Oxidation-Sensitive Polymersomes Based on Amphiphilic Diblock Copolypeptoids

Abstract

Stimuli-responsive polymersomes formed by amphiphilic block copolymers have attracted substantial attention as smart and robust containers for drug delivery and nano/micro-reactors. Bio-sourced amphiphilic diblock copolypeptoids were developed that can self-assemble into oxidation-responsive unilamellar vesicles. These vesicles can burst under the action of reactive oxygen species which can be the hydrogen peroxide, or the singlet oxygen produced by light-activation of photosensitizer with spatiotemporal control.Polysarcosine (PSar, also called poly(N-methyl glycine)) was selected as the hydrophilic block, due to its resistance to protein adsorption and low toxicity, similar to PEG. We designed and synthesized poly(N-3-(methylthio)propyl glycine) as the hydrophobic block. Its polyglycine backbone is the same as that of PSar, and especially its hydrophobic N-substituents, thioether side-chains, can be oxidized to hydrophilic sulfoxides. These oxidation-responsive polymersomes entirely based on N-substituted poly(amino acid)s were biocompatible as confirmed by cell viability tests, and may find applications in drug delivery, biosensing, biodetection, and nano-/micro-reactors.The Supporting Information is available free of charge on the ACS Publications website at DOI:… Materials and methods, experimental details, characterization data (PDF).Videos of vesicle disruption under the stimuli of H2O2 or light irradiation (AVI).

Synthesis and self-assembly of poly(ethylene glycol)-block-poly(N-3-(methylthio)propyl glycine) and their oxidation-sensitive polymersomes

“…have been frequently reported as smart drug carriers [24][25][26]. In a previous work, we synthesized a thioether-bearing polypeptoid, poly(N-3-(methylthio)propyl glycine) (PMeSPG), and prepared polymersomes from PMeSPG-b-PSar block copolymers [27]. As the hydrophobic thioethers can be oxidized into hydrophilic sulfoxides, the obtained polymersomes showed oxidation-responsive bursting in the presence of hydrogen peroxide (H2O2).…”

“…The monomer MeSPG-NTA was prepared as described in our previous work [27]. The synthesis of PEG-b-PMeSPG was performed through the ROP of N-3-(methylthio)propyl glycine N-thiocarboxyanhydride (MeSPG-NTA) using amino-terminated PEG with molecular weight (MW) of 2000 Da (PEG45-NH2) as a macromolecular initiator (Fig.…”

“…Besides nanoprecipitation, double emulsion method is another interesting approach to prepare polymersomes with the advantage of high yield, where the bilayer vesicles were formed from water-in-oil-in-water (W/O/W) double emulsions [38,39]. In the previous work, we used this method successfully to prepare polypeptoid vesicles [27]. Here we prepared EM2 polymersomes by double emulsion method (experimental details in Supporting information).…”

“…During the oxidation of D-glucose into gluconolactone by the catalysis of GOx, H2O2 is generated in presence of dissolved oxygen. It is H2O2 that transfers the hydrophobic thioether groups of PMeSPG into hydrophilic sulfoxides [27], eventually inducing the destabilization of polymersomes (Fig. 4A).…”

Controlled ring-opening polymerization of N-(3-tert-butoxy-3-oxopropyl) glycine derived N-carboxyanhydrides towards well-defined peptoid-based polyacids

“…While a range of polypeptoids with differing N-substituents have been successfully synthesized by ring-opening polymerization (ROP) of N-substituted glycine derived N-carboxyanhydrides (R-NCAs) 1,3 or N-thiocarboxyanhydride (R-NTA), 4 the structural diversity of N-substituents has been largely limited to various hydrocarbons (e.g., alkyl, [5][6][7][8][9][10] aromatic, 11,12 allyl, 13 propargyl) 14,15 and thioether groups. 16 While propargyl and allyl N-substituents can be further derivatized to install various functional groups on the polypeptoid polymers post-polymerization, the efficiency and extent of derivation vary with the nature of the functional groups and polymer chain length. 13,14,[17][18][19] Thus, it is desirable to design and develop controlled ring-opening polymerization of R-NCA monomers bearing functional N-substituents to enable access to well-defined polypeptoids that have quantitative functional sidechain presence and tailorable polymer chain length.…”