Biomolecule-polymer conjugates are constructs that take advantage of the functional or otherwise beneficial traits inherent to biomolecules and combine them with synthetic polymers possessing specially tailored properties. The rapid development of novel biomolecule-polymer conjugates based on proteins, peptides, or nucleic acids has ushered in a variety of unique materials, which exhibit functional attributes including thermo-responsiveness, exceptional stability, and specialized specificity. Key to the synthesis of new biomolecule-polymer hybrids is the use of controlled polymerization techniques coupled with either grafting-from, grafting-to, or grafting-through methodology, each of which exhibit distinct advantages and/or disadvantages. In this review, we present recent progress in the development of biomolecule-polymer conjugates with a focus on works that have detailed the use of grafting-from methods employing ATRP, RAFT, or ROMP.
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.
Poly(styrenyl acetal trehalose) (pSAT), composed of trehalose side chains linked to a polystyrene backbone via acetals, stabilizes a variety of proteins and enzymes against fluctuations in temperature. A promising application of pSAT is conjugation of the polymer to therapeutic proteins to reduce renal clearance. To explore this possibility, the safety of the polymer was first studied. Investigation of acute toxicity of pSAT in mice showed that there were no adverse effects of the polymer at a high (10 mg/kg) concentration. The immune response (antipolymer antibody and cytokine production) in mice was also studied. No significant antipolymer IgG was detected for pSAT, and only a transient and low level of IgM was elicited. pSAT was also safe in terms of cytokine response. The polymer was then conjugated to a granulocyte colony stimulating factor (GCSF), a therapeutic protein that is approved by the Federal Drug Administration, in order to study the biodistribution of a pSAT conjugate. A siteselective, two-step synthesis approach was developed for efficient conjugate preparation for the biodistribution study resulting in 90% conjugation efficiency. The organ distribution of GCSF−pSAT was measured by positron emission tomography and compared to controls GCSF and GCSF−poly(ethylene glycol), which confirmed that the trehalose polymer conjugate improved the in vivo half-life of the protein by reducing renal clearance. These findings suggest that trehalose styrenyl polymers are promising for use in therapeutic protein−polymer conjugates for reduced renal clearance of the biomolecule.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.