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Chemoselective, Postpolymerization Modification of Bioactive, Degradable Polymers.

ABSTRACT: Degradable polymers promote sustainability, mitigate environmental impact, and facilitate biological applications. Tailoring degradable polymers is challenging because installing functional group-rich side chains is difficult when the backbone itself is susceptible to degradation. A convenient means of side chain installation is through postpolymerization modification (PPM). In functionalizing polyoxazinones, a class of degradable polymers generated by the ring-opening metathesis polymerization (ROMP), we predictably found PPM challenging. Even the versatile azide-alkyne cycloaddition click reaction was ineffective. To solve this problem, we screened PPM reactions whose efficiencies could be assessed using photochemistry (excimer formation). The mildest, pH-neutral process was functionalization of a ketone-containing polymer to yield either oxime (acid labile)- or alkyoxylamine (stable)-substituted polymers. Using this approach, we equipped polymers with fluorophores, reporter groups, and bioactive epitopes. These modifications imbued the polymers with distinctive spectral properties and biological activities. Thus, polyoxazinones are now tunable through a modular method to diversify these macromolecules' function.

SUBMITTER: Fishman JM

PROVIDER: S-EPMC6690479 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Chemoselective, Postpolymerization Modification of Bioactive, Degradable Polymers.

Fishman Joshua M JM Zwick Daniel B DB Kruger Austin G AG Kiessling Laura L LL

Biomacromolecules 20190122 2

Degradable polymers promote sustainability, mitigate environmental impact, and facilitate biological applications. Tailoring degradable polymers is challenging because installing functional group-rich side chains is difficult when the backbone itself is susceptible to degradation. A convenient means of side chain installation is through postpolymerization modification (PPM). In functionalizing polyoxazinones, a class of degradable polymers generated by the ring-opening metathesis polymerization ...[more]

PMID: 30608163

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Project description:UNLABELLED:Recent studies reveal many biomaterial vaccine carriers are able to activate immunostimulatory pathways, even in the absence of other immune signals. How the changing properties of polymers during biodegradation impact this intrinsic immunogenicity is not well studied, yet this information could contribute to rational design of degradable vaccine carriers that help direct immune response. We use degradable poly(beta-amino esters) (PBAEs) to explore intrinsic immunogenicity as a function of the degree of polymer degradation and polymer form (e.g., soluble, particles). PBAE particles condensed by electrostatic interaction to mimic a common vaccine approach strongly activate dendritic cells, drive antigen presentation, and enhance T cell proliferation in the presence of antigen. Polymer molecular weight strongly influences these effects, with maximum stimulation at short degradation times--corresponding to high molecular weight--and waning levels as degradation continues. In contrast, free polymer is immunologically inert. In mice, PBAE particles increase the numbers and activation state of cells in lymph nodes. Mechanistic studies reveal that this evolving immunogenicity occurs as the physicochemical properties and concentration of particles change during polymer degradation. This work confirms the immunological profile of degradable, synthetic polymers can evolve over time and creates an opportunity to leverage this feature in new vaccines. STATEMENT OF SIGNIFICANCE:Degradable polymers are increasingly important in vaccination, but how the inherent immunogenicity of polymers changes during degradation is poorly understood. Using common rapidly-degradable vaccine carriers, we show that the activation of immune cells--even in the absence of other adjuvants--depends on polymer form (e.g., free, particulate) and the extent of degradation. These changing characteristics alter the physicochemical properties (e.g., charge, size, molecular weight) of polymer particles, driving changes in immunogenicity. Our results are important as many common biomaterials (e.g., PLGA) are now known to exhibit immune activity that alters how vaccines are processed. Thus, the results of this study could contribute to more rational design of biomaterial carriers that also actively direct the properties of responses generated by vaccines.

Dataset Information

Chemoselective, Postpolymerization Modification of Bioactive, Degradable Polymers.

Publications

Chemoselective, Postpolymerization Modification of Bioactive, Degradable Polymers.

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