Synthesis of Poly(thioester sulfonamide)s via the Ring-Opening Copolymerization of Cyclic Thioanhydride with N-Sulfonyl Aziridine Using Mild Phosphazene Base.

Providing access to diverse polymer structures is highly desirable, which helps to explore new polymer materials. Poly(thioester sulfonamide)s, combining both the advantages of thioesters and amides, however, are rarely available in polymer chemistry. Here, the ring-opening copolymerization (ROCOP) of cyclic thioanhydride with N-sulfonyl aziridine using mild phosphazene base, resulting in well-defined poly(thioester sulfonamide)s with highly alternative structures, high yields, and controlled molecular weights, is reported. Additionally, benefiting from the mild catalytic process, this ROCOP can be combined with ROCOP of N-sulfonyl aziridines with cyclic anhydrides to produce novel block copolymers.

Facile Multicomponent Polymerization and Postpolymerization Modification via an Effective Meldrum's Acid-Based Three-Component Reaction.

Providing access to highly diverse polymer structures by multicomponent reactions is highly desirable; efficient Meldrum's acid-based multicomponent reactions, however, have been rarely highlighted in polymer chemistry. Here, the three-component reaction of Meldrum's acid, indole, and aldehyde is introduced into polymer synthesis. Direct multicomponent polymerization of Meldrum's acid, dialdehyde, and diindole can perform under mild conditions, resulting in complex Meldrum's acid-containing polymers with well-defined structures, and high molecular weights. Additionally, nearly quantitative postpolymerization modification can also perform via this Meldrum's acid-based multicomponent reaction. These results indicate that Meldrum's acid-based multicomponent reaction will be a potential tool to prepare novel polymers.

Polymerization-Induced Self-Assembly to Produce Prodrug Nanoparticles with Reduction-Responsive Camptothecin Release and pH-Responsive Charge-Reversible Property.

Polymerization-induced self-assembly has been demonstrated to be a powerful strategy for fabricating polymeric nanoparticles in the last two decades. However, the stringent requirements for the monomers greatly limit the chemical versatility of PISA-based functional nanoparticles and expanding the monomer family of PISA is still highly desirable. Herein, a camptothecin analogue (CPTM) is first used as the monomer in PISA. Prodrug nanoparticles with reduction-responsive camptothecin release behavior are fabricated at 10% solid concentration (100 mg g-1 ). Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) and poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) are used as the macro RAFT agents to comediate the RAFT dispersion polymerization of CPTM in ethanol to produce the PHPMA/PDEAEMA-stabilized nanoparticles. The PDEAEMA chains become hydrophobic and are in the collapsed state at physiological pH values. In contrast, in the vicinity of an acidic tumor, the tertiary amine groups of PDEAEMA chains are rapidly protonated, leading to fast hydrophobic-hydrophilic transitions and charge reversal. Such fast charge-reversal results in enhanced cancer cell internalization of the prodrug nanoparticles, thus achieving superior anticancer efficacy.

Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery.

Drug delivery systems (DDS) based on functionalized polymeric nanoparticles have attracted considerable attention. Although great advances have been reported in the past decades, the fabrication efficiency and reproducibility of polymeric nanoparticles are barely satisfactory due to the intrinsic limitations of the traditional self-assembly method, which severely prevent further applications of the intelligent DDS. In the last decade, a new self-assembly method, which is usually called polymerization-induced self-assembly (PISA), has become a powerful strategy for the fabrication of the polymeric nanoparticles with bespoke morphology. The PISA strategy efficiently simplifies the fabrication of polymeric nanoparticles (combination of the polymerization and self-assembly in one pot) and allows the fabrication of polymeric nanoparticles at a relatively high concentration (up to 50 wt%), making it realistic for large-scale production of polymeric nanoparticles. In this review, the developments of PISA-based polymeric nanoparticles for drug delivery are discussed.

Hyperbranched Multicyclic Polymer Built from Tailored Multifunctional Monocyclic Prepolymer.

A simple and efficient method to construct a hyperbranched multicyclic polymer is introduced. First, a tailored trithiocarbonate with two terminal anthracene units and three azide groups is successfully synthesized, and this multifunctional trithiocarbonate is used as chain transfer agent (CTA) to afford anthracene-telechelic polystyrene (PS) via reversible addition-fragmentation chain transfer (RAFT) polymerization. After that, linear PS is irradiated under 365 nm UV light to achieve the cyclization process. The monocyclic polymer further reacts with sym-dibenzo-1,5-cyclooctadiene-3,7-diyne via "A2 +B3 " strategy based on a self-accelerating click reaction to produce hyperbranched multicyclic polymer. The structures and properties of the polymers are characterized by nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), UV-vis spectrophotometry, and triple-detection size-exclusion chromatography (TD-SEC). The number of monocyclic units of the resultant hyperbranched multicyclic polymer reaches about 21 based on multi-angle laser light scattering (MALLS) measurements. The plot of intrinsic viscosity versus molecular weight reveals that the α value of the unique hyperbranched multicyclic polymer is lower than both hyperbranched polymers and cyclic polymers.

Efficient Synthesis of Polymer Prodrug by Thiol-Acrylate Michael Addition Reaction and Fabrication of pH-Responsive Prodrug Nanoparticles.

In this study, an efficient method is proposed for the synthesis of polymer prodrug with acid-liable linkage via thiol-acrylate Michael addition reaction of the camptothecin with tethering acrylate group and polymer scaffold containing multiple thiol groups. The polymer scaffold P(HEO2MA)- b-P(HEMA-DHLA) is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization of the methacrylate of lipoic acid (HEMA-LA) using poly(2-(2-hydroethoxy) ethyl methacrylate) (PHEO2MA) as macro-RAFT agent followed by reduction of the disulfides in lipoic acid (LA) groups to give polymer scaffold with dihydrolipoic acid (DHLA) pendent groups. Acrylate-tethering camptothecin (ACPT) is connected to P(HEO2MA)- b-P(HEMA-DHLA) via Michael addition reaction between thiol and acrylate with a high coupling efficiency (95%). Amphiphilic polymer prodrug P(HEO2MA)- b-P(HEMA-DHLA-CPT) spontaneously self-assembles into nanoparticles in an aqueous solution and exhibits a CPT loading content as high as 40.1%. The prodrug nanoparticles with the acid-liable ß-thiopropionate linkages can release CPT under acidic conditions, and the prodrug nanoparticles show similar cytotoxicity to HeLa cells as free CPT. Overall, the prodrug nanoparticles with high drug loading contents and acid-liable linkages are promising for pH-responsive anticancer therapy.

Efficient Fabrication of Photosensitive Polymeric Nano-objects via an Ingenious Formulation of RAFT Dispersion Polymerization and Their Application for Drug Delivery.

An ingenious formulation of RAFT dispersion polymerization based on photosensitive monomers of 2-nitrobenzyl methacrylate (NBMA) and 7-(2-methacryloyloxy-ethoxy)-4-methyl-coumarin (CMA) is reported herein. Various morphologies, such as spherical micelle, nanoworm, lamella, and vesicle, are fabricated at up to 20% solids content. Photoinduced cleavage of the NBMA moieties and dimerization of the coumarin moieties are simultaneously triggered upon UV (365 nm) irradiation. The former endows the cores of the nano-objects with abundant carboxyl groups, resulting in the transformation of the hydrophobic cores to hydrophilic ones. The latter induces the core-cross-linking of the nano-objects, which endows the nano-objects with enhanced structural stability and prevents the nanoparticle-to-unimer disassembly. The resultant nano-objects exhibit superior structural stability and excellent performances for drug delivery, including high drug loadings, pH-stimuli release, and high-efficient endosomal escape.

Fabrication of Reductive-Responsive Prodrug Nanoparticles with Superior Structural Stability by Polymerization-Induced Self-Assembly and Functional Nanoscopic Platform for Drug Delivery.

A highly efficient strategy, polymerization-induced self-assembly (PISA) for fabrication of the polymeric drug delivery systems in cancer chemotherapy is reported. Diblock prodrug copolymer, PEG-b-P(MEO2MA-co-CPTM) was used as the macro-RAFT agent to fabricate prodrug nanoparticles through PISA. The advantages of fabricating intelligent drug delivery system via this approach are as following: (1) Simultaneous fulfillment of polymerization, self-assembly, and drug encapsulation in one-pot at relatively high concentration (100 mg/mL); (2) Almost complete monomer conversion allows direct application of the resultant prodrug nanoparticles without further purification; (3) Robust structures of the resultant prodrug nanoparticles, because the cross-linker was used as the comonomer, resulted in core-cross-linking simultaneously with the formation of the prodrug nanoparticles; (4) The drug content in the resultant prodrug nanoparticles can be accurately modulated just via adjusting the feed molar ratio of MEO2MA/CPTM in the synthesis of PEG-b-P(MEO2MA-co-CPTM). The prodrug nanoparticles with similar diameters but various drug contents were obtained using different prodrug macro-CTA. In consideration of the long-term biological toxicity, the prodrug nanoparticles with higher drug content exhibit more excellent anticancer efficiency due to that lower dosage of them are enough for effectively killing HeLa cells.

Formation of Hexagonally Packed Hollow Hoops and Morphology Transition in RAFT Ethanol Dispersion Polymerization.

Similar to the traditional self-assembly strategy, polymerization induced self-assembly and reorganization (PISR) can produce a myriad of polymeric morphologies through morphology transitions. Besides the chain length ratio (R) of the hydrophobic to the hydrophilic blocks, the chain mobility in the intermediate nano-objects, which is a requisite for morphology transition, is a determining factor in the formation of the final morphology. Although various morphologies have been fabricated, hexagonally packed hollow hoops (HHHs) with highly ordered internal structure have not, to the best of our knowledge, been prepared by PISR. In this article, the fabrication of HHHs through morphology transition from large compound vesicles to HHHs is reported. HHHs with highly regular internal structure may have significance in theoretical research and practical applications of nanomaterials.

Bioreducible cross-linked nanoshell enhances gene transfection of polycation/DNA polyplex in vivo.

In this study, we have prepared a self-cross-linking PEG-based branched polymer, which easily forms a bioreducible nanoshell around polyplexes of cationic polymer and DNA, simply via heating the polyplex dispersions in the presence of this self-cross-linking branched polymer. This nanoshell can prevent the polyplex from dissociation and aggregation in physiological fluids without inhibiting the electrostatic interactions between the polymer and DNA. Furthermore, glutathione (GSH) can act as a stimulus to open the nanoshell after it has entered the cell. The polyplexes coated with the bioreducible nanoshell show an obvious enhancement in gene transfection in vivo compared with bare polyplexes.

Stimuli-triggered growth and removal of a bioreducible nanoshell on nanoparticles.

A new and easy method of stimuli-triggered growth and removal of a bioreducible nanoshell on nanoparticles is reported. The results show that pH or temperature could induce the aggregation of disulfide-contained branched polymers at the surface of nanoparticles; subsequently, the aggregated polymers could undergo intermolecular disulfide exchange to cross-link the aggregated polymers, forming a bioreducible polymer shell around nanoparticles. When these nanoparticles with a polymer shell are treated with glutathione (GSH) or d,l-dithiothreitol (DTT), the polymer shell could be easily removed from the nanoparticles. The potential application of this method is demonstrated by easily growing and removing a bioreducible shell from liposomes, and improvement of in vivo gene transfection activity of liposomes with a bioreducible PEG shell.

Galactose-based amphiphilic block copolymers: synthesis, micellization, and bioapplication.

Redox-responsive amphiphilic diblock copolymers, poly(6-O-methacryloyl-D-galactopyranose-co-2-(N,N-dimethylaminoethyl) methacrylate)-b-poly(pyridyl disulfide ethyl methylacrylate) (P(MAGP-co-DMAEMA)-b-PPDSMA) were obtained by deprotection of poly((6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-D-galactopyranose)-co-DMAEMA)-b-PPDSMA [P(MAlpGP-co-DMAEMA)-b-PPDSMA], which were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization of PDSMA using P(MAlpGP-co-DMAEMA) as macro-RAFT agent. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies showed that diblock copolymers P(MAGP-co-DMAEMA)-b-PPDSMA can self-assemble into micelles. Doxorubicin (DOX) could be encapsulated by P(MAGP-co-DMAEMA)-b-PPDSMA upon micellization and released upon adding glutathione (GSH) into the micelle solution. The galactose functional groups in the PMAGP block had specific interaction with HepG2 cells, and P(MAGP-co-DMAEMA)-b-PPDSMA can act as gene delivery vehicle. So, this kind of polymer has potential applications in hepatoma-targeting drug and gene delivery and biodetection.

One-pot synthesis of redox-responsive polymers-coated mesoporous silica nanoparticles and their controlled drug release.

A versatile one-pot strategy for the preparation of reversibly cross-linked polymer-coated mesoporous silica nanoparticles (MSNs) via surface reversible addition-fragmentation chain transfer (RAFT) polymerization is presented for the first time in this paper. The less reactive monomer oligo(ethylene glycol) acrylate (OEGA) and the more reactive cross-linker N,N'-cystaminebismethacrylamide (CBMA) are chosen to be copolymerized on the external surfaces of RAFT agent-functionalized MSNs to form the cross-linked polymer shells. Owing to the reversible cleavage and restoration of disulfide bonds via reduction/oxidation reactions, the polymer shells can control the on/off switching of the nanopores and regulate the drug loading and release. The redox-responsive release of doxorubicin (DOX) from this drug carrier is realized. The protein adsorption, in vitro cytotoxicity assays, and endocytosis studies demonstrate that this biocompatible vehicle is a potential candidate for delivering drugs. It is expected that this versatile grafting strategy may help fabricate satisfying MSN-based drug delivery systems for clinical application.

DPA-Zinc around Polyplexes Acts Like PEG to Reduce Protein Binding While Targeting Cancer Cells.

Gene therapy holds great promise as an effective treatment for many diseases of genetic origin. Gene therapy works by employing cationic polymers, liposomes, and nanoparticles to condense DNA into polyplexes via electronic interactions. Then, a therapeutic gene is introduced into target cells, thereby restoring or changing cellular function. However, gene transfection efficiency remains low in vivo due to high protein binding, poor targeting ability, and substantial endosomal entrapment. Artificial sheaths containing PEG, anions, or zwitterions can be introduced onto the surface of gene carriers to prevent interaction with proteins; however, they reduce the cellular uptake efficacy, endosomal escape, targeting ability, thereby, lowering gene transfection. Here, it is reported that linking dipicolylamine-zinc (DPA-Zn) ions onto polyplex nanoparticles can produce a strong hydration water layer around the polyplex, mimicking the function of PEGylation to reduce protein binding while targeting cancer cells, augmenting cellular uptake and endosomal escape. The polyplexes with a strong hydration water layer on the surface can achieve a high gene transfection even in a 50% serum environment. This strategy provides a new solution for preventing protein adsorption while improving cellular uptake and endosomal escape.

A unique aliphatic tertiary amine chromophore: fluorescence, polymer structure, and application in cell imaging.

Although photoluminescence of tertiary aliphatic amines has been extensively studied, the usage of this fundamental chromophore as a fluorescent probe for various applications has unfortunately not been realized because their uncommon fluorescence is easily quenched, and strong fluorescence has been observed only in vapor phase. The objective of this study is how to retain the strong fluorescence of tertiary amines in polymers. Tertiary amines as branching units of the hyperbranched poly(amine-ester) (HypET) display relatively strong fluorescence (Φ = 0.11-0.43). The linear polymers with tertiary amines in the backbone or as the side group are only very weakly fluorescent. The tertiary amine of HypET is easily oxidized under ambient conditions, and red-shifting of fluorescence for the oxidized products has been observed. The galactopyranose-modified HypET exhibits low cytotoxicity and bright cell imaging. Thus, this study opens a new route of synthesizing fluorescent materials for cell imaging, biosensing, and drug delivery.

Spiropyran-based hyperbranched star copolymer: synthesis, phototropy, FRET, and bioapplication.

Photo- and pH-responsive amphiphilic hyperbranched star copolymers, poly(6-O-methacryloyl-1,2;3,4-di-O-isopropylidene-d-galactopyranose)[poly(2-(N,N-dimethylaminoethyl) methacrylate)-co-poly(1'-(2-methacryloxyethyl)-3',3'-dimethyl-6-nitro-spiro(2H-1-benzo-pyran-2,2'-indoline))](n)s [HPMAlpGP(PDMAEMA-co-PSPMA)(n)], were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of the DMAEMA and the SPMA using hyperbranched PMAlpGP as a macro RAFT agent. In aqueous solution, the copolymers self-assembled to form core-shell micelles with HPMAlpGP core and PDMAEMA-co-PSPMA shell. The hydrophobic fluorescent dye nitrobenzoxadiazolyl derivative (NBD) was loaded into the spiropyran-containing micelles. The obtained micelles not only have the photochromic properties, but also modulate the fluorescence of NBD through fluorescence resonance energy transfer (FRET), which was also observed in living cells. Slight fluorescence intensity decrease of the spiropyran in merocyanine (ME) form was observed after five UV-visible light irradiation cycles. The cytotoxicity of the HPMAlpGP(PDMAEMA-co-PSPMA)(n) micelles was lower than that of 25k PEI. All the results revealed that these photoresponsive nanoparticles are a good candidate for cell imaging and may find broad applications in biological areas such as biological diagnosis, imaging, and detection.

Biocompatible zwitterionic sulfobetaine copolymer-coated mesoporous silica nanoparticles for temperature-responsive drug release.

A novel nanocontainer, which could regulate the release of payloads, has been successfully fabricated by attaching zwitterionic sulfobetaine copolymer onto the mesoporous silica nanoparticles (MSNs). RAFT polymerization is employed to prepare the hybrid poly(2-(dimethylamino)ethyl methacrylate)-coated MSNs (MSN-PDMAEMA). Subsequently, the tertiary amine groups in PDMAEMA are quaternized with 1,3-propanesultone to get poly(DMAEMA-co-3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate)-coated MSNs [MSN-Poly(DMAEMA-co-DMAPS)]. The zwitterionic PDMAPS component endows the nanocarrier with biocompatibility, and the PDMAEMA component makes the copolymer shell temperature-responsive. Controlled release of loaded rhodamine B has been achieved in the saline solutions.

Spiropyran-based polymeric vesicles: preparation and photochromic properties.

A direct access to photochromic polymeric vesicles was demonstrated via polymerization-induced self-assembly and reorganization (PISR). The resulting vesicles displayed interesting photochromic behaviors different from that of their free polymer chains in DMF, and the vesicles exhibited stronger fluorescence and excellent photostability due to confinement of conformational flexibility of the polymer chains in aggregates.

Silver Nanoparticles Covered with pH-Sensitive Camptothecin-Loaded Polymer Prodrugs: Switchable Fluorescence "Off" or "On" and Drug Delivery Dynamics in Living Cells.

A unique drug delivery system, in which silver nanoparticles (AgNPs) are covered with camptothecin (CPT)-based polymer prodrug, has been developed, and the polymer prodrug, in which the CPT is linked to the polymer side chains via an acid-labile ß-thiopropionate bond, is prepared by RAFT polymerization. For poly(2-(2-hydroxyethoxy)ethyl methacrylate-co-methacryloyloxy-3-thiahexanoyl-camptothecin)@AgNPs [P(HEO2MA-co-MACPT)@AgNPs], the polymer thickness on the AgNP surface is around 5.9 nm (TGA method). In vitro tests in buffer solutions at pH = 7.4 reveal that fluorescence of the CPT in the hybrid nanoparticles is quenched due to the nanoparticle surface energy transfer (NSET) effect, but under acidic conditions, the CPT fluorescence is gradually recovered with gradual release of the CPT molecules from the hybrid nanoparticles through cleavage of the acid-labile bond. The NSET "on" and "off" is induced by the CPT-AgNP distance change. This unique property makes it possible to track the CPT delivery and release process from the hybrid nanoparticles in the living cells in a real-time manner. The internalization and intracellular releasing tests of the hybrid nanoparticles in the HeLa cells demonstrate that the lysosome containing the hybrid nanoparticles displays CPT blue fluorescence due to release of the CPT under acidic conditions, and the drug-releasing kinetics shows fluorescence increase of the released CPT with incubation time. The cytotoxicity of hybrid nanoparticles is dependent on activity of the acid-labile bond. Therefore, this is a potential efficient drug delivery system in cancer therapy and a useful approach to study the mechanism of release process in the cells.

Fabrication of Functional Nano-objects through RAFT Dispersion Polymerization and Influences of Morphology on Drug Delivery.

To study the influence of self-assembled morphologies on drug delivery, four different nano-objects, spheres, nanorods, nanowires, and vesicles having aldehdye-based polymer as core, were successfully prepared via alcoholic RAFT dispersion polymerization of p-(methacryloxyethoxy)benzaldehyde (MAEBA) using poly((N,N'-dimethylamino)ethyl methacrylate) (PDMAEMA) as a macro chain transfer agent (macro-CTA) for the first time. The morphologies and sizes of the four nano-objects were characterized by TEM and DLS, and the spheres with average diameter (D) of 70 nm, the nanorods with D of 19 nm and length of 140 nm, and the vesicles with D of 137 nm were used in the subsequent cellular internalization, in vitro release, and intracellular release of the drug. The anticancer drug doxorubicin (DOX) was conjugated onto the core polymers of nano-objects through condensation reaction between aldehyde groups of the PMAEBA with primary amine groups in the DOX. Because the aromatic imine is stable under neutral conditions, but is decomposed in a weakly acidic solution, in vitro release of the DOX from the DOX-loaded nano-objects was investigated in the different acidic solutions. All of the block copolymer nano-objects show very low cytotoxicity to HeLa cells up to the concentration of 1.2 mg/mL, but the DOX-loaded nano-objects reveal different cell viability and their IC50s increase as the following order: nanorods-DOX < vesicles-DOX < spheres-DOX. The IC50 of nanowires-DOX is the biggest among the four nano-objects owing to their too large size to be internalized. Endocytosis tests demonstrate that the internalization of vesicles-DOX by the HeLa cells is faster than that of the nanorods-DOX, and the spheres-DOX are the slowest to internalize among the studied nano-objects. Relatively more nanorods localized in the acidic organelles of the HeLa cells lead to faster intracellular release of the DOX, so the IC50 of nanorods is lower than that of the vesicles-DOX.