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Construction and in vivo/in vitro evaluation of a nanoporous ion-responsive targeted drug delivery system for recombinant human interferon α-2b delivery

Authors Liu H, Zhu J, Bao P, Ding Y, Shen Y, Webster TJ, Xu Y

Received 22 March 2019

Accepted for publication 13 June 2019

Published 16 July 2019 Volume 2019:14 Pages 5339—5353

DOI https://doi.org/10.2147/IJN.S209646

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo


Hongfei Liu,1 Jie Zhu,1 Pengyue Bao,2 Yueping Ding,3 Yan Shen,4 Thomas J Webster,5 Ying Xu1

1College of Pharmacy, Jiangsu University, Zhenjiang 212013, People’s Republic of China; 2Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing 210023, People’s Republic of China; 3Jiangsu Sihuan Biopharmaceutical Co., Ltd, Wuxi 214000, People’s Republic of China; 4State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 5Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA

Background: Like most protein macromolecular drugs, the half-life of rhIFNɑ-2b is short, with a low drug utilization rate, and the preparation and release conditions significantly affect its stability.
Methods: A nanoporous ion-responsive targeted drug delivery system (PIRTDDS) was designed to improve drug availability of rhIFNα-2b and target it to the lung passively with sustained release. Chitosan rhIFNα-2b carboxymethyl nanoporous microspheres (CS-rhIFNα-2b-CCPM) were prepared by the column method. Here, an electrostatic self-assembly technique was undertaken to improve and sustain rhIFNα-2b release rate.
Results: The size distribution of the microspheres was 5∼15 μm, and the microspheres contained nanopores 300∼400 nm in diameter. The in vitro release results showed that rhIFNα-2b and CCPM were mainly bound by ionic bonds. After self-assembling, the release mechanism was transformed into being membrane diffusion. The accumulative release amount for 24 hrs was 83.89%. Results from circular dichrogram and SDS-PAGE electrophoresis showed that there was no significant change in the secondary structure and purity of rhIFNα-2b. Results from inhibition rate experiments for A549 cell proliferation showed that the antitumor activity of CS-rhIFNα-2b-CCPM for 24 hrs retained 91.98% of the stock solution, which proved that the drug-loaded nanoporous microspheres maintained good drug activity. In vivo pharmacokinetic experimental results showed that the drugs in CS-rhIFNα-2b-CCPM can still be detected in vivo after 24 hrs, equivalent to the stock solution at 6 hrs, which indicated that CS-rhIFNα-2b-CCPM had a certain sustained-release effect in vivo. The results of in vivo tissue distribution showed that CS-rhIFNα-2b-CCPM was mainly concentrated in the lungs of mice (1.85 times the stock solution). The pharmacodynamics results showed that CS-rhIFNα-2b-CCPM had an obvious antitumor effect, and the tumor inhibition efficiency was 29.2%.
Conclusion: The results suggested a novel sustained-release formulation with higher drug availability and better lung targeting from CS-rhIFNα-2b-CCPM compared to the reference (the stock solution of rhIFNα-2b), and, thus, should be further studied.

Keywords: nanoporous, ion-responsive, recombinant human interferon α-2b, ion exchange technique, sustained release, lung targeting


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