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Synthesis of Zwitterionic and Trehalose Polymers with Variable Degradation Rates and Stabilization of Insulin.

ABSTRACT: Polymers that stabilize biomolecules are important as excipients in protein formulation. Herein, we describe a class of degradable polymers that have tunable degradation rates depending on the polymer backbone and can stabilize proteins to aggregation. Specifically, zwitterion- and trehalose-substituted polycaprolactone, polyvalerolactone, polycarbonate, and polylactide were prepared and characterized with regards to their hydrolytic degradation and ability to stabilize insulin to mechanical agitation during heat. Ring-opening polymerization (ROP) of allyl-substituted monomers was performed by using organocatalysis, resulting in well-defined alkene-substituted polymers with good control over molecular weight and dispersity. The polymers were then modified by using photocatalyzed thiol-ene reactions to install protein-stabilizing carboxybetaine and trehalose side chains. The resulting polymers were water-soluble and exhibited a wide range of half-lives, from 12 h to more than 3 months. The polymers maintained the ability to stabilize the therapeutic protein insulin from activity loss due to aggregation, demonstrating their potential as degradable excipients for protein formulation.

SUBMITTER: Pelegri-O'Day EM

PROVIDER: S-EPMC8259896 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Synthesis of Zwitterionic and Trehalose Polymers with Variable Degradation Rates and Stabilization of Insulin.

Pelegri-O'Day Emma M EM Bhattacharya Arvind A Theopold Nik N Ko Jeong Hoon JH Maynard Heather D HD

Biomacromolecules 20200505 6

Polymers that stabilize biomolecules are important as excipients in protein formulation. Herein, we describe a class of degradable polymers that have tunable degradation rates depending on the polymer backbone and can stabilize proteins to aggregation. Specifically, zwitterion- and trehalose-substituted polycaprolactone, polyvalerolactone, polycarbonate, and polylactide were prepared and characterized with regards to their hydrolytic degradation and ability to stabilize insulin to mechanical agi ...[more]

PMID: 32369347

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Project description:Insulin, the oldest U.S. Food and Drug Administration (FDA)-approved recombinant protein and a World Health Organization (WHO) essential medicine for treating diabetes globally, faces challenges due to its storage instability. One approach to stabilize insulin is the addition of poly(trehalose methacrylate) (pTrMA) as an excipient. The polymer increases the stability of the peptide to heat and mechanical agitation and has a low viscosity suitable for injection and pumps. However, the safety and stabilizing mechanism of pTrMA is not yet known and is required to understand the potential suitability of pTrMA as an insulin excipient. Herein is reported the immune response, biodistribution, and insulin plasma lifetime in mice, as well as investigation into insulin stabilization. pTrMA alone or formulated with ovalbumin did not elicit an antibody response over 3 weeks in mice, and there was no observable cytokine production in response to pTrMA. Micropositron emission tomography/microcomputer tomography of 64Cu-labeled pTrMA showed excretion of 78-79% ID/cc within 24 h and minimal liver accumulation at 6-8% ID/cc when studied out to 120 h. Further, the plasma lifetime of insulin in mice was not altered by added pTrMA. Formulating insulin with 2 mol equiv of pTrMA improved the stability of insulin to standard storage conditions: 46 weeks at 4 °C yielded 87.0% intact insulin with pTrMA present as compared to 7.8% intact insulin without the polymer. The mechanism by which pTrMA-stabilized insulin was revealed to be a combination of inhibiting deamidation of amino acid residues and preventing fibrillation, followed by aggregation of inactive and immunogenic amyloids all without complexing insulin into its hexameric state, which could delay the onset of insulin activity. Based on the data reported here, we suggest that pTrMA stabilizes insulin as an excipient without adverse effects in vivo and is promising to investigate further for the safe formulation of insulin.

Dataset Information

Synthesis of Zwitterionic and Trehalose Polymers with Variable Degradation Rates and Stabilization of Insulin.

Publications

Synthesis of Zwitterionic and Trehalose Polymers with Variable Degradation Rates and Stabilization of Insulin.

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