Abstract
Polyethylene glycol (PEG) is a multifunctional polymer that has many uses in medical and biological applications. Recently, PEG has been mainly used in developing nanomaterial-based drug delivery systems (DDS). PEG is characterized by its high solubility, biological inertness, and ability to escape from immune cells (stealthiness) after systemic injection. The most challenging problem for PEGylated nanomaterials is their rapid elimination from the bloodstream after repeated doses of systemic injection, called accelerated blood clearance (ABC). Therefore, in this study, the effect of PEGylated nanomaterial dose concentration on ABC induction will be investigated using quantitative, histological, and immunohistochemical analyses. A higher dose concentration (2 mg/kg) of PEGylated gold nanoparticles (PEG-coated AuNPs) reduced the ABC phenomenon when intravenously injected into mice preinjected with the same dose. In contrast, a lower dose concentration (< 1 mg/kg) significantly induced the ABC phenomenon by the rapid elimination of the second dose of PEG-coated AuNPs from the bloodstream. To explain the relationship between the dose concentration (from PEG and AuNPs) and the induction of ABC, the biodistribution of PEG-coated AuNPs in liver and spleen [reticuloendothelial systems (RES)-rich organs] was investigated. The injected dose of PEG-coated AuNPs accumulated mainly in the hepatic Kupffer cells and hepatocytes. Similarly, spleen red pulp received a higher amount of the injected dose of PEG-coated AuNPs. However, the biodistriution profiles of PEG-coated AuNPs after the first and second dose for different dose concentrations varied in RES-rich organs. Additionally, the number of B lymphocytes, which have an important role in producing anti-PEG immunoglobulin (Ig)M, was affected by the repeated dose of PEG-coated AuNPs in the spleen. Therefore, for effective nanomaterial-based DDS development, dose optimization of PEG molecules that express PEGylated nanomaterials is important to reduce the ABC phenomenon effect. The ideal concentration of PEG molecules used to coat nanomaterials and the role of RES-rich organs must be determined to control the ABC phenomenon effect of PEGylated nanomaterials.
Similar content being viewed by others
References
Abu Lila AS, Kiwada H, Ishida T (2013) The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J Control Release 172:38–47. https://doi.org/10.1016/j.jconrel.2013.07.026
Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 5:505–515. https://doi.org/10.1021/mp800051m
Awaad A (2015) Histopathological and immunological changes induced by magnetite nanoparticles in the spleen, liver and genital tract of mice following intravaginal instillation. J Basic Appl Zool 71C:32–47. https://doi.org/10.1016/j.jobaz.2015.03.003
Awaad A, Adly MA, Hosny D (2018) Spleen immunotoxicities induced by intratesticular injection of magnetic nanoparticles and the role of Echinacea purpurea extract: a histological and immunohistochemical study. J Histotechnology 41:94–110. https://doi.org/10.1080/01478885.2018.1472857
Borges da Silva H, Fonseca R, Pereira RM, Cassado Ados A, Álvarez JM, D’Império Lima MR (2015) Splenic macrophage subsets and their function during blood-borne infections. Front Immunol 6:480. https://doi.org/10.3389/fimmu.2015.00480
Cesta MF (2006) Normal structure, function, and histology of the spleen. Toxicol Pathol 34:455–465. https://doi.org/10.1080/01926230600867743
Chen D, Ganesh S, Wang W, Amiji M (2019) The role of surface chemistry in serum protein corona-mediated cellular delivery and gene silencing with lipid nanoparticles. Nanoscale 11:8760–8775. https://doi.org/10.1039/C8NR09855G
Cheng X, Wang C, Su Y, Luo X, Liu X, Song Y, Deng Y (2018) Enhanced opsonization-independent phagocytosis and high response ability to opsonized antigen-antibody complexes: a new role of Kupffer cells in the accelerated blood clearance phenomenon upon repeated injection of PEGylated emulsions. Mol Pharm 15:3755–3766. https://doi.org/10.1021/acs.molpharmaceut.8b00019
Chrai SS, Murari R, Ahmad I (2002) Liposomes (a review) part two: drug delivery systems. BioPharm Int 15:40–43
Dykman L, Khlebtsov N (2012) Gold nanoparticles in biomedical applications: recent advances and perspectives. Chem Soc Rev 41:2256–2282
Feng Q, Liu Y, Huang J, Chen K, Huang J, Xiao K (2018) Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. Sci Rep 8:2082
Ghosh P, Han G, De M, Kim CK, Rotello VM (2008) Gold nanoparticles in delivery applications. Adv Drug Deliv Rev 60:1307–1315. https://doi.org/10.1016/j.addr.2008.03.016
Hamasaki S, Kobori T, Yamazaki Y et al (2018) Effects of scavenger receptors-1 class A stimulation on macrophage morphology and highly modified advanced glycation end product-protein phagocytosis. Sci Rep 8:5901. https://doi.org/10.1038/s41598-018-24325-y
Ishida T, Harashima H, Kiwada H (2001) Interactions of liposomes with cells in vitro and in vivo: opsonins and receptors. Curr Drug Metab 2:397–409
Ishida T, Harada M, Wang XY, Ichihara M, Irimura K, Kiwada H (2005) 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 105:305–317. https://doi.org/10.1016/j.jconrel.2005.04.003
Ishida T, Atobe K, Wang X, Kiwada H (2006) Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J Control Release 15:251–258. https://doi.org/10.1016/j.jconrel.2006.08.017
Ishida T, Wang X, Shimizu T, Nawata K, Kiwada H (2007) PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. J Control Release 122:349–355. https://doi.org/10.1016/j.jconrel.2007.05.015
Ishida T, Kashima S, Kiwada H (2008) The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. J Control Release 126:162–165. https://doi.org/10.1016/j.jconrel.2007.11.009
Israelachvili J (1997) The different faces of poly(ethylene glycol). Proc Natl Acad Sci USA 94:8378–8379. https://doi.org/10.1073/pnas.94.16.8378
Kamps JA, Kruijt JK, Kuiper J, Van Berkel TJ (1991) Uptake and degradation of human low-density lipoprotein by human liver parenchymal and Kupffer cells in culture. Biochem J 276:135–140. https://doi.org/10.1042/bj2760135
Kierstead PH, Okochi H, Venditto VJ et al (2015) The effect of polymer backbone chemistry on the induction of the accelerated blood clearance in polymer modified liposomes. J Control Release 213:1–9. https://doi.org/10.1016/j.jconrel.2015.06.023
Kim E, Koo H (2019) Biomedical applications of copper-free click chemistry: in vitro, in vivo, and ex vivo. Chem Sci 10:7835–7851. https://doi.org/10.1039/C9SC03368H
Kim JH, Sim GS, Bae JT et al (2008) Synthesis and anti-melanogenic effects of lipoic acid-polyethylene glycol ester. J Pharm Pharmacol 60:863–870. https://doi.org/10.1211/jpp.60.7.0007
Klibanov AL, Maruyama K, Beckerleg AM, Torchilin VP, Huang L (1991) Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim Biophys Acta 1062:142–148. https://doi.org/10.1016/0005-2736(91)90385-L
Koide H, Asai T, Hatanaka K et al (2008) Particle size-dependent triggering of accelerated blood clearance phenomenon. Int J Pharm 362:197–200. https://doi.org/10.1016/j.ijpharm.2008.06.004
Koide H, Asai T, Hatanaka K et al (2010) T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes. Int J Pharm 392:218–223. https://doi.org/10.1016/j.ijpharm.2010.03.022
Laverman P, Carstens MG, Boerman OC et al (2001) Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharmacol Exp Ther 298:607–612
Lopes TCM, Silva DF, Costa WC et al (2018) Accelerated blood clearance (ABC) phenomenon favors the accumulation of tartar emetic in Pegylated liposomes in BALB/c mice liver. Patholog Res Int 2018:7. https://doi.org/10.1155/2018/9076723
Martin F, Oliver AM, Kearney JF (2001) Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14:617–629. https://doi.org/10.1016/S1074-7613(01)00129-7
Maruyama K, Yuda T, Okamoto A, Kojima S, Suginaka A, Iwatsuru M (1992) Prolonged circulation time in vivo of large unilamellar liposomes composed of distearoyl phosphatidylcholine and cholesterol containing amphipathic poly(ethylene glycol). Biochim Biophys Acta 1128:44–49. https://doi.org/10.1016/0005-2760(92)90255-T
Mima Y, Hashimoto Y, Shimizu T, Kiwada H, Ishida T (2015) Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol Pharm 12:2429–2435. https://doi.org/10.1021/acs.molpharmaceut.5b00144
Nenseter MS, Gudmundsen O, Roos N, Maelandsmo G, Drevon CA, Berg T (1992) Role of liver endothelial and Kupffer cells in clearing low density lipoprotein from blood in hypercholesterolemic rabbits. J Lipid Res 33:867–877. https://doi.org/10.1016/S0022-2275(20)41512-3
Nie Q, Jia D, Yang H et al (2017) Conjugation to 10 kDa linear PEG extends serum half-life and preserves the receptor-binding ability of mmTRAIL with minimal stimulation of PEG-specific antibodies. Mol Pharm 14:502–512. https://doi.org/10.1021/acs.molpharmaceut.6b00964
Patsula V, Horák D, Kučka J et al (2019) Synthesis and modification of uniform PEG-neridronate-modified magnetic nanoparticles determines prolonged blood circulation and biodistribution in a mouse preclinical model. Sci Rep 9:10765. https://doi.org/10.1038/s41598-019-47262-w
Perrault SD, Walkey C, Jennings T, Fischer HC, Chan WC (2009) Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett 9:1909–1915. https://doi.org/10.1021/nl900031y
Poste G, Papahadjopoulos D, Vail WJ (1976) Lipid vesicles as carriers for introducing biologically active materials into cells. Methods Cell Biol 14:33–71. https://doi.org/10.1016/S0091-679X(08)60468-9
Sapra P, Allen TM (2003) Ligand-targeted liposomal anticancer drugs. Prog Lipid Res 42:439–462. https://doi.org/10.1016/S0163-7827(03)00032-8
Schöttler S, Becker G, Winzen S et al (2016) Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat Nanotechnol 11:372–377
Senior JH (1987) Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst 3:123–193
Shimada K, Miyagishima A, Sadzuka Y et al (1995) Determination of the thickness of the fixed aqueous layer around polyethyleneglycol-coated liposomes. J Drug Target 3:283–289. https://doi.org/10.3109/10611869509015957
Shimizu T, Ishida T, Kiwada H (2013) Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon. Immunobiology 218:725–732. https://doi.org/10.1016/j.imbio.2012.08.274
Singh R, Norret M, House MJ et al (2016) Dose-dependent therapeutic distinction between active and passive targeting revealed using transferrin-coated PGMA nanoparticles. Small 12:351–359. https://doi.org/10.1002/smll.201502730
Su Y, Liu M, Liang K, Liu X, Song Y, Deng Y (2018a) Evaluating the accelerated blood clearance phenomenon of PEGylated nanoemulsions in rats by intraperitoneal administration. AAPS PharmSciTech 19:3210–3218. https://doi.org/10.1208/s12249-018-1120-2
Su Y, Wang L, Liang K et al (2018b) The accelerated blood clearance phenomenon of PEGylated nanoemulsion upon cross administration with nanoemulsions modified with polyglycerin. Asian J Pharm Sci 13:44–53. https://doi.org/10.1016/j.ajps.2017.07.003
Verhoef JJ, Anchordoquy TJ (2013) Questioning the use of PEGylation for drug delivery. Drug Deliv Transl Res 3:499–503
Wang C, Cheng X, Su Y et al (2015) Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs. Int J Nanomedicine 10:3533–3545. https://doi.org/10.2147/IJN.S82481
Wang FL, Ye X, Wu YF, Wang HH, Sheng CM, Peng DY, Chen WD (2019) Pharmacokinetics, pharmacodynamics and drug transport and metabolism time interval of two injections and first-dose dependent of accelerated blood clearance phenomenon induced by PEGylated liposomal gambogenic acid: the contribution of PEG-specific IgM. J Pharm Sci 108:641–651. https://doi.org/10.1016/j.xphs.2018.10.027
Webster R, Elliott V, Park BK, Walker D, Hankin M, Taupin P (2009) PEG and PEG conjugates toxicity: towards an understanding of the toxicity of PEG and its relevance to PEGylated biologicals. In: Veronese FM (ed) PEGylated protein drugs: basic science and clinical applications milestones in drug therapy. Birkhäuser, Basel. https://doi.org/10.1007/978-3-7643-8679-5_8
Xu H, Ye F, Hu M et al (2015) Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection. Drug Deliv 22:598–607. https://doi.org/10.3109/10717544.2014.885998
Yang W, Liu S, Bai T, Keefe AJ, Zhang L et al (2014) Poly(carboxybetaine) nanomaterials enable long circulation and prevent polymer-specific antibody production. Nano Today 9:10–16. https://doi.org/10.1016/j.nantod.2014.02.004
Yip V, Palma E, Tesar DB et al (2014) Quantitative cumulative biodistribution of antibodies in mice: effect of modulating binding affinity to the neonatal Fc receptor. Mabs 6:689–696. https://doi.org/10.4161/mabs.28254
Zamora-Justo JA, Abrica-González P, Vázquez-Martínez GR, Muñoz-Diosdado A, Balderas-López JA, Ibáñez-Hernández MA (2019) Polyethylene glycol-coated gold nanoparticles as DNA and atorvastatin delivery systems and cytotoxicity evaluation. J Nanomaterials 2019:1–11. https://doi.org/10.1155/2019/5982047
Zandvoort A, Timens W (2002) The dual function of the splenic marginal zone: essential for initiation of anti-TI-2 responses but also vital in the general first-line defense against blood-borne antigens. Clin Exp Immunol 130:4–11. https://doi.org/10.1046/j.1365-2249.2002.01953.x
Acknowledgements
The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number 14/442. Also, the authors would like to extend their appreciation to Taibah University for its supervision support.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Abu-Dief, A.M., Alsehli, M. & Awaad, A. A higher dose of PEGylated gold nanoparticles reduces the accelerated blood clearance phenomenon effect and induces spleen B lymphocytes in albino mice. Histochem Cell Biol 157, 641–656 (2022). https://doi.org/10.1007/s00418-022-02086-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00418-022-02086-0