N, Higuchi K, Harada N, Ohshima H, Terada H . Phagocytic uptake of polystyrene microspheres by alveolar macrophages: effects of the size and surface properties of the microspheres. Colloid Surf B 2003; 27: 33–9.

    CAS  Article  Google Scholar 

  2. 2

    Moghimi SM, Szebeni J . Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 2003; 42: 463–78.

    CAS  Article  Google Scholar 

  3. 3

    Moghimi SM, Hunter AC, Murray JC . Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 2001; 53: 283–318.

    CAS  Google Scholar 

  4. 4

    Neradovic D, Soga O, Nostrum CFV, Hennink WE . The effect of the processing and formulation parameters on the size of nanoparticles based on block copolymers of poly(ethylene glycol) and poly(N-isopropylacrylamide) with and without hydrolytically sensitive groups. Biomaterials 2004; 25: 2409–18.

    CAS  Article  Google Scholar 

  5. 5

    Moghimi SM, Hunter AC . Poloxamers and poloxamines in nanoparticle engineering and experimental medicine. Trends Biotechnol 2000; 18: 412–20.

    CAS  Article  Google Scholar 

  6. 6

    Moghimi SM . Mechanisms regulating body distribution of nanospheres conditioned with pluronic and tetronic block copolymers. Adv Drug Del Rev 1995; 16: 183–93.

    CAS  Article  Google Scholar 

  7. 7

    Vandorpe J, Schacht E, Dunn S, Hawley A, Stolnik S, Davis SS, et al. Long circulating biodegradable poly(phosphazene) nanoparticles surface modified with poly(phosphazene)-poly (ethylene oxide) copolymer. Biomaterials 1997; 18: 1147–52.

    CAS  Article  Google Scholar 

  8. 8

    Wilkins DJ, Myers PA . Studies on the relationship between the electrophoretic properties of colloids and their blood clearance and organ distribution in the rat. Br J Exp Pathol 1966; 47: 568–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Peracchia MT, Fattal E, Desmaele D, Besnard M, Noel JP, Gomis MJ, et al. Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J Control Release 1999; 60: 121–8.

    CAS  Article  Google Scholar 

  10. 10

    Li YP, Pei YY, Zhang XY, Gu ZH, Zhou ZH, Yuan WF, et al. PEGylated PLGA nanoparticles as protein carriers: synthesis, preparation and biodistribution in rats. J Control Release 2001; 71: 203–11.

    CAS  Article  Google Scholar 

  11. 11

    Huang M, Wu W . Synthesis of poly [poly (ethylene glycol)-cyanoacrylate-co-hexadecyl cyanoacrylate] used for the preparation of nanoparticles. Chin J Pharm 2005; 36: 152–5.

    CAS  Google Scholar 

  12. 12

    Nam YS, Kang HS, Park JY, Park TG, Han SH, Chang IS . New micelle-like polymer aggregates made from PEI-PLGA diblock copolymers: micellar characteristics and cellular uptake. Biomaterials 2003; 24: 2053–9.

    CAS  Article  Google Scholar 

  13. 13

    Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnisch S, et al. ‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B Biointerfaces 2000; 18: 301–13.

    CAS  Article  Google Scholar 

  14. 14

    Gaur U, Sahoo SK, De TK, Ghosh PC, Maitra A, Ghosh PK . Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system. Int J Pharm 2000; 202: 1–10.

    CAS  Article  Google Scholar 

  15. 15

    Nguyen CA, Allémann E, Schwash G, Doelker E, Gurny R . Cell interaction studies of PLA-MePEG nanoparticles. Int J Pharm 2003; 254: 69–72.

    CAS  Article  Google Scholar 

  16. 16

    Bocca C, Caputo O, Cavalli R, Gabriel L, Miglietta A, Gasco MR . Phagocytic uptake of fluorescent stealth and non-stealth solid lipid nanoparticles. Int J Pharm 1998; 175: 185–93 17.

    CAS  Article  Google Scholar 

  17. 17

    Illum L, Hunneyball IM, Davis SS . The effect of hydrophilic coatings on the uptake of colloidal particles by the liver and by peritoneal macrophages. Int J Pharm 1986; 29: 53–65.

    CAS  Article  Google Scholar 

  18. 18

    Moghimi SM . Mechanisms of splenic clearance of blood cells and particles–towards development of splenotropic agents. Adv Drug Del Rev 1995; 17: 103–15.

    CAS  Article  Google Scholar 

  19. 19

    Moghimi SM, Porter CJH, Muir IS, Illum L, Davis SS . Nonphagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. Biochem Biophys Res Commun 1991; 177: 861–6.

    CAS  Article  Google Scholar 

  20. 20

    Moghimi SM, Hedeman H, Muir IS, Illum L, Davis SS . An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen. Biochem Biophys Acta 1993; 1157: 233–40.

    CAS  Article  Google Scholar 

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Correspondence to Wei Wu or Xiu-li Wei.

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Project supported by the Shanghai Municipal Committee of Science and Technology (Grant No 0243nm067) and the Shanghai Education Bureau for Excellent Young High Education Teacher Candidates (Grant No 03YQHB008).

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Huang, M., Wu, W., Qian, J. et al. Body distribution and in situ evading of phagocytic uptake by macrophages of long-circulating poly (ethylene glycol) cyanoacrylate-co-n-hexadecyl cyanoacrylate nanoparticles. Acta Pharmacol Sin 26, 1512–1518 (2005). https://doi.org/10.1111/j.1745-7254.2005.00216.x

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Keywords

  • nanotechnology
  • tissue distribution
  • polyethylene glycols
  • cynoacrylates
  • polymers
  • spleen

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