Modulating Boronic Ester Stability in Block Copolymer Micelles via the Neighbor Effect of Copolymerized Tertiary Amines for Controlled Release of Polyphenolic Drugs

Abstract

The traceless and pH-sensitive properties of boronic esters are attractive for the synthesis of polymer-drug conjugates, but current platforms suffer from both low stability under physiologically relevant conditions and synthetically demanding optimization to tune drug release profiles. We hypothesized that the high catechol affinity and stability of Wulff-type boronic acids could be mimicked by copolymerization of phenyl boronic acid with a tertiary amine and subsequent micellization. This strategy yielded a versatile platform for the preparation of reversible polymer−drug conjugates, which more than doubled the oxidative stability of encapsulated polyphenolic drug cargo at physiologically relevant pH and enabled simple and incremental tuning of drug release kinetics. Moreover, we validated, with 19 F NMR, that these copolymers exhibit uniquely high catechol affinity that could not be replicated by combinations of similarly functionalized small molecules. Overall, this report demonstrates that copolymerization of boronic acid and tertiary amine monomers is a powerful and modular approach to improving boronic ester chemistry for drug delivery applications.

Reaction‐induced morphology control in block copolymers

“…Additionally, performing the functionalization reaction at room temperature enabled the formation of uniform spherical micelles confirmed through dynamic light scattering and TEM imaging, which may suggest that increased incompatibility at lower temperatures was critical for establishing ordered nanostructures. The in situ modification of BCPs in solution can also be leveraged to drive the dissociation of pre‐formed BCP particles, which can be particularly advantageous in applications that require the controlled release of payload and guest molecules, such as for drug delivery 63,64 . Conventionally, photo‐ or thermal‐induced changes in functional groups from the BCP segments promote solubility of the solvophobic block(s), which can trigger morphological changes of micelles, like dissociation and release of a drug payload 65,66 …”

“…The in situ modification of BCPs in solution can also be leveraged to drive the dissociation of pre-formed BCP particles, which can be particularly advantageous in applications that require the controlled release of payload and guest molecules, such as for drug delivery. 63,64 Conventionally, photo-or thermalinduced changes in functional groups from the BCP segments promote solubility of the solvophobic block(s), which can trigger morphological changes of micelles, like dissociation and release of a drug payload. 65,66 Reactions with BCPs that already exhibit ordered nanostructures can be used to induce order-to-order transitions, through which the resulting morphology can be collectively determined by a balance between multiple competing factors including interfacial tension and repulsion/stretching in the coronal chains of the BCPs.…”

Enantiomer Recognition Based on Chirality Transfer from Chiral Amines to Ternary Dynamic Covalent Systems

“…Boronic acids and boronate materials have attracted wide research attention due to their biocompatibility, degradability, and sensitivity to external stimuli. − In particular, arylboronic acids exhibit a rich reactivity, which endows arylboronic acid–based materials with a broad diversity of applications. , Boronates are usually synthesized by constructing reversible dynamic chemical bonds between boronic acid and cis 1,2- or 1,3-dihydroxy compounds including diols, catechols, phosphates, salicylic acid, siloxanes, and basic diacids. − In addition, the boron atom in boronic acid or boronates has an empty p -orbital that provides Lewis acidity and capacity of coordination with electron donors such as F – , CN – , amino, hydroxyl, and carboxylic acid groups. − Benefiting from these properties, organic boronic acids and boronates containing functional groups can recognize or capture sugars, glycoproteins, glucosamines, amino acids, RNA, ATP, and germs. − …”

Validation of an MD simulation approach for electrical field responsive micelles and their application in drug delivery

“…This enables simple drug formulation and ease of manufacturing; other advanced drug delivery systems (DDSs) are complicated to prepare and have inherent problems that hinder their large-scale production stably and consistently. These two advantages of micelles have spurred their acceptance as a first-line drug formulation technology 5 , 6 .…”