Self-assembly Promoted Crystallization of Diblock Copolypeptoids in Solution

Comprehensive Summary,Great efforts have been lately devoted to fabricating well-defined nanostructures using crystallization-driven self-assembly(CDSA)strategy.The influence of self-assembly on crystallization is also of great interest.Here,a series of amphiphilic diblock copolypeptoids poly(N-allylglycine)-b-poly(N-octylglycine)modified with cysteamine hydrochloride((PNAG-g-NH_(2))-b-PNOG)were synthesized by ring-opening polymerization(ROP)and post-polymerization functionalization.The diblock copolypeptoid is comprised of one hydrophobic crystalline PNOG block and one hydrophilic amorphous block,which can aggregate into nanostructured assemblies with soluble PNAG-g-NH_(2) as the corona layer and PNOG as the inner core in aqueous solution.With a systematic study by differential scanning calorimetry(DSC)and wide-angle X-ray scattering(WAXS),we demonstrated that the self-assembly of the block copolymers strengthens the crystallization of the PNOG block.

Dual Photo/Thermo-Responsive Polypeptoids

A series of polypeptoids with dual photo/thermo-responsiveness were prepared by incorporating both azobenzene(Azo)group and oligo(ethylene glycol)(OEG)segment into the side chains.Firstly,the N-substituted-N-carboxyanhydride(NNCA)monomers with different Azo and OEG groups were synthesized,and then a single NNCA ring-openning polymerization was performed to afford dual-responsive polypeptoids without any post-polymerization modification.The ultra-violet/visible(UV/Vis)photo-responsive behaviors of the polypeptoids were achieved by cis-trans photoisomerization of the Azo group and confirmed by both ^(1)H-NMR and UV/Vis spectroscopy.The thermo-responsive behaviors were realized by both OEG segment and Azo group and confirmed by UV/Vis spectroscopy and dynamic light scattering.This work demonstrated the synthetic pathway for dual responsive polypeptoids using NNCA monomers with two responsive groups and revealed the potential of polypeptoids as smart materials that could respond to different environmental stimuli.

Combinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application

Biologics play an essential role in treating various indications from cancers to the metabolic diseases,while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane.Hence,there remains an unmet need to develop safe,potent approaches to augment intracellular protein delivery efficiency.Here,we described a facile multicomponent reaction system for generating a small library of redox-responsive cationic polypeptoids with high biocompatibility.The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency,thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly.After endo-lysosomal escape,the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol,owing to the intracellular glutathione(GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone.As a result,we screened a promising platform reagent for efficient cytosolic protein delivery application.

Open-vessel Synthesis of Poly-N-methoxyethylglycine

Polypeptoids are widely used in biological applications owing to their diverse functions and proteolytic stability.One type of polypeptoids,poly-N-methoxyethylglycine(P-Nmeg),has been found to possess remarkable hydrophilicity and notable properties in terms of protein,cell,and bacterial antifouling.However,the currently known synthesis methods of P-Nmeg include solid-phase synthesis,which is time-consuming and difficult to scale up,and N-substituted N-carboxyanhydride(NNCA)ring-opening polymerization,whose monomers were difficult to store.In this study,we used the chemical stable Nmeg N-phenoxycarbonyl(NPC)as the monomer,which was obtained without the use of highly toxic reactants,such as phosgene or phosphorus halide,to synthesize P-Nmeg under open-vessel conditions.By adding BnNH_(2) as an initiator at 80℃,we can obtain controllable short chain length P-Nmeg with narrow dispersity.

Accelerated heterogenous ring-opening polymerization towards well-defined helical poly(N-allyl alanine)with clickable side chains

Well-defined poly(N-allyl alanine)has been synthesized by heterogenous ring-opening polymerization(HROP)of less reactive N-allyl-alanine N-carboxyanhydride,using acetic acid as the catalyst and benzylamine as the initiator,in non-polar n-hexane.Interestingly,the polymerization exhibited typical features of living polymerization though both monomer(liquid)and polymer(solid)have minimal solubility in n-hexane.The obtained polymer showed a stable helix structure independent of the temperatures screened,as evidenced by circular dichroism analysis.Also,the preliminary study demonstrated that the side chains can be post-functionalized through thiol-ene click chemistry with quantitative conversion.Together,this work provides guidance for the development of accelerated HROP of other liquid monomers bearing low reactivity.Besides,the helical and functionalizable poly(N-allyl alanine)could be a useful“clickable platform”for the design of variable biomaterials via efficient click chemistry.

Alkali-metal hexamethyldisilazide initiated polymerization on alpha-amino acid N-substituted N-carboxyanhydrides for facile polypeptoid synthesis

Polypeptoids have been explored as mimics of polypeptides,owing to polypeptoids'superior stability upon proteolysis.Polypeptoids can be synthesized from one-pot ring-opening polymerization of amino acid N-substituted N-carboxyanhydrides(NNCAs).However,the speed of polymerization of NNCAs can be very slow,especially for NNCAs bearing a bulky N-substitution group.This hindered the exploration on polypeptoids with more diverse structures and functions.Therefore,it is in great need to develop advanced strategies that can accelerate the polymerization on inactive NNCAs.Hereby,we report that lithium/sodium/potassium hexamethyldisilazide(Li/Na/KHMDS)initiates a substantially faster polymerization on NNCAs than do commonly used amine initiators,especially for NNCAs with bulky N-substitution group.This fast NNCA polymerization will increase the structure diversity and application of polypeptoids as synthetic mimics of polypeptides.

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

Amphiphilic block copolymers poly(ethylene glycol)-block-poly(N-3-(methylthio)propyl glycine)(PEGb-PMeSPG)were synthesized via ring-opening polymerization of N-3-(methylthio)propyl glycine Nthiocarboxyanhydride(MeSPG-NTA)initiated by amino-terminated PEG.The self-assemblies of three PEG-b-PMeSPG copolymers with different PMeSPG block lengths were first prepared by nanoprecipitation method using THF and DMF,respectively,as the organic solvent,and their morphologies were studied by Cryo-EM and DLS.To prepare polymersomes loaded with glucose oxidase(GOx),double emulsion method followed by extrusion treatment was employed.The oxidation-responsive disruption of polymersomes was achieved upon the introduction of glucose because of the oxidants generated insitu by GOx/glucose.