In vivo Studies on Pharmacokinetics, Toxicity and Immunogenicity of Polyelectrolyte Nanocapsules Functionalized with Two Different Polymers: Poly-L-Glutamic Acid or PEG
Received 13 September 2019
Accepted for publication 19 October 2019
Published 5 December 2019 Volume 2019:14 Pages 9587—9602
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Mr Davin Leif
Peer reviewer comments 2
Editor who approved publication: Dr Thomas Webster
Alicja Karabasz,1 Krzysztof Szczepanowicz,2 Agnieszka Cierniak,3,4 Renata Mezyk-Kopec,1 Grzegorz Dyduch,5 Marta Szczęch,2 Joanna Bereta,1 Monika Bzowska1
1Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland; 2Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Kraków, Poland; 3Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland; 4Department of Biochemistry, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland; 5Department of Pathomorphology, Jagiellonian University Medical College, Kraków, Poland
Correspondence: Monika Bzowska
Department of Cell Biochemistry, Faculty of Biochemistry, Jagiellonian University in Kraków, Biophysics and Biotechnology, 7 Gronostajowa Street, Kraków 30-387, Poland
Tel/Fax +48 12 664 63 88
Background: The functionalization of a nanoparticle surface with PEG (polyethylene glycol) is an approach most often used for extending nanomaterial circulation time, enhancing its delivery and retention in the target tissues, and decreasing systemic toxicity of nanocarriers and their cargos. However, because PEGylated nanomedicines were reported to induce immune response including production of anti-PEG antibodies, activation of the complement system as well as hypersensitivity reactions, hydrophilic polymers other than PEG are gaining interest as its replacement in nanomaterial functionalization. Here, we present the results of in vivo evaluation of polyelectrolyte nanocapsules with biodegradable, polyelectrolyte multilayer shells consisting of poly-l-lysine (PLL) and poly-l-glutamic (PGA) acid as a potential drug delivery system. We compared the effects of nanocapsules functionalized with two different “stealth” polymers as the external layer of tested nanocapsules was composed of PGA (PGA-terminated nanocapsules, NC-PGA) or the copolymer of poly-l-lysine and polyethylene glycol (PEG-terminated nanocapsules, NC-PEG).
Methods: Nanocapsules pharmacokinetics, biodistribution and routes of eliminations were analysed postmortem by fluorescence intensity measurement. Toxicity of intravenously injected nanocapsules was evaluated with analyses of blood morphology and biochemistry and by histological tissue analysis. DNA integrity was determined by comet assay, cytokine profiling was performed using flow cytometer and detection of antibodies specific to PEG was performed by ELISA assay.
Results: We found that NC-PGA and NC-PEG had similar pharmacokinetic and biodistribution profiles and both were eliminated by hepatobiliary and renal clearance. Biochemical and histopathological evaluation of long-term toxicity performed after a single as well as repeated intravenous injections of nanomaterials demonstrated that neither NC-PGA nor NC-PEG had any acute or chronic hemato-, hepato- or nephrotoxic effects. In contrast to NC-PGA, repeated administration of NC-PEG resulted in prolonged increased serum levels of a number of cytokines.
Conclusion: Our results indicate that NC-PEG may cause undesirable activation of the immune system. Therefore, PGA compares favorably with PEG in equipping nanomaterials with stealth properties. Our research points to the importance of a thorough assessment of the potential influence of nanomaterials on the immune system.
Keywords: polyelectrolyte nanocapsules, stealth polymers, animal studies
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