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.
Four-arm star-shaped copolymers, TPE-star-P(DMA-co-BMA-co-Gd), containing TPE cores with an aggregation-induced emission (AIE) feature, a T 1 -type magnetic resonance (MR) contrast agent, and amphiphilic cationic arms, are synthesized. By taking advantage of non-covalent interactions between star copolymers and bacteria surfaces, bimodal fluorometric/MR detection and concomitant inhibition of both Gram-positive and Gram-negative bacteria strains in aqueous media are explored.
We report on the fabrication of organic/inorganic hybrid micelles of amphiphilic block copolymers physically encapsulated with hydrophobic drugs within micellar cores and stably embedded with superparamagnetic iron oxide (SPIO) nanoparticles within hydrophilic coronas, which possess integrated functions of chemotherapeutic drug delivery and magnetic resonance (MR) imaging contrast enhancement. Poly(ε-caprolactone)-b-poly(glycerol monomethacrylate), PCL-b-PGMA, and PCL-b-P(OEGMA-co-FA) amphiphilic block copolymers were synthesized at first by combining ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), and post- modification techniques, where OEGMA and FA are oligo(ethylene glycol) monomethyl ether methacrylate and folic acid-bearing moieties, respectively. A model hydrophobic anticancer drug, paclitaxel (PTX), and 4 nm SPIO nanoparticles were then loaded into micellar cores and hydrophilic coronas, respectively, of mixed micelles fabricated from PCL-b-PGMA and PCL-b-P(OEGMA-co-FA) diblock copolymers by taking advantage of the hydrophobicity of micellar cores and strong affinity between 1,2-diol moieties in PGMA and Fe atoms at the surface of SPIO nanoparticles. The controlled and sustained release of PTX from hybrid micelles was achieved, exhibiting a cumulative release of ~61% encapsulated drugs (loading content, 8.5 w/w%) over ~130 h. Compared to that of surfactant-stabilized single SPIO nanoparticles (r(2) = 28.3 s(-1) mM(-1) Fe), the clustering of SPIO nanoparticles within micellar coronas led to considerably enhanced T(2) relaxivity (r(2) = 121.1 s(-1) mM(-1) Fe), suggesting that hybrid micelles can serve as a T(2)-weighted MR imaging contrast enhancer with improved performance. Moreover, preliminary experiments of in vivo MR imaging were also conducted. These results indicate that amphiphilic block copolymer micelles surface embedded with SPIO nanoparticles at the hydrophilic corona can act as a new generation of nanoplatform integrating targeted drug delivery, controlled release, and disease diagnostic functions.
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