Step-Growth Glycopolymers with a Defined Tacticity for Selective Carbohydrate-Lectin Recognition.

Glycopolymers are potent candidates for biomedical applications by exploiting multivalent carbohydrate-lectin interactions. Owing to their specific recognition capabilities, glycosylated polymers can be utilized for targeted drug delivery to certain cell types bearing the corresponding lectin receptors. A fundamental challenge in glycopolymer research, however, is the specificity of recognition to receptors binding to the same sugar unit (e.g., mannose). Variation of polymer backbone chirality has emerged as an effective method to distinguish between lectins on a molecular level. Herein, we present a facile route toward producing glycopolymers with a defined tacticity based on a step-growth polymerization technique using click chemistry. A set of polymers have been fabricated and further functionalized with mannose moieties to enable lectin binding to receptors relevant to the immune system (mannose-binding lectin, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin, and dendritic and thymic epithelial cell-205). Surface plasmon resonance spectrometry was employed to determine the kinetic parameters of the step-growth glycopolymers. The results highlight the importance of structural complexity in advancing glycopolymer synthesis, yet multivalency remains a main driving force in lectin recognition.

Hierarchy of Complex Glycomacromolecules: From Controlled Topologies to Biomedical Applications.

Carbohydrates bearing a distinct complexity use a special code (Glycocode) to communicate with carbohydrate-binding proteins at a high precision to manipulate biological activities in complex biological environments. The level of complexity in carbohydrate-containing macromolecules controls the amount and specificity of information that can be stored in biomacromolecules. Therefore, a better understanding of the glycocode is crucial to open new areas of biomedical applications by controlling or manipulating the interaction between immune cells and pathogens in terms of trafficking and signaling, which would become a powerful tool to prevent infectious diseases. Even though a certain level of progress has been achieved over the past decade, synthetic glycomacromolecules are still lagging far behind naturally existing glycans in terms of complexity and precision because of insufficient and inefficient synthetic techniques. Currently, specific targeting at a cellular level using synthetic glycomacromolecules is still challenging. It is obvious that multidisciplinary collaborations are essential between different specialized disciplines to enhance the carbohydrate receptor-targeting paradigm for new biomedical applications. In this Perspective, recent developments in the synthesis of sophisticated glycomacromolecules are highlighted, and their biological and biomedical applications are also discussed in detail.

The In Vitro, Ex Vivo, and In Vivo Effect of Polymer Hydrophobicity on Charge-Reversible Vectors for Self-Amplifying RNA.

RNA technology has the potential to revolutionize vaccination. However, the lack of clear structure-property relationships in relevant biological models mean there is no clear consensus on the chemical motifs necessary to improve RNA delivery. In this work, we describe the synthesis of a series of copolymers based on the self-hydrolyzing charge-reversible polycation poly(dimethylaminoethyl acrylate) (pDMAEA), varying the lipophilicity of the additional co-monomers. All copolymers formed stable polyplexes, showing efficient complexation with model nucleic acids from nitrogen/phosphate (N/P) ratios of N/P = 5, with more hydrophobic complexes exhibiting slower charge reversal and disassembly compared to hydrophilic analogues. The more hydrophobic copolymers outperformed hydrophilic versions, homopolymer controls and the reference standard polymer (polyethylenimine), in transfection assays on 2D cell monolayers, albeit with significantly higher toxicities. Similarly, hydrophobic derivatives displayed up to a 4-fold higher efficacy in terms of the numbers of cells expressing green fluorescent protein (GFP+) cells in ex vivo human skin (10%) compared to free RNA (2%), attributed to transfection enrichment in epithelial cells. In contrast, in a mouse model, we observed the reverse trend in terms of RNA transfection, with no observable protein production in more hydrophobic analogues, whereas hydrophilic copolymers induced the highest transfection in vivo. Overall, our results suggest an important relationship between the vector lipophilicity and RNA transfection in vaccine settings, with polymer biocompatibility potentially a key parameter in effective in vivo protein production.