Pharmaceutical Research

, Volume 32, Issue 8, pp 2727–2735 | Cite as

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

  • Jorrit J. Water
  • YongTae Kim
  • Morten J. Maltesen
  • Henrik Franzyk
  • Camilla Foged
  • Hanne M. Nielsen
Research Paper

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.

KEY WORDS

antimicrobial peptides hyaluronic acid hydrogel nanoparticles microfluidics nanogels 

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

Supplementary material

11095_2015_1658_MOESM1_ESM.docx (31 kb)
ESM 1(DOCX 31 kb)
11095_2015_1658_MOESM2_ESM.docx (34 kb)
ESM 2(DOCX 34 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jorrit J. Water
    • 1
  • YongTae Kim
    • 2
  • Morten J. Maltesen
    • 3
  • Henrik Franzyk
    • 4
  • Camilla Foged
    • 1
  • Hanne M. Nielsen
    • 1
  1. 1.Section for Biologics, Department of PharmacyUniversity of CopenhagenCopenhagenDenmark
  2. 2.George W. Woodruff School of Mechanical Engineering, Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyAtlantaUSA
  3. 3.Biopharma Application DevelopmentNovozymes A/SBagsvaerdDenmark
  4. 4.Section for Natural Products Research, Department of Drug Design and PharmacologyUniversity of CopenhagenCopenhagenDenmark

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