Defining Structure‐Function Relationships of Amphiphilic Excipients Enables Rational Design of Ultra‐Stable Biopharmaceuticals

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Biopharmaceuticals are the fastest-growing class of drugs in healthcare industry, but their global reach is severely limited by propensity for rapid aggregation. Currently, surfactant excipients such as polysorbates and poloxamers used to prevent protein aggregation, which significantly extends shelf-life. Unfortunately, these themselves unstable, oxidizing rapidly into 100s distinct compounds, some cause severe adverse events patients. Here, highly stable, well-defined, modular nature amphiphilic polyacrylamide-derived leveraged isolate key mechanisms responsible excipient-mediated stabilization. With a library compositionally identical structurally excipients, new property quantified, compositional dispersity, that excipient performance utilized this rationally design ultra-stable increase stability notoriously unstable biopharmaceutical, monomeric insulin, an order magnitude. This comprehensive generalizable understanding structure-function relationships represents paradigm shift formulation biopharmaceuticals, moving away from trial-and-error screening approaches toward rational design.

Language: Английский

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Enhanced Bone Targeting of Poly(l-glutamic acid)s through Cationic or Aromatic Substitution

Biomacromolecules, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Poly(l-glutamic acid)s (PLGs) are promising bone-targeting ligands due to their high molecular weight and facile preparation. Nevertheless, the efficiency of PLGs is still relatively low, validating necessity further enhance targeting through structural optimization. Herein, we report use a heteropolypeptide strategy improve bone incorporation another side-chain functionality for enhanced affinity with tissues. Specifically, introduction cationic amino or aromatic phenolic residues resulted in ∼2.3-fold ∼1.6-fold increase vivo targeting, respectively. Cationic modification not only improved minerals but also exhibited prolonged retention tissues more than 60 days. This work highlights library screen optimize performance polypeptide materials, offering polymeric materials design bone-related nanomedicine.

Language: Английский

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Morphologically and Functionally Tunable Nanostructures Self‐Assembled from Azopyridine‐Containing Block Copolymers

Advanced Functional Materials, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract Hierarchical structures with enhanced performances are of growing importance in many fields, but their preparation suffers from tedious and multistep procedures. There remain challenges to transfer magnify the molecular functions hierarchical pursue more unique applications. Herein, a facile one‐step approach for fabrication assembling amphiphilic copolymers, poly(ethylene glycol)‐ block ‐poly(6‐(4‐(4‐pyridyazo)phenoxy)hexyl methacrylate) (PEG‐ b ‐PAzoPy) controlled morphologies functions, is reported. Various including three‐dimensional raspberry‐like assemblies, worm networks (WNs), large compound vesicles obtained through heating‐cooling‐aging process THF/ethanol. The fluorescence detection p ‐nitrophenol at ultralow concentrations (10 −12 m ) realized by formation nonfluorescent nitrophenol‐WNs complexes, taking advantage high surface area cavities WNs. Furthermore, highly efficient nanofiltration composite membrane constructed WNs on commercial polypropylene membrane. More interestingly, using simple 2H,2H,3H,3H‐perfluoroundecanoic acid as H‐bond donor PEG‐ ‐PAzoPy acceptor, they can form complexes further assemble into nanowires ordered liquid crystalline stripes. This study not only offers strategy design also facilitates application advanced materials various fields.

Language: Английский

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Leveraging Triphenylphosphine-Containing Polymers to Explore Design Principles for Protein-Mimetic Catalysts

Published: April 15, 2024

Complex interactions between non-coordinating residues are significant yet commonly overlooked components of macromolecular catalyst function. While these have been demonstrated to impact binding affinities and catalytic rates in metalloenzymes, the roles similar structural elements synthetic polymeric catalysts remain underexplored. Using a model Suzuki-Miyuara cross-coupling reaction, we performed series systematic studies probe interconnected effects metal-ligand cross-links, electrostatic interactions, local rigidity polymer catalysts. To achieve this, novel bi-functional triphenylphosphine acrylamide (BisTPPAm) monomer was synthesized evaluated alongside an analogous monofunctional (TPPAm). In copolymer catalysts, increased initial reaction were observed for copolymers untethered by Pd complexation (BisTPPAm-containing) as compared Pd-cross-linked (TPPAm-containing). Further, incorporating through secondary structure-like revealed nonmonotonic relationships composition rate, demonstrating potential tunable behavior sphere interactions. Finally, rigorous cheminformatics featurization strategies statistical modeling, quantitated chemical descriptors substrate conditions on performance. Collectively, results provide insights into composition, structure, function protein-mimetic copolymers.

Language: Английский

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Elucidating structure-function relationships of amphiphilic copolymer excipients to enhance the stability of biopharmaceuticals

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 19, 2024

Biopharmaceuticals are the fastest growing class of drugs in healthcare industry, but their global reach is severely limited by propensity for rapid aggregation. Currently, surfactant excipients such as polysorbates and poloxamers used to prevent protein aggregation, which significantly extends shelf-life. Unfortunately, these themselves unstable, oxidizing rapidly into 100s distinct compounds, some cause severe adverse events patients. Here, we leverage highly stable, well-defined, modular nature amphiphilic polyacrylamide-derived isolate key mechanisms responsible excipient-mediated stabilization. With a library compositionally identical structurally copolymers, quantify multiple relationships between polymer properties fundamental phenomena rationally design new ultra-stable excipients, increasing stability notoriously unstable biopharmaceutical, monomeric insulin, an order magnitude. This comprehensive generalizable understanding excipient structure-function represents paradigm shift formulation biopharmaceuticals, moving away from trial-and-error screening approaches towards rational design.

Language: Английский

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Structure-Function Insights into Thermoresponsive Copolymers as Lanthanide Precipitants

Published: July 31, 2024

The synthetic toolbox for stimuli-responsive polymers has broadened to include many variables of tunable control, making these materials applicable in diverse technologies. However, unraveling the key composition-structure-function relationships facilitate ground-up design remains a challenge due inherent dispersity sequence and conformations polymers. We here present systematic study using model system copolymers with thermoresponsive (N-isopropylacrylamide) backbone addition metal-chelating (acrylic acid) hydrophobic structural comonomers evaluate their efficiency at isolation technologically critical lanthanide ions. ion extraction by precipitation was quantitated metallochromic dye reveal trends relating copolymer hydrophobicity improved separations. Further, we examined role different dictating solution-phase conformation polymer presence absence ions, identify features comonomer that influence efficiency. Finally, identified how local proximity thermoresponsive, chelating, subunits metal manipulating multiblock polymerization. Through mechanistic analysis, propose binding-then-assembly process through which ions are coprecipitated macromolecular chelators.

Language: Английский

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Leveraging Triphenylphosphine-Containing Polymers to Explore Design Principles for Protein-Mimetic Catalysts

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(25), P. 17404 - 17413

Published: June 12, 2024

Complex interactions between noncoordinating residues are significant yet commonly overlooked components of macromolecular catalyst function. While these have been demonstrated to impact binding affinities and catalytic rates in metalloenzymes, the roles similar structural elements synthetic polymeric catalysts remain underexplored. Using a model Suzuki-Miyuara cross-coupling reaction, we performed series systematic studies probe interconnected effects metal-ligand cross-links, electrostatic interactions, local rigidity polymer catalysts. To achieve this, novel bifunctional triphenylphosphine acrylamide (BisTPPAm) monomer was synthesized evaluated alongside an analogous monofunctional (TPPAm). In copolymer catalysts, increased initial reaction were observed for copolymers untethered by Pd complexation (BisTPPAm-containing) compared Pd-cross-linked (TPPAm-containing). Further, incorporating through secondary structure-like revealed nonmonotonic relationships composition rate, demonstrating potential tunable behavior secondary-sphere interactions. Finally, rigorous cheminformatics featurization strategies statistical modeling, quantitated chemical descriptors substrate conditions on performance. Collectively, results provide insights into among composition, structure, function protein-mimetic copolymers.

Language: Английский

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Dynamic Implications of Noncovalent Interactions in Amphiphilic Single-Chain Polymer Nanoparticles

ACS Macro Letters, Journal Year: 2024, Volume and Issue: 13(7), P. 889 - 895

Published: July 3, 2024

Single-chain polymer nanoparticles (SCNPs) combine the chemical diversity of synthetic polymers with intricate structure biopolymers, generating versatile biomimetic materials. The mobility chain segments at length scales similar to secondary structural elements in proteins is critical SCNP and thus function. However, influence noncovalent interactions used form SCNPs (e.g., hydrogen-bonding secondary-like structure) on these conformational dynamics challenging quantitatively assess. To isolate effects dynamics, we synthesized a series amphiphilic copolymers containing dimethylacrylamide monomers capable forming different interactions: (1) di(phenylalanine) acrylamide that forms intramolecular β-sheet-like cross-links, (2) phenylalanine hydrogen-bonds but lacks defined local structure, (3) benzyl has lowest propensity for hydrogen-bonding. Each formed folded structures comparable those intrinsically disordered proteins, as observed by size exclusion chromatography small angle neutron scattering. polymers, characterized combination dynamic light scattering spin echo spectroscopy, was well described using Zimm internal friction (ZIF) model, highlighting role each interaction additively restrict relaxations SCNPs. These results demonstrate utility scale control guiding design functional materials refined binding sites tunable kinetics.

Language: Английский

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Structure–Function Insights into Thermoresponsive Copolymers as Lanthanide Precipitants

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

The synthetic toolbox for stimuli-responsive polymers has broadened to include many tunable variables, making these materials applicable in diverse technologies. However, unraveling the key composition–structure–function relationships facilitate ground-up design remains a challenge due inherent dispersity sequence and conformations polymers. We here present systematic study of using model system copolymers with thermoresponsive (N-isopropylacrylamide) backbone addition metal-chelating (acrylic acid) hydrophobic structural comonomers evaluate their efficiency at isolating technologically critical lanthanide ions. ion extraction by precipitation was quantitated metallochromic dye reveal trends relating copolymer hydrophobicity improved separations. Further, we examined role different dictating solution-phase conformation polymer presence absence ions, correlated features comonomer efficiency. Finally, identified how local proximity thermoresponsive, chelating, subunits facilitates metal manipulating multiblock polymerization. Through mechanistic analysis, propose binding-then-assembly process through which ions are coprecipitated macromolecular chelators.

Language: Английский

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