Supramolecular chemical biology for applications in protein modification and nanomedicine

Supramolecular chemistry is a diverse field that encompasses host-guest interactions, mechanical bond formation, metal coordination, and other noncovalent chemistries. The design strategies of supramolecular chemistry have been implemented in a diverse set of applications, but has seen limited use in the field of chemical biology. By combining supramolecular chemistry with chemical biology, new discoveries and advances could be made that would not be possible without a supramolecular approach. This work therefore sought to combine supramolecular strategies and chemical biology for applications in protein modification and nanomedicine. By using cucurbituril host-guest chemistry, a supramolecular-promoted copper-free click chemistry reaction was developed for protein modification. Cucurbituril host-guest chemistry was additionally explored as a selective protecting group for either the N terminus in the case of cucurbit[7]uril (CB7), or as a lysine protecting group in the case of cucurbit[6]uril (CB6). Supramolecular interactions were further utilized in the design of new turn-on diagnostic probes for 129Xe NMR/MRI detection of cancer, via the rotaxane-mediated suppression, and subsequent activation of Xe-CB6 host-guest interactions. Lastly, self-assembled protein-based nanomaterials were explored for applications in chemotherapeutic drug delivery to glioblastomas, with a special focus on how the morphology of protein-based nanomaterials can affect their biodistributions and drug delivery efficacies. Throughout this work, supramolecular interactions are interwoven with applications and techniques in chemical biology to achieve new advances that would not be possible otherwise

Supramolecular strategies for protein immobilization and modification.

Protein immobilization and modification are widely used techniques in the fields of chemical biology and biomaterials science. While covalent strategies based on small molecules are traditionally used, supramolecular chemistry offers numerous useful opportunities for guiding the modification locations on complex protein landscapes and introducing different degrees of reversibility into the products. In this opinion, we highlight recent advances in using supramolecular interactions, particularly host-guest chemistry, for controlling protein modification and immobilization. We discuss supramolecular strategies for protein-conjugate purification and capture, as well as for protein modification via host-guest interactions and metal coordination. Lastly, we address recent advances in utilizing supramolecular interactions to direct covalent protein modification. These examples of supramolecular chemical biology present opportunities to advance a wide range of applications, including proteomics and drug delivery

Supramolecular strategies for protein immobilization and modification.

Protein immobilization and modification are widely used techniques in the fields of chemical biology and biomaterials science. While covalent strategies based on small molecules are traditionally used, supramolecular chemistry offers numerous useful opportunities for guiding the modification locations on complex protein landscapes and introducing different degrees of reversibility into the products. In this opinion, we highlight recent advances in using supramolecular interactions, particularly host-guest chemistry, for controlling protein modification and immobilization. We discuss supramolecular strategies for protein-conjugate purification and capture, as well as for protein modification via host-guest interactions and metal coordination. Lastly, we address recent advances in utilizing supramolecular interactions to direct covalent protein modification. These examples of supramolecular chemical biology present opportunities to advance a wide range of applications, including proteomics and drug delivery

Networks of High Aspect Ratio Particles to Direct Colloidal Assembly Dynamics and Cellular Interactions

Injectable colloids that self-assemble into three-dimensional networks are promising materials for applications in regenerative engineering, as they create open systems for cellular infiltration, interaction, and activation. However, most injectable colloids have spherical morphologies, which lack the high material-biology contact areas afforded by higher aspect ratio materials. To address this need, injectable high aspect ratio particles (HARPs) were developed that form three-dimensional networks to enhance scaffold assembly dynamics and cellular interactions. HARPs were functionalized for tunable surface charge through layer-by-layer electrostatic assembly. Positively charged Chitosan-HARPs had improved particle suspension dynamics when compared to spherical particles or negatively charged HARPs. Chit-HARPs were used to improve the suspension dynamics and viability of MIN6 cells in three-dimensional networks. When combined with negatively charged gelatin microsphere (GelMS) porogens, Chit-HARPs reduced GelMS sedimentation and increased overall network suspension, due to a combination of HARP network formation and electrostatic interactions. Lastly, HARPs were functionalized with fibroblast growth factor 2 (FGF2) to highlight their use for growth factor delivery. FGF2-HARPs increased fibroblast proliferation through a combination of 3D scaffold assembly and growth factor delivery. Taken together, these studies demonstrate the development and diverse uses of high aspect ratio particles as tunable injectable scaffolds for applications in regenerative engineering

Codelivery of synergistic antimicrobials with polyelectrolyte nanocomplexes to treat bacterial biofilms and lung infections.

Bacterial biofilm infections, particularly those of Pseudomonas aeruginosa (PA), have high rates of antimicrobial tolerance and are commonly found in chronic wound and cystic fibrosis lung infections. Combination therapeutics that act synergistically can overcome antimicrobial tolerance; however, the delivery of multiple therapeutics at relevant dosages remains a challenge. We therefore developed a nanoscale drug carrier for antimicrobial codelivery by combining approaches from polyelectrolyte nanocomplex (NC) formation and layer-by-layer electrostatic self-assembly. This strategy led to NC drug carriers loaded with tobramycin antibiotics and antimicrobial silver nanoparticles (AgTob-NCs). AgTob-NCs displayed synergistic enhancements in antimicrobial activity against both planktonic and biofilm PA cultures, with positively charged NCs outperforming negatively charged formulations. NCs were evaluated in mouse models of lung infection, leading to reduced bacterial burden and improved survival outcomes. This approach therefore shows promise for nanoscale therapeutic codelivery to treat recalcitrant bacterial infections

Rotaxane-mediated suppression and activation of cucurbit[6]uril for molecular detection by (129)Xe hyperCEST NMR.

We report a method for blocking interactions between (129)Xe and cucurbit[6]uril (CB6) until activation by a specific chemical event. We synthesized a CB6-rotaxane that allowed no (129)Xe interaction with the CB6 macrocycle component until a cleavage event released the CB6, which then produced a (129)Xe@CB6 NMR signal. This contrast-upon-activation (129)Xe NMR platform allows for modular synthesis and can be expanded to applications in detection and disease imaging