Proteins are therapeutically important due to their incredible specificity, with over 130 protein therapeutics FDA approved. However, proteins suffer from instability during transportation and storage as well as rapid clearance once administered. Degradation of protein therapeutics poses a risk to patient safety stemming from inadequate dosage or immunogenicity and rapid clearance increases the need for frequent injections. Polymers such as poly(ethylene glycol) (PEG) have been conjugated to therapeutic proteins to improve their pharmacokinetic properties, yet most do not enhance protein stability to stresses associated with transportation and storage. Excipients have been used to improve protein stability against environmental stresses, but do not protect against degradation and clearance in vivo. We present a polymer, utilizing the stabilizing capabilities of trehalose as side chains, that not only enhances the pharmacokinetic properties of biomolecules, but also improves stability to multiple environmental stresses. We confirmed the thermal and mechanical stabilization of human insulin against aggregation when the trehalose glycopolymer (PolyProtek) was either added as an excipient or attached as a conjugate using high performance liquid chromatography and dynamic light scattering. Moreover, the insulin-PolyProtek conjugate exhibited prolonged plasma circulation time in mice and retained its bioactivity after exposure to elevated temperature. Finally, PolyProtek did not exhibit in vivo toxicity, indicating its biocompatibility. These results highlight the potential of this polymer with trehalose side chains as a PEG alternative.

Polymer with trehalose side chains enhances the stability and in vivo plasma lifetime of insulin

253rd National Meeting (2017)

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