Original articles
Xiangjun Meng, Zhi Zhang, Jin Tong, Hui Sun, John Paul Fawcett, Jingkai Gu. The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) in rat[J]. Acta Pharmaceutica Sinica B, 2021, 11(4): 1003-1009

The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) in rat
Xiangjun Menga,c, Zhi Zhanga, Jin Tonga, Hui Suna, John Paul Fawcetta, Jingkai Gua,b
a Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China;
b Beijing Institute of Drug Metabolism, Beijing 102209, China;
c School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-PLA) is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier (nanocarrier) in drug delivery. Understanding the in vivo fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery systems. However, acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of PEG-PLA. In this study, the pharmacokinetics, biodistribution, metabolism and excretion of PEG-PLA were investigated in rat after intravenous administration. The results show that unchanged PEG-PLA is mainly distributed to spleen, liver, and kidney before being eliminated in urine over 48 h mainly (>80%) in the form of its PEG metabolite. Our study provides a clear and comprehensive picture of the in vivo fate of PEG-PLA which we anticipate will facilitate the scientific design and safety evaluation of PEG-PLA-based nanocarrier drug delivery systems and thereby enhance their clinical development.
Key words:    Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)    Polymer    Nanocarrier material    Pharmacokinetics    Biodistribution    Metabolism    Excretion    Rat   
Received: 2020-11-01     Revised: 2020-12-23
DOI: 10.1016/j.apsb.2021.02.018
Funds: This work was supported by the National Natural Science Foundation of China (Grant Nos. 81872831 and 82030107) and the National Science and Technology Major Projects for significant new drugs creation of the 13th five-year plan (2017ZX09101001 and 2018ZX09721002007, China).
Corresponding author: Jingkai Gu, gujk@jlu.edu.cn     Email:gujk@jlu.edu.cn
Author description:
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Xiangjun Meng
Zhi Zhang
Jin Tong
Hui Sun
John Paul Fawcett
Jingkai Gu

1. Su H, Wang Y, Liu S, Wang Y, Liu Q, Liu G, et al. Emerging transporter-targeted nanoparticulate drug delivery systems. Acta Pharm Sin B 2019;9:49-58.
2. Zhao QH, Qiu LY. An overview of the pharmacokinetics of polymerbased nanoassemblies and nanoparticles. Curr Drug Metab 2013;14:832-9.
3. Wang AZ, Langer R, Farokhzad OC. Nanoparticle delivery of cancer drugs. Annu Rev Med 2012;63:185-98.
4. Liu GW, Prossnitz AN, Eng DG, Cheng Y, Subrahmanyam N, Pippin JW, et al. Glomerular disease augments kidney accumulation of synthetic anionic polymers. Biomaterials 2018;178:317-25.
5. Li J, Burgess DJ. Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment. Acta Pharm Sin B 2020;10:2110-24.
6. Buggins TR, Dickinson PA, Taylor G. The effects of pharmaceutical excipients on drug disposition. Adv Drug Deliv Rev 2007;59:1482-503.
7. Goole J, Lindley DJ, Roth W, Carl SM, Amighi K, Kauffmann JM, et al. The effects of excipients on transporter mediated absorption. Int J Pharm 2010;393:17-31.
8. Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm 2004;278:119-31.
9. Ren X, Mao X, Si L, Cao L, Xiong H, Qiu J, et al. Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration. Eur J Pharm Biopharm 2008;70:279-88.
10. Huang WX, Desai M, Tang Q, Yang R, Vivilecchia RV, Joshi Y. Elimination of metformin-croscarmellose sodium interaction by competition. Int J Pharm 2006;311:33-9.
11. Rafiei P, Haddadi A. Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application:pharmacokinetics and biodistribution profile. Int J Nanomedicine 2017;12:935-47.
12. Wang Q, Liu Y, Pu C, Zhang H, Tan X, Gou J, et al. Drug-polymer interaction, pharmacokinetics and antitumor effect of PEGPLA/taxane derivative TM-2 micelles for intravenous drug delivery. Pharm Res 2018;35:208.
13. Balachandra A, Chan EC, Paul JP, Ng S, Chrysostomou V, Ngo S, et al. A biocompatible reverse thermoresponsive polymer for ocular drug delivery. Drug Deliv 2019;26:343-53.
14. Singh P, Carrier A, Chen Y, Lin S, Wang J, Cui S, et al. Polymeric microneedles for controlled transdermal drug delivery. J Control Release 2019;315:97-113.
15. Rajput MKS, Kesharwani SS, Kumar S, Muley P, Narisetty S, Tummala H. Dendritic cell-targeted nanovaccine delivery system prepared with an immune-active polymer. ACS Appl Mater Interfaces 2018;10:27589-602.
16. Battistella C, Klok HA. Controlling and monitoring intracellular delivery of anticancer polymer nanomedicines. Macromol Biosci 2017; 17.
17. Dou T, Wang J, Han C, Shao X, Zhang J, Lu W. Cellular uptake and transport characteristics of chitosan modified nanoparticles in Caco-2 cell monolayers. Int J Biol Macromol 2019;138:791-9.
18. Wang T, Guo Y, He Y, Ren T, Yin L, Fawcett JP, et al. Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein. Acta Pharm Sin B 2020;10:2002-9.
19. Kermanizadeh A, Balharry D, Wallin H, Loft S, Møller P. Nanomaterial translocation-the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organsda review. Crit Rev Toxicol 2015;45:837-72.
20. Martin P, Giardiello M, McDonald TO, Rannard SP, Owen A. Mediation of in vitro cytochrome p450 activity by common pharmaceutical excipients. Mol Pharm 2013;10:2739-48.
21. Qiu L, Li Q, Huang J, Wu Q, Tu K, Wu Y, et al. In vitro effect of mPEG(2k)-PCL(x) micelles on rat liver cytochrome P450 enzymes. Int J Pharm 2018;552:99-110.
22. Li W, Li X, Gao Y, Zhou Y, Ma S, Zhao Y, et al. Inhibition mechanism of P-glycoprotein mediated efflux by mPEG-PLA and influence of PLA chain length on P-glycoprotein inhibition activity. Mol Pharm 2014;11:71-80.
23. Li L, Yi T, Lam CW. Interactions between human multidrug resistance related protein (MRP2; ABCC2) and excipients commonly used in self-emulsifying drug delivery systems (SEDDS). Int J Pharm 2013; 447:192-8.
24. Stevanović M, Maksin T, Petković J, Filipic M, Uskoković D. An innovative, quick and convenient labeling method for the investigation of pharmacological behavior and the metabolism of poly(D,L-lactideco-glycolide) nanospheres. Nanotechnology 2009;20:335102.
25. Peracchia MT, Fattal E, Desmaële D, Besnard M, Noël JP, Gomis JM, etal.StealthPEGylatedpolycyanoacrylatenanoparticlesforintravenous administration and splenic targeting. J Control Release 1999;60:121-8.
26. Drasler B, Vanhecke D, Rodriguez-Lorenzo L, Petri-Fink A, RothenRutishauser B. Quantifying nanoparticle cellular uptake:which method is best?. Nanomedicine (Lond) 2017;12:1095-9.
27. Oerlemans C, Bult W, Bos M, Storm G, Nijsen JF, Hennink WE. Polymeric micelles in anticancer therapy:targeting, imaging and triggered release. Pharm Res 2010;27:2569-89.
28. Kore G, Kolate A, Nej A, Misra A. Polymeric micelle as multifunctional pharmaceutical carriers. J Nanosci Nanotechnol 2014;14:288-307.
29. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res 1993;10:1093-5.
30. Fraser JR, Laurent TC, Pertoft H, Baxter E. Plasma clearance, tissue distribution and metabolism of hyaluronic acid injected intravenously in the rabbit. Biochem J 1981;200:415-24.
31. Wood KM, Wusteman FS, Curtis CG. The degradation of intravenously injected chondroitin 4-sulphate in the rat. Biochem J 1973;134:1009-13.
32. Moghimi SM, Hunter AC. Capture of stealth nanoparticles by the body's defences. Crit Rev Ther Drug Carrier Syst 2001;18:527-50.
33. Popielarski SR, Hu-Lieskovan S, French SW, Triche TJ, Davis ME. A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 2. In vitro and in vivo uptake results. Bioconjug Chem 2005;16:1071-80.
34. Tsuji H, Ikarashi K. In vitro hydrolysis of poly(L-lactide) crystalline residues as extended-chain crystallites. Part I:long-term hydrolysis in phosphate-buffered solution at 37 degrees C. Biomaterials 2004;25:5449-55.
35. Gillet LC, Navarro P, Tate S, Röst H, Selevsek N, Reiter L, et al. Targeted data extraction of the MS/MS spectra generated by dataindependent acquisition:a new concept for consistent and accurate proteome analysis. Mol Cell Proteomics 2012;11. O111.016717.
36. Letchford K, Burt H. A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures:micelles, nanospheres, nanocapsules and polymersomes. Eur J Pharm Biopharm 2007;65:259-69.
37. Sharma D, Singh J. Long-term glycemic control and prevention of diabetes complications in vivo using oleic acid-grafted-chitosan-zincinsulin complexes incorporated in thermosensitive copolymer. J Control Release 2020;323:161-78.
38. Zhu X, Chen Y, Subramanian R. Comparison of informationdependent acquisition, SWATH, and MS(All) techniques in metabolite identification study employing ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Anal Chem 2014;86:1202-9.
39. Gao F, McDaniel J, Chen EY, Rockwell HE, Nguyen C, Lynes MD, et al. Adapted MS/MS(ALL) shotgun lipidomics approach for analysis of cardiolipin molecular species. Lipids 2018;53:133-42.
40. Zhou X, Meng X, Cheng L, Su C, Sun Y, Sun L, et al. Development and application of an MS(ALL)-based approach for the quantitative analysis of linear polyethylene glycols in rat plasma by liquid chromatography triple-quadrupole/time-of-flight mass spectrometry. Anal Chem 2017;89:5193-200.
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