The delicate influence of minute structural difference, such as regiochemistry, on self-assembly and phase behaviors has been commonly observed in small molecules but rarely in synthetic polymers. Herein, we report the precision synthesis of a series of double-chain giant surfactant regioisomers and their distinct phase structures and phase behaviors. These giant surfactants possess a hydroxyl-functionalized cubic T8 polyhedral oligomeric silsesquioxane head and two polystyrene tails tethered at para-, meta-, and ortho-configurations and were prepared following the sequential “click” method. As revealed by temperature-dependent small-angle X-ray scattering and bright-field transmission electron microscopy, their order–disorder transition temperatures decrease in the order of ortho-, meta-, and para-isomers, while order–order transitions were observed in the meta-isomer from lamellae to double gyroids and in the ortho-isomer from double gyroids to hexagonal cylinders upon increasing temperature. The mechanisms are elucidated by the influence of the tethering positions on the different free energy contributions, i.e., the interfacial energy, the head-to-head interaction, and the entropic energy of the tails. The distinct assembly behaviors of the three regioisomers are unusual in macromolecules yet resemble small molecules. It opens an avenue to fine-tune the macromolecular assembly at the level of molecular precision.

This paper is aimed at comparing the effects of flexible and rigid blocks on the morphologies of multicompartment aggregates self-assembled from two kinds of fluorinated ABC triblock terpolymers, in which polyisobutylene (PIB) with a low glass transition temperature (Tg ∼ −67 °C) and polystyrene (PS) with high Tg (∼100 °C) were selected as the flexible and rigid blocks, respectively. The fluorinated triblock terpolymers (abbreviated as PIB-b-PDMAEMA-b-POFPMA and PS-b-PDMAEMA-b-POFPMA, respectively) with similar relative block lengths were synthesized via consecutive oxyanion-initiated polymerization (OIP) of 2-N,N-(dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate (OFPMA) using pre-functionalized PIB-O−K+ or PS-O−K+ as the macroinitiators. These terpolymers could self-assemble in aqueous solution since the PDMAEMA block is hydrophilic, PIB and PS blocks are hydrophobic, while the POFPMA block is both hydrophobic and lipophobic. The self-assembly behavior was analyzed by transmission electron microscopy (TEM). It has been demonstrated that PIB-b-PDMAEMA-b-POFPMA with the flexible PIB block could self-assemble into four types of reproducible nanostructures with the increase of polymer concentrations, including multicompartment micelles, fiber-like aggregates, nanotubules and rod-like aggregates. More interestingly, a uniform zig-zag pattern was observed on the surface of these rod-like aggregates after the solution was maintained without stirring for one week. In contrast, for the PS-b-PDMAEMA-b-POFPMA system containing a rigid PS block, the similar morphologies were rarely observed, except for spherical, hamburger and flower-like multicompartment nanostructures. The present work reveals that the flexibility or rigidity of the hydrophobic segment as well as the polymer concentration exerts a big influence on both the self-assembly behavior and formation of diversified morphologies.

Radiation is one of the most widely used methods for cancer diagnosis and therapy. Herein, we report a new type of radiation sensitizer (Fc-PEG) by a facile one-step reaction of conjugating the hydrophilic PEG chain with hydrophobic ferrocene molecule. The chemical composition and structure of Fc-PEG have been thoroughly characterized by FT-IR, NMR, GPC, and MALDI-TOF mass spectrometry. This Fc-PEG conjugate could self-assemble in aqueous solution into spherical aggregates, and it was found that the exposure to 4 Gy of X-ray radiation have little influence on the shape and size of these aggregates. After the chemical bonding with PEG chains, the uptake level of Fe element could be enhanced via the formation of aggregates. The live/dead, CCK-8, as well as apoptosis assays, indicated that the death of cancer cells can be obviously increased by X-ray radiation after the incubation of these Fc-based nanoconjugates, which might be served as the radiation sensitizer toward cancer cells. We suggest that this radiosensitizing effect comes from the enhancement of reactive oxygen specimen (ROS) level as denoted by both flow cytometric and fluorescence microscopic analysis. The enhanced radiation sensitivity of cancer cells is contributed by the synergic effect of Fe-induced radiation-sensitizing and the increased uptake of nanoconjugates after polymeric grafting.

A new kind of reduction-cleavable polymer-camptothecin (CPT) prodrug has been developed, in which the polymer backbone consists of a biodegradable diblock polyphosphoester (PBYP-b-PEEP), and a modified CPT is linked onto the pendant alkynes of PBYP via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to yield the polymeric prodrug, abbreviated as (PBYP-g-ss-CPT)-b-PEEP. The resulting prodrug could self-assemble into uniform prodrug micelles in aqueous solution. Since the releasable disulfide carbonate between the CPT and the polyphosphoester would be disrupted under an intracellular reducing environment, the disassociation of prodrug micelles could result in a rapid release of the CPT parent drug. The chemical structures of the intermediate polymers and a polymeric prodrug have been fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The self-assembly behavior of the prodrug was investigated by the fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The DLS results indicated that these prodrug micelles were relatively stable in neutral pH media, but could be degraded under the reductive conditions. The in vitro drug release studies showed that the CPT release from prodrug micelles was proceeded in a glutathione (GSH)-dependent manner. A methyl thiazolyl tetrazolium (MTT) assay demonstrated that the prodrug micelles could efficiently inhibit the proliferation of HepG2 cells. In addition, the intracellular uptake of prodrug micelles could efficiently release CPT into HepG2 cells, which was observed using a live cell imaging system. All these results indicated that this GSH-responsive polymeric prodrug has high potential for reduction-triggered cancer chemotherapy.

A series of well-defined three-armed star-block copolymers containing poly(ethylene glycol) monomethyl ether (mPEG) and poly(ε-caprolactone) (PCL) blocks linked with acid-cleavable acetal groups, designated as (mPEG-acetal-PCL-acetal-)3 or (mPEG-a-PCL-a-)3, have been prepared via a “coupling-onto” method based on ring-opening polymerization (ROP) and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “Click” chemistry. The chemical compositions and structures, as well as the molecular weights and molecular weight distributions (PDIs) of these copolymers have been fully characterized by 1H NMR, FT-IR, and GPC measurements. Differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) analyses demonstrated that the thermal behaviors of the star-block copolymers strongly depended on the relative lengths of PEG and PCL blocks in the arms. The self-assembly behaviors of these amphiphilic star-block copolymers were investigated by a fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The results showed that they could self-assemble into spherical micelles at low concentrations and mainly formed short rod-like micelles at high concentrations. Moreover, the acid-cleavable properties of these star-block copolymers were systematically studied by 1H NMR, GPC, and DLS measurements, and the results indicated that they were relatively stable in neutral pH media, but could be degraded under acidic conditions. The in vitro DOX release studies showed that DOX was released from drug-loaded micelles in a pH-sensitive manner. MTT assays demonstrated that these star-block copolymers possess low cytotoxicity against L929 cells and HeLa cells, and the DOX-loaded micelles exhibit a higher inhibition of the proliferation of HeLa cells in comparison with free DOX. Moreover, the results from the live cell imaging system and flow cytometry analysis revealed that these polymeric micelles could efficiently deliver and release DOX into the nuclei of HeLa cells. These pH-triggered shell-sheddable micelles are highly promising for the efficient intracellular delivery of hydrophobic anti-cancer drugs.

An acid-labile and PEGylated polyphosphoester-doxorubicin prodrug (PBYP-g-PEG-g-DOX) was prepared via a combination of ring-opening polymerization (ROP) and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click” chemistry. The resulting multifunctional prodrug was then used to interact with α-cyclodextrin (α-CD) to fabricate a novel supramolecular hydrogel based on inclusion complexation.

Novel galactosamine (Gal)-modified polymeric micelles which were responsive to both reduction (via the disulfide group, -ss-) and pH (acetal group, -a-) were constructed from poly(ethylethylene phosphate)-a-poly(ε-caprolactone)-ss-poly[2-(dimethylamino)ethyl methacrylate] (Gal-PEEP-a-PCL-ss-PDMAEMA) terpolymers in order to develop a multifunctional bioreducible system for the targeted co-delivery of anticancer drugs and DNA. These multifunctional terpolymers were synthesized via a combination of ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP) and a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction. The chemical structures, chemical compositions, the molecular weights and molecular weight distributions of these terpolymers have been fully characterized, and their self-assembly behavior was studied in detail. The interaction between the terpolymers and DNA was studied by an agarose gel retardation assay. The physical properties of the resulting polyplexes were further determined by zeta potential, dynamic light scattering (DLS) and TEM analyses. The micelles containing the acetal and disulfide groups could be dissociated in an intracellular environment. The reduction- and pH-triggered release of doxorubicin (DOX) from DOX-loaded micelles showed that the release of DOX was accelerated at pH 5.0 and pH 7.4 with 10 mM cytoplasmic glutathione (GSH), and that the release rate was further enhanced at pH 5.0 with 10 mM GSH. A methyl thiazolyl tetrazolium (MTT) assay indicated that the blank micelles displayed relatively low cytotoxicity towards HeLa and HepG2 cells. Although the DOX-loaded micelles could efficiently prohibit the growth of both cell types, they exhibited much higher cytotoxicity towards HepG2 cells than HeLa cells. In addition, the intracellular uptake and transfection of Gal-PEEP-a-PCL-ss-PDMAEMA/DNA/DOX polyplexes into HepG2 cells was more efficient than that into HeLa cells, as revealed by a live cell imaging system, owing to specific ligand–receptor interactions between Gal and asialoglycoprotein receptors overexpressed on the surface of HepG2 cells. These results provide a facile strategy for the preparation of multifunctional biodegradable polymeric micelles that may act as a promising platform for the targeted intracellular co-delivery of hydrophobic drugs and nucleic acids.

A new kind of reduction-cleavable polymer-camptothecin (CPT) prodrug has been developed, in which the polymer backbone consists of a biodegradable diblock polyphosphoester (PBYP-b-PEEP), and a modified CPT is linked onto the pendant alkynes of PBYP via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to yield the polymeric prodrug, abbreviated as (PBYP-g-ss-CPT)-b-PEEP. The resulting prodrug could self-assemble into uniform prodrug micelles in aqueous solution. Since the releasable disulfide carbonate between the CPT and the polyphosphoester would be disrupted under an intracellular reducing environment, the disassociation of prodrug micelles could result in a rapid release of the CPT parent drug. The chemical structures of the intermediate polymers and a polymeric prodrug have been fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The self-assembly behavior of the prodrug was investigated by the fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The DLS results indicated that these prodrug micelles were relatively stable in neutral pH media, but could be degraded under the reductive conditions. The in vitro drug release studies showed that the CPT release from prodrug micelles was proceeded in a glutathione (GSH)-dependent manner. A methyl thiazolyl tetrazolium (MTT) assay demonstrated that the prodrug micelles could efficiently inhibit the proliferation of HepG2 cells. In addition, the intracellular uptake of prodrug micelles could efficiently release CPT into HepG2 cells, which was observed using a live cell imaging system. All these results indicated that this GSH-responsive polymeric prodrug has high potential for reduction-triggered cancer chemotherapy.