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A series of eight-arm tapered star copolymers 8[P(I-co-S)x]-POSS were synthesized by the coupling reaction between octavinyl POSS and the tapered living copolymer chains obtained from statistical anionic copolymerization.

A triple stimuli-responsive nanoparticle derived from a noncovalently grafted amphiphilic copolymer was reported. The noncovalent graft copolymer, abbreviated as Dex-β-CD/Fc-PLA, was constructed by the host–guest interactions between β-cyclodextrin (β-CD) grafted dextran (Dex-β-CD) and ferrocene (Fc) terminated poly(lactide) (Fc-PLA). The synthetic Dex-β-CD/Fc-PLA copolymers and precursors were characterized by 1H NMR, FT-IR, UV-Vis, GPC, 2D NOESY 1H NMR and cyclic voltammetry (CV) analyses. The noncovalent amphiphilic copolymers could self-assemble into spherical nanoparticles (NPs) with dextran as the hydrophilic shell and PLA as the hydrophobic core in aqueous solution. The average particle size of Dex-β-CD/Fc-PLA NPs decreased from 118 nm to 79 nm with the increasing amount of hydrophobic PLA segments. Ascribed to the integration of many benzoic imine bonds and Fc groups, the NPs could remain stable at pH 7.4 but decomposed in the acidic and oxidizing (NaClO and positive voltage) media, as indicated by DLS and TEM measurements. The copolymer was used to encapsulate the hydrophobic anticancer drug doxorubicin (DOX) to achieve DOX-loaded NPs, which showed rather low drug release under simulated physiological conditions but significantly enhanced release in the simulated oxidizing and acidic media. MTT assays revealed that the pristine copolymer possessed low toxicity against both normal and cancer cells, but the DOX/Dex-β-CD/Fc-PLA NPs showed much higher selective toxicity on A549 cancer cells than normal HUVEC cells. Furthermore, the results from fluorescence microscopy demonstrated that these NPs could efficiently deliver and release DOX into the nuclei of A549 cells. The present biocompatible copolymers with triple stimuli-sensitivities are promising for the efficient intracellular delivery of hydrophobic anticancer drugs.

A tadpole-shaped amphiphilic copolymer containing cyclic hydrophobic poly(e-caprolactone) (PCL) and two hydrophilic poly(ethylene glycol) (PEG) tails, PEG-b-(c-PCL)-b-PEG, was rationally designed and prepared by a combination of ring-opening polymerization (ROP), chain end modification and intermolecular Cu-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reaction. Firstly, cyclic PCL with two pendent alkynyl groups (c-PCL-2alkynyl) was prepared via successive ROP, a bimolecular CuAAC “click” reaction and transformation of pendent hydroxyl groups to alkynyl groups. Subsequently, a tadpole-shaped amphiphilic copolymer PEG-b-(c-PCL)-b-PEG was fabricated by the CuAAC “click” reaction between c-PCL-2alkynyl and azido-terminated PEG (PEG-N3). For the comparison purpose, a linear triblock copolymer [PEG-b-(l-PCL)-b-PEG] and a 4-arm star copolymer (2PEG-b-2PCL) with comparable molecular weights and compositions were also synthesized. All these polymers were fully characterized by size exclusion chromatography (SEC), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. In addition, the self-assembly behavior, drug loading capacity and in vitro cytotoxicity of the tadpole-shaped amphiphilic copolymer and its linear and 4-arm star analogues were preliminarily investigated. It was found that the assemblies of PEG-b-(c-PCL)-b-PEG showed a similar spherical morphology but a smaller size compared with those of PEG-b-(l-PCL)-b-PEG and 2PEG-b-2PCL. The in vitro cytotoxicities against L929 fibroblast cells and HeLa cells evaluated by MTT assays revealed that the copolymers, especially PEG-b-(c-PCL)-b-PEG and 2PEG-b-2PCL, exhibited favorable biocompatibility, which might be potentially used as nanoscale drug delivery systems.

One important, yet less explored molecular parameter of star polymers is the distribution of arms in three dimensional (3D) space. Herein, we describe the synthesis of a series of mixed [2:6] hetero-arm star polymers whose arms are precisely arranged on a cubic scaffold of T8 polyhedral oligomeric silsesquioxane (POSS). The synthesis begins with regio-isomeric Janus POSS compounds (para-, meta-, and ortho-isomers) with two hydroxylethyl and six vinyl pendant groups. Two poly(e-caprolactone) (PCL) chains are grown from the hydroxyls by Sn(Oct)2-mediated ring-opening polymerization. The vinyls are then converted to azides for subsequent “grafting” of six polystyrene (PS) arms onto POSS. The configuration of the final star polymers was thoroughly characterized by NMR, FT-IR, SEC, and MALDI-TOF mass spectrometry. This serves as the first few examples of mixed-arm star polymers with precise distribution of multiple arms, providing an intriguing platform for the study of their self-assembly.

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.

Multiple drugs in combinatory therapy can improve the treatment of cancer due to their efficient reduction of multidrug resistance (MDR) of tumor cells. In this paper, we first synthesized a reduction-sensitive dextran-ss-camptothecin (Dex-ss-CPT, or Dex-CPT) prodrug conjugated by a disulfide bond, and a pH-responsive dextran-hyd-doxorubicin (Dex-hyd-DOX, or Dex-DOX) prodrug linked with an acid-cleavable hydrazone group. The chemical structures of the intermediate polymers and polymeric prodrugs have been fully characterized by 1H NMR, FT-IR, UV-Vis and HPLC analyses, respectively. Both prodrugs could self-assemble into uniform particles in aqueous solution. Subsequently, in vitro synergistic drug release of the two prodrugs was studied by methyl thiazolyl tetrazolium (MTT) assay. The reduction of a disulfide linker generates a thiol intermediate that is followed by intramolecular cyclization and the cleavage of the neighboring carbonate bridge, thus releasing native CPT molecules from the Dex-ss-CPT micelles. Similarly, the pH-sensitive hydrazone bond is broken under intracellular acidic conditions and the DOX parent drug is released from the Dex-hyd-DOX micelles. Finally, in vivo pharmacokinetics and biodistribution were investigated via intravenous administration with various formulations to treat 4T1 tumor-bearing mice. Meanwhile, the antitumor activity was also studied. This work demonstrates an effective anti-cancer prodrug design platform, which is expected to be useful for the treatment of various tumors.

Poly(ethyl ethylene phosphate) (PEEP) modified cellulose nanocrystals (CNCs) (CNC-g-PEEP) were synthesized through a “grafting onto” process, in which a combination of ring-opening polymerization (ROP) and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click” chemistry was utilized. The resulting suspension of negatively-charged CNC-g-PEEP nanocrystals could be used to encapsulate doxorubicin (DOX) by electrostatic interactions and release the drug in the tumor cell environment.

A series of well-defined three-armed star-block copolymers containing poly(ethylene glycol) monomethyl ether (mPEG) and poly(e-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.

In this study, three PEGylated doxorubicin (DOX) prodrugs with acid-labile acetal and carbamate linkages have been prepared via the combination of Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of alkyne and azide (CuAAC) “click” reaction and ammonolysis reaction. The chemical structures of the prodrugs and the drug contents were characterized by 1H NMR, FT-IR and HPLC analyses. To avoid some side effects caused by the acidic degradation products from conventional hydrophobic polymers, DOX was directly linked to the PEG chain. These prodrugs could self-assemble into micelles in aqueous solution with DOX as the core and PEG chains as the corona. The dissociation of prodrug micelles was confirmed by monitoring the size change as a function of time through DLS analysis. Compared with free DOX, the pH-triggered DOX release of prodrugs exhibited a well-controlled and faster release behavior at pH 5.0 than at pH 7.4. In vitro cytotoxicity tests against HeLa cells by MTT assay demonstrated that these prodrugs displayed the desirable antitumor activity. The intracellular drug release was observed by a live cell imaging system at different DOX dosages. This work provides a strategy for the preparation of a new type of pH-cleavable and water-soluble antitumor prodrug for cancer chemotherapy.

To prevent the disassembly of drug-loaded micelles under the high dilution conditions of the bloodstream, one of the efficient methods is to achieve the cross-linkage inside the micellar core. In this study, we have developed a kind of novel folate-conjugated core cross-linked polyphosphoester micelle with acid-cleavable acetal groups (ACCL-FA). These polyphosphoester-based cross-linked micelles possessed a much smaller size and enhanced stability compared to the uncross-linked (UCL) counterpart, and also showed good biodegradability and low cytotoxicity. The in vitro release studies revealed that the doxorubicin (DOX)-loaded ACCL micelles showed excellent stability with minimal drug release under neutral conditions, and displayed fast micellar dissociation and drug release in the presence of acid or phosphodiesterase I (PDE I). Moreover, with the comparison of the in vitro antitumor activity for free DOX, the DOX-loaded ACCL micelles, the DOX-loaded ACCL-FA micelles and the DOX-loaded folate-conjugated acid-insensitive cross-linked (CCL-FA) micelles, it could be found that the DOX-loaded ACCL-FA micelles exhibited higher inhibition of the proliferation of KB cells. In addition, these FA-decorated ACCL micelles showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated core cross-linked biodegradable micelles are highly promising for targeted cancer chemotherapy.

We report here a strategy that allows the preparation of a novel water-soluble polymeric prodrug, paclitaxel–poly(ethyl ethylene phosphate) conjugated with folic acid molecules (abbreviated as PTX–PEEP–FA). PTX was directly used as an initiator for the ring-opening polymerization (ROP) of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP) under the catalysis of Sn(Oct)2 to fabricate an amphiphilic PTX–PEEP, followed by covalently conjugating a FA moiety via esterification to obtain the biodegradable and targeted polymeric prodrug PTX–PEEP–FA. The chemical structure of the prodrug was characterized by 1H NMR and MALDI-TOF mass spectroscopy. TEM and DLS measurements showed that these prodrugs could self-assemble in aqueous solution to form micelles with PTX as the core and PEEP–FA as the corona, and the average particle size was less than 130 nm. The hydrophobic PTX core could be further used to load more water-insoluble anti-cancer drugs, such as PTX or doxorubicin (DOX), while the hydrophilic PEEP–FA chain endowed micelles with good stability during systemic circulation and significantly improved controlled-release properties compared to free PTX or DOX. Live cell imaging system was utilized to monitor the cellular uptake process of DOX-loaded PTX–PEEP–FA micelles for HeLa and KB cells, respectively. The results revealed that these drug-loaded micelles with FA on their surface could remarkably improve cell endocytosis. In vitro biological evaluations confirmed that PTX–PEEP–FA, simultaneously acted as both a prodrug and drug delivery carrier, could achieve the aims of increased drug loading efficiency, reduced cytotoxicity, and enhanced targeting efficacy.

This paper reports the design and synthesis of fluoroalkyl-functionalized polyhedral oligomeric silsesquioxane (FPOSS)-based shape amphiphiles with two distinct topologies: (i) mono-tethered FPOSS-poly(e-caprolactone) (PCL) and (ii) FPOSS tethered with two polymer chains possessing different compositions, namely, polystyrene (PS) and PCL, denoted as PS–(FPOSS)–PCL. The synthetic strategy features an efficient “growing-from” and “click-functionalization” approach. From a monohydroxyl-functionalized heptavinyl POSS, a PCL chain was grown via ring opening polymerization (ROP) of e-caprolactone; subsequent thiol–ene “click” chemistry with 1H,1H,2H,2H-perfluoro-1-decanethiol allowed the facile introduction of seven perfluorinated alkyl chains onto the POSS head. Similarly, PS–(FPOSS)–PCL was synthesized from a PS precursor bearing both hydroxyl group and heptavinyl POSS at the ω-end, which was prepared by living anionic polymerization and hydrosilylation. The compounds were fully characterized by 1H NMR, 13C NMR, FT-IR spectroscopy, MALDI-TOF mass spectrometry, and size exclusion chromatography. The introduction of perfluorinated molecular cluster into polymers is expected to make them surface-active while the interplay between crystallization and fluorophobic/fluorophilic bulk phase separation in these shape amphiphiles shall lead to intriguing self-assembly behavior and novel hierarchical structures. This study has demonstrated FPOSS as a versatile building block in the construction of shape amphiphiles and established a general and efficient method to introduce such fluorous molecular clusters into polymers.