Formulation and characterization of insulin nanoclusters for a controlled release

Mia Danielsen, Paul Joseph Kempen, Thomas Lars Andresen, Andrew James Urquhart*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


The growing interest in biopharmaceuticals combined with the challenges regarding formulation and delivery continues to encourage the development of new and improved formulations of this class of therapeutics. Nanoclusters (NCs) represent a type of formulation strategy where the biopharmaceutical is clustered in a reversible manner to function as both the therapeutic and the vehicle. In this study, insulin NCs (INCs) were formulated by a new methodology of first crosslinking proteins followed by desolvation. Crosslinking of the protein with the reducible DTSSP crosslinker improved control of the INC synthesis process to give INCs with a mean size of 198 ± 7 nm and a mean zeta potential of − 39 ± 1 mV. Crosslinking and clustering of insulin did not induce cytotoxicity or major differences in the biological activity compared to the free unmodified protein. The potency of the crosslinked insulin and the INCs appeared slightly lower than that of the unmodified protein, and significantly higher doses of the INCs compared to the free protein were applied to achieve similar blood sugar lowering effects in vivo. Interestingly, the INCs allowed for high doses to be subcutaneously delivered with prolonged efficacy without being lethal in rats.
Original languageEnglish
Article number123658
JournalInternational Journal of Biological Macromolecules
Number of pages14
Publication statusPublished - 2023


  • Crosslinking
  • Insulin
  • Nanoclusters


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