pH-Responsive Polyion Complex Vesicle with Polyphosphobetaine Shells

Abstract

When a bioactive molecule is taken into cells by endocytosis, it is sometimes unable to escape from the lysosomes, resulting in inefficient drug release. We prepared pH-responsive polyion complex (PIC) vesicles that collapse under acidic conditions such as those inside a lysosome. Furthermore, under acidic conditions, cationic polymer was released from the PIC vesicles to break the lysosome membranes. Diblock copolymers (PM and PA) consisting of water-soluble zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) block and cationic or anionic blocks were synthesized via reversible addition-fragmentation chain transfer (RAFT) radical polymerization. Poly(3-(methacrylamidopropyl) trimethylammonium chloride) (PMAPTAC) and poly(sodium 6-acrylamidohexanoate) (PAaH) were used as the cationic and anionic blocks, respectively. The pendant hexanoate groups in the PAaH block are ionized in basic water and in phosphate buffered saline (PBS), while the hexanoate groups are protonated in acidic water. In basic water, PIC vesicles were formed from a charge neutralized mixture of oppositely charged diblock copolymers. At the interface of PIC vesicle and water exists biocompatible PMPC shells. Under acidic conditions, the PIC vesicles collapsed, because the charge balance shifted due to protonation of the PAaH block. After collapse of the PIC vesicles, PA formed micelles composed of protonated PAaH core and PMPC shells, while PM was released as unimers. PIC vesicles can encapsulate hydrophilic nonionic guest molecules into their hollow core. Under acidic conditions, the PIC vesicles can release the guest molecules and PM. The cationic PM can break the lysosome membrane to efficiently release the guest molecules from the lysosomes to the cytoplasm.

Mucopenetrating Zwitterionic Micelles

“…Zwitterionic homo‐ and copolymeric hydrogels are explored towards their tailorable swelling and absorption behavior, their antimicrobial protein‐resistant and cytophobic properties, as self‐healing material, or to control the differentiation of mesenchymal stem cells among others. Further, integrating zwitterionic polymers into colloidal assemblies was explored including their use as surface coating of solid nanoparticles, as emulsified (cargo‐loaded) nanoparticles, or as building blocks in polymer micelles and vesicles . In the context of mucopenetration, polyzwitterions remain largely unexplored.…”

Lyotropic Morphology Transition of Double Zwitterionic Diblock Copolymer Aqueous Solutions

“…[ 15–18 ] Ion‐complexation in charged hydrophilic polymers has been often applied as a driving force for self‐assembly. [ 15,19,20 ] However, as far as we are aware, the ordered morphology transition in concentrated double hydrophilic block copolymer aqueous solutions has hardly been investigated so far except for the pioneering work by Armes and co‐workers. [ 21 ] A double hydrophilic copolymer composed of poly(ethylene oxide) (PEO) and poly[2‐(methacryloyloxy)ethyl phosphorylcholine] (PMPC) produced ordered morphologies and showed the morphology transition depending on the polymer concentration.…”

Complex Formation of Sulfobetaine Surfactant and Ionic Polymers and Their Stimuli Responsivity

“…13,14 A betaine polymer has temperature responsivity of an upper critical solution temperature (UCST) type 15−17 and pH-responsiveness 18−20 that vary greatly depending on the functional group of the ionic part and has a high solubility in water 2,3,18,21 and is dependent on the added salt concentration, 2,18,22 regardless of the type of functional group. Utilizing its properties, it has been widely studied for gels, 23,24 micelles, 20,25 brushes, 13,26 vesicles, 19,22 surfactant, 27,28 monolayer, 5,14 etc.…”

“…Betaine polymer, which is a kind of zwitterionic polymer, has an equal number of negatively charged functional group and positively charged functional group. − Due to its structural characteristics, it has high biocompatibility with less protein adsorption − and less adherence to blood cells − and is therefore being applied to new medical materials. , The effect of the added salt on the conformation of the polymer chain in the aqueous solution is exactly opposite of that of the common ionic chain polymer: the ionic chain polymer is contracted by the added salt, , while the betaine chain polymer is extended. , A betaine polymer has temperature responsivity of an upper critical solution temperature (UCST) type − and pH-responsiveness − that vary greatly depending on the functional group of the ionic part and has a high solubility in water ,,, and is dependent on the added salt concentration, ,, regardless of the type of functional group. Utilizing its properties, it has been widely studied for gels, , micelles, , brushes, , vesicles, , surfactant, , monolayer, , etc.…”

“…There are various types of polymeric micelles and vesicles, prepared by using diblock , or triblock copolymers , consisting of hydrophilic and hydrophobic chains, or prepared by mixing two diblock copolymers composed of a non-ionic polymer or zwitterionic polymer chain and an ionic polymer chains (anionic or cationic). ,− By controlling the design of the polymer structures and the combination of polymer chains to be mixed, it is possible to have responsiveness to stimuli such as temperature responsivity (LCST (lower critical solution temperature) − or UCST type ,, ), pH-responsivity, , photoresponsivity, , and enzyme responsivity. , …”