Polyion Complex Micelles for Protein Delivery Benefit from Flexible Hydrophobic Spacers in the Binding Group

Abstract

Although a range of polymer–protein polyion complex (PIC) micelle systems have been developed in the literature, relatively little attention has been paid to the influence of polymer structure on the assembly, or to the mechanism of disassembly. In this work, Förster resonance energy transfer is used in combination with light sheet fluorescence microscopy and isothermal calorimetry to monitor the formation and stability of PIC micelles with various carboxylic‐acid‐based binding blocks in MCF‐7 cancer spheroid models. All micelles are stable in the presence of free protein, but are unstable in solutions with an ionic strength >200 mm and prone to disassembly at reduced pH. Introducing carbon spacers between the backbone and the binding carboxylic acid results in improved PIC micelle stability at physiological pH, but also increases the pKa of the binding moiety, resulting in improved protein release upon cell uptake. These results give important insights into how to tune PIC micelle stability for controlled protein release in biological environments.

On Complex Coacervate Core Micelles: Structure-Function Perspectives

“…Protein encapsulation with neutral-hydrophobic-charged triblock copolymers produces association colloids with higher stability. The hydrophobic block is less sensitive towards salt and pH variations and provides a barrier to protect the protein-rich coacervate [ 109 , 110 , 111 ]. Increasing the hydrophobicity of the charged block by the addition of carbon spacers between the polymer backbone and the charged side chains results in higher salt stability of protein-loaded C3Ms [ 109 ].…”

“…The hydrophobic block is less sensitive towards salt and pH variations and provides a barrier to protect the protein-rich coacervate [ 109 , 110 , 111 ]. Increasing the hydrophobicity of the charged block by the addition of carbon spacers between the polymer backbone and the charged side chains results in higher salt stability of protein-loaded C3Ms [ 109 ]. Association of cytochrome C with poly(ethylene glycol)- block -poly(aminopalmitic acid)- block -poly( l -aspartic acid) (PEG- b -PAPA- b -PAsp) triblock polypeptides yielded onion-like micelles with a protein-rich coacervate core, a hydrophobic PAPA shell, and a hydrophilic PEG corona [ 110 ].…”

Enhancing Cationic Drug Delivery with Polymeric Carriers: The Coulomb‐pH Switch Approach

“…Depending on the design of the negatively charged polymer, protonation is incomplete and the electrostatic interaction with the cationic drug is only weakened, but not eliminated. [ 27 ] While the drug can still be released over time, the introduction of an amine that is highly charged at pH5 can add repulsive forces that push the drug out of the polymer matrix quickly.…”

Recent Advances in Nanoplatforms for the Treatment of Osteosarcoma

“…In the absence of certain temperature conditions and ionic strength, nanomicelles may not remain stable (e.g., in solutions with ionic strength >200 mm and under low pH conditions) ( 81 ). Although nanomicelles with hydrophobic cores provide a superior carrier environment for the encapsulation of insoluble anticancer drugs, researchers still face challenges such as uncontrolled (non-continuous) drug release, immunogenicity, interactions with other soluble liquid molecules, and poor stability in vivo .…”