Dispersion Polymerization versus Emulsifier-Free Emulsion Polymerization for Nano-Object Fabrication: A Comprehensive Comparison.

Although the preparation of nano-objects by emulsifier-free controlled/living radical emulsion polymerization has drawn much attention, the morphologies of these formed objects are difficult to predict and to reproduce because of the much more complex nucleation mechanisms of emulsion polymerization compared to only one self-assembling nucleation mechanism of controlled radical dispersion polymerization. The present study compares dispersion polymerization with emulsifier-free emulsion polymerization in terms of nucleation mechanism, polymerization kinetics, and disappearance behavior of the macrochain transfer agent, gel permeation chromatograms curves of the obtained block copolymer as well as the structural and morphological differences between the produced nano-objects on the basis of published data. Moreover, the effects of the inherently heterogeneous nature of emulsion polymerization on the mechanism of reversible addition-fragmentation transfer polymerization and the nano-object morphology are examined, and efficient agitation and adequate solubility of the core-forming monomer in water are identified as the most crucial factors for the fabrication of nonspherical nano-objects.

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.

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.

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.

Multiple functional hyperbranched poly(amido amine) nanoparticles: synthesis and application in cell imaging.

The hyperbranched poly(amido amine) nanoparticles (HPAMAM NPs) with multiple functions, such as biodegradability, autofluorescence, and specific affinity, were successfully prepared by Michael addition dispersion polymerization of CBA, AEPZ, and N-galactosamine hydrochloride (or N-glucosamine hydrochloride) in a mixture of methanol/water. The resultant NPs displayed strong photoluminescence, high photostability, broad absorption, and emission (from 430 to 620 nm) spectra. The fluorescence from HPAMAM NPs may be attributed to the tertiary amine chromophore. The incubation results of the liver cancer cells, HepG2, with the NPs showed that the NPs are nontoxic and can be recognized by asialoglycoprotein receptors on the surface of HepG2 and then can be internalized. Therefore, they have potential applications in bioimaging and drug or gene delivery.

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.

Fluorescent mannose-functionalized hyperbranched poly(amido amine)s: synthesis and interaction with E. coli.

A water-soluble, biodegradable and fluorescent hyperbranched poly(amidoamine) with mannose groups on their surface (M-HPAMAM) has been successfully prepared, and the synthetic strategy includes Michael addition polymerization of diacrylamide with 1-(2-aminoethyl)piperazine and, subsequently, surface modification with mannosamine. The photoluminescence of M-HPAMAM was enhanced significantly due to the surface mannose groups. Incubation of E. coli with M-HPAMAMs yielded brightly fluorescent bacteria clusters, but the fluorescent intensity of the aqueous solution lowered. This indicates that the M-HPAMAMs have strong affinity with bacteria due to their polyvalent interactions. Based on the size and the amount of bacteria clusters formed, the bacteria with the concentrations higher than 10(2) cfu/mL can be detected.

Formation of Vesicular Morphologies via Polymerization Induced Self-Assembly and Re-Organization.

A facile and feasible strategy for the preparation of vesicular morphologies has been developed using reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymerization of styrene has been performed in a selected solvent, methanol, using S-1-dodecyl-S-(α,α'-dimethyl-α″-acetic acid)trithiocarbonate (TC)-terminated poly(4-vinylpyridine) as chain transfer agent and stabilizer. Various morphologies including spherical vesicles, nanotubes, and compound vesicles with different shapes are obtained by changing the feed ratios and reaction conditions. The final nanostructural materials are formed through formation of the block copolymers, self-assembly, and re-organization of the morphology in a one-pot polymerization. The latter two are induced by the propagation of PS blocks. The preparation of nanostructural materials can be performed at a concentration higher than 0.5 g · mL(-1) , thus this method offers a practical approach to prepare nanostructural materials on a large scale.

CO2-Responsive Nano-Objects with Assembly-Related Aggregation-Induced Emission and Tunable Morphologies.

CO2-responsive polymeric nano-objects with assembly-related aggregation-induced emission (AIE) are obtained via polymerization-induced self-assembly (PISA) of 2-(dimethylamino)ethyl methacrylate (DMAEMA), 2-(4-formylphenoxy)ethyl methacrylate (MAEBA), and 4-(1,2,2-triphenylvinyl)phenyl methacrylate (TPEMA). These nano-objects exhibit, depending on the feed of MAEBA, a morphology evolution process from spherical micelles to vesicles. Due to the presence of DMAEMA units, CO2 promotes morphology transformation of the nano-objects from spheres to a mixture of "jellyfish" and vesicles and vesicles to complex vesicles. Moreover, TPEMA endows the AIE feature to these nano-objects, offering a strategy to monitor the morphology evolution process in real time. Thus, this approach is significant for exploring the assembly mechanism of copolymer in polymerization-induced self-assembly and designing multistimuli-responsive polymeric nanomaterials with tunable morphologies and sizes.

Synthesis and Fluorescent Properties of Biodegradable Hyperbranched Poly(amido amine)s.

Disulfide-functionalized hyperbranched poly(amido amine)s (HPAMAMs) were synthesized by Michael addition polymerization of N,N'-cystaminebisacrylamide and 1-(2-aminoethyl)piperazine. The novel HPAMAMs displayed bright fluorescence, and the emissions bands cover nearly the whole visible wavelength range. When polymer solutions were excited at 330-385, 460-490, and 510-550 nm, blue, green, and red solutions were observed, respectively. The HPAMAMs are biodegradable and they can be easily cleaved by 2-mercaptoethanol or glutathione, leading to a decrease in the fluorescence intensity. Studies of applications of the biocompatible and biodegradable HPAMAMs in fluorescence imaging technology and biological science are in progress.

A facile strategy to control polymer topology by variation of controlled radical polymerization mechanisms.

A facile strategy for control of the polymer topologies can be achieved simply by tuning the feed molar ratio of catalyst to transfer agent in the controlled radical polymerization.

Photo-responsive camptothecin-based polymeric prodrug coated silver nanoparticles for drug release behaviour tracking via the nanomaterial surface energy transfer (NSET) effect.

A hybrid drug delivery system was successfully fabricated by attaching a camptothecin (CPT)-based polymeric prodrug onto the surface of silver nanoparticles (AgNPs). PEG was employed as a macro-RAFT agent in RAFT polymerization to synthesize a branched star copolymer, to which CPT is linked through the photo-responsive o-nitrobenzyl linkage. In vitro tests indicate that the fluorescence of CPT in the polymeric prodrug is quenched by AgNPs based on the nanomaterial surface energy transfer (NSET) effect and the fluorescence recovers when the CPT molecules are released from hybrid nanoparticles. Thus, the variation of fluorescence intensity is bound up with the drug release behaviours, which may enable this AgNP-based drug delivery system to trace the intracellular drug release process and observe the distribution of released CPT in cells.