Advertisement

Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 66–75 | Cite as

Effects of stability of PEGylated micelles on the accelerated blood clearance phenomenon

  • Yuqing Su
  • Mengyang Liu
  • Yan Xiong
  • Junqiang Ding
  • Xinrong Liu
  • Yanzhi SongEmail author
  • Yihui DengEmail author
Original Article
  • 39 Downloads

Abstract

Accelerated blood clearance (ABC) is a phenomenon where the blood clearance rate of the carrier system is substantially raised. It can be induced by repetitive injections of polyethylene glycol (PEG) (molecular weight 2000)-modified micelles (PM2000). To determine whether the PEG chain length and PEGylated micelle injection dose can have an effect on the ABC phenomenon, micelles were modified with PEGs of varying molecular weights; PEGs with molecular weights of 350, 550, 2000, 5000, 10,000, and 20,000 were used to generate the PEGylated micelles PM350, PM550, PM2000, PM10000, and PM20000, respectively. One special carrier, MCT-PM2000, was prepared with the original PM2000 formulation but also included extra medium-chain triglycerides. Our experimental results showed that PM2000 and PM5000 exhibit superior storage stability compared to that of PM350, PM550, PM10000, and PM20000. MCT-PM2000 demonstrated stronger dilution stability than PM2000. As expected, PM2000 and PM5000 induced the strongest enhancement in blood elimination rate compared to that of PM350, PM550, PM10000, and PM20000; MCT-PM2000 exhibited more intense ABC phenomenon compared to that of PM2000. In addition, induction of the ABC phenomenon by PM2000 and MCT-PM2000 was augmented when the injection dose was increased from 0.05 to 5 μmol phospholipid·kg−1. Based on our findings, we suggest that there is a positive linear relationship between stability of PEG-modified micelles and susceptibility to the ABC phenomenon. The results may be valuable for designing PEGylated micelles for multiple drug therapy.

Keywords

Accelerated blood clearance PEGylated micelles PEG chain length Lipid dose Anti- PEG IgM 

Abbreviations

5%Glu

5% (m/v) glucose for injection

HLB

the hydrophilic lipophilic balance

CMC

critical micellization concentration;

AUC

area under the curve

MRT

mean residence time

DSPE-PEGx

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-x] (x = 350, 550, 2000, 5000, 10,000 and 20,000)

MCT

medium-chain triglycerides

PM

PEGylated micelles

PE

PEGylated emulsion

PMy (y = 350, 550, 2000, 5000, 10,000 and 20,000)

micelles composed of DSPE-PEGx, x = 350, 550, 2000, 5000, 10,000 and 20,000, respectively

MCT-PM2000

micelles composed of DSPE-PEG2000 with MCT in the inner core (Weight of DSPE-PEG2000 weight of MCT, 14: 1, w/w)

PMy-PE

PMy were pre-administered into rats, and PE were injected 7 days later

PM2000(zCMC)-PE

PM2000 were pre-administered into rats at a dose of z-fold of the CMC of DSPE-PEG2000, and PE were injected 7 days later

MCT-PM2000(zCMC)-PE

MCT-PM2000 were pre-administered into rats at a dose of z-fold of the CMC of DSPE-PEG2000, and PE were injected 7 days later

CMC2000

the CMC value of the DSPE-PEG2000

EE

encapsulation efficiency

Notes

Funding information

This research was supported by the National Natural Science Foundation of China (Grant Nos. 81072602, 81373334).

Compliance with ethical standards

All institutional and national guidelines for the care and use of laboratory animals were followed.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

13346_2018_588_MOESM1_ESM.doc (44 kb)
ESM 1 (DOC 43 kb)

References

  1. 1.
    Dams ET, Laverman P, Oyen WJ, Storm G, Scherphof GL, van der Meer JW, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther. 2000;292(3):1071–9.Google Scholar
  2. 2.
    Ishida T, Maeda R, Ichihara M, Mukai Y, Motoki Y, Manabe Y, et al. The accelerated clearance on repeated injection of pegylated liposomes in rats: laboratory and histopathological study. Cell Mol Biol Lett. 2002;7(2):286.Google Scholar
  3. 3.
    Zhao Y, Wang L, Yan M, Ma Y, Zang G, She Z, et al. Repeated injection of PEGylated solid lipid nanoparticles induces accelerated blood clearance in mice and beagles. Int J Nanomedicine. 2012;7:2891–900.Google Scholar
  4. 4.
    Saadati R, Dadashzadeh S, Abbasian Z, Soleimanjahi H. Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG coating, and encapsulated anticancer drug. Pharm Res. 2013;30(4):985–95.CrossRefGoogle Scholar
  5. 5.
    Wang L, Wang C, Jiao J, Su Y, Cheng X, Huang Z, et al. Tolerance-like innate immunity and spleen injury: a novel discovery via the weekly administrations and consecutive injections of PEGylated emulsions. Int J Nanomedicine. 2014;9:3645–57.Google Scholar
  6. 6.
    Koide H, Asai T, Hatanaka K, Urakami T, Ishii T, Kenjo E, et al. Particle size-dependent triggering of accelerated blood clearance phenomenon. Int J Pharm. 2008;362(1–2):197–200.CrossRefGoogle Scholar
  7. 7.
    Mima Y, Hashimoto Y, Shimizu T, Kiwada H, Ishida T. Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol Pharm. 2015;12(7):2429–35.CrossRefGoogle Scholar
  8. 8.
    Im H-J, England CG, Feng L, Graves SA, Hernandez R, Nickles RJ, et al. Accelerated blood clearance phenomenon reduces the passive targeting of PEGylated nanoparticles in peripheral arterial disease. ACS Appl Mater Interfaces. 2016;8(28):17955–63.CrossRefGoogle Scholar
  9. 9.
    Du N, Guo W, Yu Q, Guan S, Guo L, Shen T, et al. Poly (D, L-lactic acid)-block-poly (N-(2-hydroxypropyl) methacrylamide) nanoparticles for overcoming accelerated blood clearance and achieving efficient anti-tumor therapy. Polym Chem. 2016;7(36):5719–29.CrossRefGoogle Scholar
  10. 10.
    Gaucher G, Dufresne M-H, Sant VP, Kang N, Maysinger D, Leroux J-C. Block copolymer micelles: preparation, characterization and application in drug delivery. J Control Release. 2005;109(1–3):169–88.CrossRefGoogle Scholar
  11. 11.
    Matsumura Y, Hamaguchi T, Ura T, Muro K, Yamada Y, Shimada Y, et al. Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. Brit J Cancer. 2004;91(10):1775–81.CrossRefGoogle Scholar
  12. 12.
    Matsumura Y. Poly (amino acid) micelle nanocarriers in preclinical and clinical studies. Adv Drug Deliv Rev. 2008;60(8):899–914.CrossRefGoogle Scholar
  13. 13.
    Hamaguchi T, Kato K, Yasui H, Morizane C, Ikeda M, Ueno H, et al. A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation. Brit J Cancer. 2007;97(2):170–6.CrossRefGoogle Scholar
  14. 14.
    Shiraishi K, Hamano M, Ma H, Kawano K, Maitani Y, Aoshi T, et al. Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon. J Control Release. 2013;165(3):183–90.CrossRefGoogle Scholar
  15. 15.
    Ma H, Shiraishi K, Minowa T, Kawano K, Yokoyama M, Hattori Y, et al. Accelerated blood clearance was not induced for a gadolinium-containing PEG-poly (L-lysine)-based polymeric micelle in mice. Pharm Res. 2010;27(2):296–302.CrossRefGoogle Scholar
  16. 16.
    Kaminskas LM, Mcleod VM, Porter CJ, Boyd BJ. Differences in colloidal structure of PEGylated nanomaterials dictate the likelihood of accelerated blood clearance. J Pharm Sci. 2011;100(11):5069–77.CrossRefGoogle Scholar
  17. 17.
    Ishida T, Ichikawa T, Ichihara M, Sadzuka Y, Kiwada H. Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice. J Control Release. 2004;95(3):403–12.CrossRefGoogle Scholar
  18. 18.
    Ishida T, Harada M, Wang XY, Ichihara M, Irimura K, Kiwada H. Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes. J Control Release. 2005;105(3):305–17.CrossRefGoogle Scholar
  19. 19.
    Zhao Y, Wang C, Wang L, Yang Q, Tang W, She Z, et al. A frustrating problem: accelerated blood clearance of PEGylated solid lipid nanoparticles following subcutaneous injection in rats. Eur J Pharm Biopharm. 2012;81(3):506–13.CrossRefGoogle Scholar
  20. 20.
    Perrier T, Saulnier P, Fouchet F, Lautram N, Benoît J-P. Post-insertion into lipid nanocapsules (LNCs): from experimental aspects to mechanisms. Int J Pharm. 2010;396(1–2):204–9.CrossRefGoogle Scholar
  21. 21.
    Sezgin Z, Yüksel N, Baykara T. Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs. Eur J Pharm Biopharm. 2006;64(3):261–8.CrossRefGoogle Scholar
  22. 22.
    Wang C, Cheng X, Su Y, Pei Y, Song Y, Jiao J, et al. Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs. Int J Nanomedicine. 2015;10:3533–45.Google Scholar
  23. 23.
    Su Y, Wang L, Liang K, Liu M, Liu X, Song Y, et al. The accelerated blood clearance phenomenon of PEGylated nanoemulsion upon cross administration with nanoemulsions modified with polyglycerin. Asian J Pharm Sci. 2018;13:44–53.CrossRefGoogle Scholar
  24. 24.
    Kim SY, Shin IG, Lee YM, Cho CS, Sung YK. Methoxy poly (ethylene glycol) and ϵ-caprolactone amphiphilic block copolymeric micelle containing indomethacin.: II Micelle formation and drug release behaviours. J Control Release. 1998;51(1):13–22.CrossRefGoogle Scholar
  25. 25.
    Liang K, Wang L, Su Y, Liu M, Feng R, Song Y, et al. Comparison among different “revealers” in the study of accelerated blood clearance phenomenon. Eur J Pharm Sci. 2018;114:210–6.CrossRefGoogle Scholar
  26. 26.
    Sen S, Sukul D, Dutta P, Bhattacharyya K. Solvation dynamics in aqueous polymer solution and in polymer−surfactant aggregate. J Phys Chem B. 2002;106(15):3763–9.CrossRefGoogle Scholar
  27. 27.
    Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, et al. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release. 2006;112(1):15–25.CrossRefGoogle Scholar
  28. 28.
    Ishida T, Wang X, Shimizu T, Nawata K, Kiwada H. PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. J Control Release. 2007;122(3):349–55.CrossRefGoogle Scholar
  29. 29.
    Ishida T, Ichihara M, Wang X, Kiwada H. Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes. J Control Release. 2006;115(3):243–50.CrossRefGoogle Scholar
  30. 30.
    Nicolai T, Colombani O, Chassenieux C. Dynamic polymeric micelles versus frozen nanoparticles formed by block copolymers. Soft Matter. 2010;6(14):3111–8.CrossRefGoogle Scholar
  31. 31.
    Bae YH, Yin H. Stability issues of polymeric micelles. J Control Release. 2008;131(1):2–4.CrossRefGoogle Scholar
  32. 32.
    Semple SC, Harasym TO, Clow KA, Ansell SM, Klimuk SK, Hope MJ. Immunogenicity and rapid blood clearance of liposomes containing polyethylene glycol-lipid conjugates and nucleic acid. J Pharmacol Exp Ther. 2005;312(3):1020–6.CrossRefGoogle Scholar
  33. 33.
    Shimizu T, Ishida T, Kiwada H. Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon. Immunobiology. 2013;218(5):725–32.CrossRefGoogle Scholar
  34. 34.
    Ishida T, Atobe K, Wang X, Kiwada H. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J Control Release. 2006;115(3):251–8.CrossRefGoogle Scholar
  35. 35.
    Kim CJ, Hara E, Shimizu A, Sugai M, Kimura S. Activation of B1a cells in peritoneal cavity by T cell-independent antigen expressed on polymeric micelle. J Pharm Sci. 2015;104(5):1839–47.CrossRefGoogle Scholar
  36. 36.
    Kaminskas LM, Mcleod VM, Porter H, Christopher J, Boyd BJ. Differences in colloidal structure of PEGylated nanomaterials dictate the likelihood of accelerated blood clearance. J Pharm Sci. 2011;100(11):5069–77.CrossRefGoogle Scholar
  37. 37.
    Hashimoto Y, Shimizu T, Lila ASA, Ishida T, Kiwada H. Relationship between the concentration of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) and the intensity of the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes in mice. Biol Pharm Bull. 2015;38(3):417–24.CrossRefGoogle Scholar
  38. 38.
    Ishida T, Kashima S, Kiwada H. The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. J Control Release. 2008;126(2):162–5.CrossRefGoogle Scholar
  39. 39.
    Hara E, Ueda M, Makino A, Hara I, Ozeki E, Kimura S. Factors influencing in vivo disposition of polymeric micelles on multiple administrations. ACS Med Chem Lett. 2014;5(8):873–7.CrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  1. 1.School of PharmacyShenyang Pharmaceutical UniversityBenxiPeople’s Republic of China

Personalised recommendations