Mechanochemical Drug Conjugation via pH-Responsive Imine Linkage for Polyether Prodrug Micelles

Abstract

Prodrug-type polymer–drug conjugates based on highly biocompatible functional polyethers are developed through mechanochemical post-polymerization modification. Herein, we design functional epoxide monomers of ethoxyethyl glycidyl ether (EEGE) and azidohexyl glycidyl ether (AHGE) and synthesize diblock copolyethers of PEEGE-b-PAHGE via sequential anionic ring-opening polymerization. Subsequent conversion of the functional monomers to the corresponding hydroxyl and amine groups allows for the preparation of double hydrophilic block copolyethers. Most notably, mechanochemical modification allows for the conjugation of these polymers with a highly hydrophobic and potent anticancer agent, cinnamaldehyde, through an imine linkage. The self-assembly of the resulting polymer–drug conjugates into polymeric micelles is characterized by dynamic light scattering and atomic force microscopy. The pH-responsive cleavage of the imine linkages under acidic conditions leads to the release of cinnamaldehyde with a concomitant disassembly of the polymeric micelles. The superior biocompatibility coupled with the solvent-less mechanochemical conjugation approach provides a convenient means to introduce various therapeutics for smart drug delivery.

Selective Photooxidation of Benzyl Alcohol to Benzaldehyde via H-Abstraction by Bi2.15WO6 under Alkaline Conditions

“…We, therefore, deduce that EDA reacts with a fraction of benzaldehyde to form the Schiff base in an aqueous solution, thus protecting it from overoxidation to benzoic acid. To obtain more benzaldehyde after reaction, the pH was also adjusted to acidic conditions after reaction in that the cleavage of imine bonds in Schiff bases is faster under acidic conditions than that under neutral conditions. ,, In this study, we adjusted the reacted solution to weak acidic for further hydrolysis of the Schiff base, and then the concentration of benzaldehyde was measured by HPLC. It is interesting to notice that a negligible difference can be observed in the quenching experiments when EDA was added in the reaction system (Figure S12), indicating that the oxidizing species in the oxidation process are not affected by EDA.…”

Solvent‐Free Mechanochemical Post‐Polymerization Modification of Ionic Polymers

“…Polyether is a biocompatible polymer with ultrahigh water solubility, a stealth effect, and low immunogenicity [26,27] . For this reason, polyether derivatives are currently employed when high water solubility is required, such as for drug delivery systems [28,29] and hydrogels [30,31] . Moreover, it is known that a backbone scission is a commonly observed side reaction during the mechanochemical ball‐milling of polymers, with the backbone scission rate proportional to the glass transition temperature ( T g ) of the polymer [32] .…”

“…Aldehydes with varying electronic properties ( 2 – 6 ) were evaluated in comparison to the representative benzaldehyde ( 1 ). Regardless of its electronic properties, all the selected aromatic aldehydes ( 2 , 3 ) displayed full conversion with a high isolated yield, including cinnamaldehyde ( 4 ), a well‐known anticancer drug [28] . An aldehyde with a protecting acetal group remained intact ( 5 ), and 1‐pyrenecarboxaldehyde ( 6 ), an aldehyde with a bulky moiety, also showed complete conversion.…”

Mechanochemical Preparation of Protein : hydantoin Hybrids and Their Release Properties

“…As the hydrophobic material is insoluble in water it remains associated with the protein, and will hence be incorporated into the self‐assembled protein structures [14] . It should be noted that mechanochemical procedures involving covalent bond‐formation can also be employed; for example, by mechanochemical drug conjugation leading to self‐assembled micelles [11a] . As highly complex molecules with a rich chemistry proteins are promising candidates for the development of sustainable nanomaterials, when isolated from plants (i. e., “benign by design”), industrial waste streams, or obtained as side products during food production.…”

“… [14] It should be noted that mechanochemical procedures involving covalent bond‐formation can also be employed; for example, by mechanochemical drug conjugation leading to self‐assembled micelles. [11a] As highly complex molecules with a rich chemistry proteins are promising candidates for the development of sustainable nanomaterials, when isolated from plants (i. e., “benign by design”), industrial waste streams, or obtained as side products during food production. For example, whey‐protein is obtained as a side product during cheese production, with the main constituent being β‐lactoglobulin (BLG), a small protein built up from 162 amino acid residues with a molecular weight of about 18300 Da and an isoelectric point (pI) of 5.1.…”