Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells

Abstract

Reactive oxygen species (ROS) and oxidative stress are implicated in various physiological and pathological processes, and this feature provides a vital biochemical basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidation-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidation by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidation-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer cross-linking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent cross-linking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-containing bioactive molecules.

H 2 O 2 -responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics via in vivo chromogenic assay

“…Therefore, the accurate and sensitive detection of H 2 O 2 would have significant clinical value not only for disease diagnosis but also for better understanding of disease mechanisms. However, in vivo imaging of H 2 O 2 for clinical applications remains a challenging task owing to the relatively low concentrations of H 2 O 2 in physiological environments (below ∼50 μM) (5,6). Previously, boronate-based fluorescent probes have been explored for detection of physiologic H 2 O 2 (with the detection limit at a few micromoles), relying on the H 2 O 2 -mediated transformation of arylboronates to phenols, generating fluorescence under visible light excitation (5)(6)(7)(8).…”

Reactive Oxygen, Nitrogen, and Sulfur Species (RONSS)‐Responsive Polymersomes for Triggered Drug Release

“…Recently, our group reported H 2 O 2 ‐responsive polymersomes assembled from amphiphilic BCPs with naphthylboronate‐ester‐capped self‐immolative side linkage in the hydrophobic block (Figure ) . Mitochondria‐targeted ROS‐responsive polymersomes were obtained through self‐assembly, followed by surface functionalization with targeting peptides.…”

“…Schematic illustration for the preparation of mitochondria‐targeted, ROS‐responsive multifunctional polymersomes exhibiting intracellular milieu‐triggered vesicle bilayer cross‐linking, permeability switching, and enhanced imaging/drug release features. Reproduced with permission . Copyright 2016, American Chemical Society.…”

“…As such, polymersomes have been increasingly used to construct drug nanocontainers, artificial nanoreactors, and biomimetic organelles . However, despite tremendous advances in the fabrication of RONSS‐responsive micelle‐based nanovectors, RONSS‐responsive polymersomes have been far less exploited …”

Preparation of Layer‐by‐Layer Films with Remarkably Different pH‐Stability and Release Properties Using Dual Responsive Block Copolymer Micelles

“…Amphiphilic block copolymers have been attracting attention for years due to their ability to form different types of self‐assemblies in aqueous environment which find use in biomedical applications, for example, drug carriers, sensors, fluorogenic nanostructures and vehicles for the transportation of biological molecules such as DNA, RNA, and proteins . Among polymer nanostructures such as micelles, nanocapsules, polymersomes, block copolymer micelles (BCMs) come into prominence due to enhanced permeability and retention (EPR) effect, small particle size, high loading capacity, prolonged circulation, and accumulation in the required pathological site(s) in the body …”