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



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.


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.


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.


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

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Dynamic light scattering


Dulbecco’s modified Eagle’s medium


Design of experiment


Encapsulation efficiency


Fetal bovine serum


Hank’s balanced salt solution


Host defense peptides


Human umbilical vein endothelial cell


Minimum inhibitory concentration


Multiple linear regression


Nanoparticle tracking analysis


Octenyl succinic anhydride-modified hyaluronic acid


Transmission electron microscopy


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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).

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