Controlling the Membrane Perturbation by Tuning Charge Variable Cholate-Based Macromolecules

Abstract

Access to the interior of the cell by destabilizing the natural barrier of the cell membrane is fundamental to drug and therapeutic delivery. Taking the unique facial amphiphilicity advantage of cholic acid to facilitate switching over impermeable cellular membranes, we report the synthesis of three different series of charge variable (anionic, cationic, and neutral) amphiphilic copolymers with various cholate contents and their membrane destabilization behavior. The synthesized cholate-containing amphiphilic copolymers self-organized into 80−100 nm sized nanoaggregates in aqueous media, while cholate moieties resided in the core of the self-assembled nanoparticles, as confirmed by 1 H NMR spectroscopy. The cholate-containing polymeric micelles proficiently destabilized the liposomes at pH 5.0 and pH 7.4. Interestingly, the cholate-appended neutral polymer exhibited up to 15fold enhancement in the membrane destabilization efficiency in comparison with respective cholate-based anionic or cationic polymers. Mechanistic studies using fluorescence, dynamic light scattering, and transmission electron microscopy established that the polymer−membrane interaction, subsequent reorganization, and insertion of cholate into the bilayer play a crucial role. Model drug (Nile red) encapsulation and release studies suggested the therapeutic potential of the cholate-conjugated polymeric nanoclusters.

Cholate-conjugated cationic polymers for regulation of actin dynamics

“…Next, the Boc group was deprotected from the polymers by reaction with TFA in DCM at room temperature (Scheme 1A). 41 Successful deprotection of the Boc groups was confirmed from the disappearance of the Boc-proton signal at about 1.42 ppm in the 1 H NMR spectra. 42 The 1 H NMR spectrum of deprotected side-chain Phe-containing polymer P(PEGMA- co -Phe-HEMA) ( CPF ) is shown in Fig.…”

Synthetic copolymers with natural product side‐chain pendents

“…4 Several cholic acid based macromolecular architectures have been constructed via a wide variety of polymerization strategies, including ring-opening metathesis polymerization, 5 atom transfer radical polymerization (ATRP) 6 and reversible addition fragmentation chain transfer (RAFT) polymerization, 7 and their different properties have been investigated in detail. 8,9 Different kinds of cholic-acid-conjugated polymers were prepared by RAFT polymerization, and those polymers performed extremely well in controlling membrane perturbation, 10 functioning as a drug delivery vehicle 11 and investigating the actin dynamics in cells. 12 Apart from bile acids, rosin, a naturally renewable resin derived from the exudation of conifer and pine trees, has also gained significant attention in developing smart natural product based polymers.…”

Charge variable PIB-based block copolymers as selective transmembrane ion transporters

“…The fundamental features for the design and synthesis of ion transporters are to have a hydrophobic region to promote membrane insertion and an ion-recognition domain to enhance ion selectivity. 14,15 Selective ion transport has been accelerated with the help of various interactions and binding forces, such as electrostatic forces, hydrogen bonding, ligand binding, ion-dipole interactions, etc. 16 Several artificial ionophores based on peptides, 17,18 macrocyclic materials, 19,20 amphiphilic synthetic scaffolds, 21 etc., have already been reported.…”