Ki Hyun Baea, Fan Leea, Keming Xua, Choong Tat Kengb, Sue Yee Tanb, Yee Joo Tanb,c, Qingfeng Chenb,c,d,*, and Motoichi Kurisawaa,*
a Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669.
* To whom correspondence should be addressed.
b Institute of Molecular and Cell Biology, 61 Biopolis Drive, The Proteos, Singapore 138673.
c Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
d Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore 138602.
Email: firstname.lastname@example.org, email@example.com
Published in Biomaterials in September 2015, Volume 63, Pages 146–157.
There is a lack of animal models to test the safety and efficacy of drugs which specifically target human. We developed humanized mice to directly conduct pharmacokinetics and biocompatibility studies of human PEG-IFN-α2a in vivo. These mice were established by adoptive transfer of human CD34+ fetal liver cells into NOD-scid Il2rg-/- mice. Such humanized mice with a functional human immune system allow assessment of the efficacy and safety of human therapeutic proteins in a physiologically relevant manner without immunogenicity problems. Following subcutaneous (s.c.) injection of PEG-IFN-α2a solution, its plasma concentration reached a peak within 1 day and declined to undetectable levels after 2 weeks. The mice implanted with Dex-Tyr hydrogels showed a similar trend, suggesting that PEG-IFN-α2a loaded in these hydrogels was quickly diffused out and cleared from the bloodstream. In contrast, a one-time administration of Dex-Tyr/PEG hydrogels resulted in prolonged circulation of PEG-IFN-α2a for 7 weeks. Furthermore, these hydrogels significantly increased the plasma half-life of PEG-IFN-α2a from 1.5 ± 0.2 to 15.6 ± 1.4 days. Therefore, these results demonstrated that Dex-Tyr/PEG hydrogels enabled continuous release of the encapsulated PEG-IFN-α2a in vivo. The PEG-IFN-α2a-loaded Dex-Tyr/PEG hydrogels also show therapeutic effects in a humanized mouse model of hepatitis C.
Pharmacokinetics and therapeutic effect of PEG-IFN-α2a in humanized mice. (A) Plasma concentration-time profiles following subcutaneous administration of PEG-IFN-α2a solution, Dex-Tyr hydrogels or Dex-Tyr/PEG hydrogels with 3 μm domains. (B) Plasma half-life of PEG-IFN-α2a determined from pharmacokinetics analysis. Results are presented as mean ± SD (n = 3). *P < 0.005 vs. PEG-IFN-α2a alone or Dex-Tyr hydrogels. (C and D) H&E (C) and Sirius Red (D) stained liver sections from uninfected humanized mice and HCV-infected humanized mice treated with PBS, PEG-IFN-α2a (a one-time, monthly or weekly subcutaneous injection) or Dex-Tyr/PEG hydrogels (a one-time subcutaneous implantation). Scale bars, 100 μm. (E) Serum levels of ALT in humanized mice with treatments. Results are presented as mean ± SEM (n = 5). Significance levels were set at: *P < 0.05 and **P < 0.005.
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