Hyaluronic Acid-Based Nanogels Produced by Microfluidics-Facilitated Self-Assembly Improves the Safety Profile of the Cationic Host Defense Peptide Novicidin

Abstract

Purpose

Cationic host defence peptides constitute a promising class of therapeutic drug leads with a wide range of therapeutic applications, including anticancer therapy, immunomodulation, and antimicrobial activity. Although potent and efficacious, systemic toxicity and low chemical stability have hampered their commercial development. To overcome these challenges a novel nanogel-based drug delivery system was designed.

Method

The peptide novicidin was self-assembled with an octenyl succinic anhydride-modified analogue of hyaluronic acid, and this formulation was optimized using a microfluidics-based quality-by-design approach.

Results

By applying design-of-experiment it was demonstrated that the encapsulation efficiency of novicidin (15% to 71%) and the zeta potential (−24 to −57 mV) of the nanogels could be tailored by changing the preparation process parameters, with a maximum peptide loading of 36 ± 4%. The nanogels exhibited good colloidal stability under different ionic strength conditions and allowed complete release of the peptide over 14 days. Furthermore, self-assembly of novicidin with hyaluronic acid into nanogels significantly improved the safety profile at least five-fold and six-fold when tested in HUVECs and NIH 3T3 cells, respectively, whilst showing no loss of antimicrobial activity against Escherichia coli and Staphylococcus aureus.

Conclusion

Formulation in nanogels could be a viable approach to improve the safety profile of host defence peptides.

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Abbreviations

DLS:

Dynamic light scattering

DMEM:

Dulbecco’s modified Eagle’s medium

DoE:

Design of experiment

EE%:

Encapsulation efficiency

FBS:

Fetal bovine serum

HBSS:

Hank’s balanced salt solution

HDPs:

Host defense peptides

HUVEC:

Human umbilical vein endothelial cell

MIC:

Minimum inhibitory concentration

MLR:

Multiple linear regression

NTA:

Nanoparticle tracking analysis

OSA-HA:

Octenyl succinic anhydride-modified hyaluronic acid

TEM:

Transmission electron microscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge Prof. Robert Langer at MIT for his generous support and discussion on the use of microfluidic devices. We also acknowledge Karina Juul Vissing, Thara Qais Hussein and Maria Læssøe Pedersen for their technical support. Pall Thor Ingvarsson, PhD, is acknowledged for assistance with the experimental design; The Danish Agency for Science and Technology and Innovation (DanCARD, grant no. 06-097075) for financial support, The Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen for providing access to imaging facilities and Adam Bohr, PhD, for his assistance. Lastly, Innovation Fund Denmark (041-2010-3) is acknowledged for co-financing the HPLC system.

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Correspondence to Hanne M. Nielsen.

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Water, J.J., Kim, Y., Maltesen, M.J. et al. Hyaluronic Acid-Based Nanogels Produced by Microfluidics-Facilitated Self-Assembly Improves the Safety Profile of the Cationic Host Defense Peptide Novicidin. Pharm Res 32, 2727–2735 (2015). https://doi.org/10.1007/s11095-015-1658-6

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KEY WORDS

  • antimicrobial peptides
  • hyaluronic acid
  • hydrogel nanoparticles
  • microfluidics
  • nanogels