Polymeric Micelles Loading Proteins through Concurrent Ion Complexation and pH‐Cleavable Covalent Bonding for In Vivo Delivery

Abstract

Protein drugs have great potential as targeted therapies, yet their application suffers from several drawbacks, such as instability, short half‐life, and adverse immune responses. Thus, protein delivery approaches based on stimuli‐responsive nanocarriers can provide effective strategies for selectively enhancing the availability and activation of proteins in targeted tissues. Herein, polymeric micelles with the ability of encapsulating proteins are developed via concurrent ion complexation and pH‐cleavable covalent bonding between proteins and block copolymers directed to pH‐triggered release of the protein payload. Carboxydimethylmaleic anhydride (CDM) is selected as the pH‐sensitive moiety, since the CDMamide bond is stable at physiological pH (pH 7.4), while it cleaves at pH 6.5, that is, the pathophysiological pH of tumors and inflammatory tissues. By using poly(ethylene glycol)‐poly(l‐lysine) block copolymers having 45% CDM addition, different proteins with various sizes and isoelectric points are loaded successfully. By using myoglobin‐loaded micelles (myo/m) as a model, the stability of the micelles in physiological conditions and the dissociation and release of functional myoglobin at pH 6.5 are successfully confirmed. Moreover, myo/m shows extended half‐life in blood compared to free myoglobin and micelles assembled solely by polyion complex, indicating the potential of this system for in vivo delivery of proteins.

On Complex Coacervate Core Micelles: Structure-Function Perspectives

“…However, the toxicity of these linkers lowers the biocompatibility and the irreversible crosslinking hampers the triggered release of the protein at the targeted site. This has motivated the development of reversible crosslinking strategies involving labile bonds, which can be cleaved upon specific environmental triggers, allowing the C3Ms to be stable at physiological conditions but disassemble at the site of action [ 113 , 114 , 115 , 116 ]. For example, crosslinking via disulphide bonds yielded highly stable C3Ms under physiological conditions.…”

Effect of Mixing Ratio of Oppositely Charged Block Copolymers on Polyion Complex Micelles for In Vivo Application

“…Thus, the formation of micelles is expected to weaken the 1 H-NMR signals from protons located within the micellar core due to the restricted internal molecular motion. In fact, it has been reported that the peaks from protons of molecules encapsulated in the core of micelles showed significantly decreased intensity [22][23][24]. Here, 1 H-NMR measurements were made with PIC/m prepared in a 10 mM deuterium phosphate buffer (pD = 7.0).…”

Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: Current advances and perspectives

“…These PIC micelles were also employed as long-circulating enzyme carriers that maintained the enzymatic activity of catalase. pH-Responsive myoglobin-loaded PIC micelles were prepared via concurrent ion complexation and pH-cleavable amide crosslinking between the myoglobin guest and carboxy-dimethyl maleic anhydride-modified PEG- b -PLL host [ 224 ]. These micelles were stable under physiological pH with enhanced circulation time in vivo , while rapidly dissociated at pH 6.5 with the release of an intact protein payload.…”