Consecutive Reversible Addition-fragmentation Chain Transfer Research Articles

A self-cascade terpolymer platform for amplified chemo-chemodynamic therapy with synergistic immunogenic cell death enhancement

Chemodynamic therapy, which relies on the generation of cytotoxic radicals, can be amplified by a nanoplatform that produces hydroxyl radicals while also compromising natural radical scavenging mechanisms. For this purpose, a well-defined amphiphilic terpolymer, poly(oligo(ethylene glycol) monomethyl ether methacrylate)-block-poly(N,N-dimethyl aminoethyl methacrylate-statistical-monomer bearing ferrocene graft via azobenzene linker) (POEGMA-b-P(DMAEMA-st-(M-Azo-Fc), denoted as PAzo-Fc) is prepared by a consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization technique, and is further used for doxorubicin (DOX) encapsulation to afford DOX-loaded stabilized nanomicelles, DOX@PAzo-Fc with an average hydrodynamic diameter of 86.0 nm. DOX@PAzo-Fc shows a self-cascade property for amplified CDT. That is, Azo cleavage-induced glutathione (GSH) depletion alleviates reactive oxygen species (ROS) scavenging. Together with the DOX-enhanced hydrogen peroxide generation, the Fc-mediated Fenton reaction is boosted for enhanced CDT. More importantly, the resulting amplified cascade chemo-chemodynamic therapy exerts a synergistic immunogenic cell death (ICD) enhancement effect for effective cancer immunotherapy, which further resulted in a high tumor inhibition rate of 87.8 % in murine tumor models. The uniqueness of this study is the construction of a minimalist nanoplatform based on M-Azo-Fc units for amplified CDT via simultaneously producing hydroxyl radicals and compromising natural radical scavenging mechanisms. Overall, this self-cascade terpolymer platform fabricated herein offers a facile yet robust approach for advanced combinatory cancer therapy with great potential for clinical translations.

“Schizophrenic” self-assembly of dual thermoresponsive block copolymers bearing a zwitterionic and a non-ionic hydrophilic block

Several series of presumed dual thermo-responsive diblock copolymers consisting of one non-ionic and one zwitterionic block were synthesized via consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization. For all copolymers, poly(N-isopropylmethacrylamide) was chosen as non-ionic block that shows a coil-to-globule collapse transition of the lower critical solution temperature (LCST) type. In contrast, the chemical structure of zwitterionic blocks, which all belonged to the class of poly(sulfobetaine methacrylate)s, was varied broadly, in order to tune their coil-to-globule collapse transition of the upper critical solution temperature (UCST) type. All polymers were labeled with a solvatochromic fluorescent end-group. The dual thermo-responsive behavior and the resulting multifarious temperature-dependent self-assembly in aqueous solution were mapped by temperature-resolved turbidimetry, 1H NMR spectroscopy, dynamic light scattering (DLS), and fluorescence spectroscopy. Depending on the relative positions between the UCST-type and LCST-type transition temperatures, as well as on the width of the window in-between, all the four possible modes of stimulus-induced micellization can be realized. This includes classical induced micellization due to a transition from a double hydrophilic, or respectively, from a double hydrophobic to an amphiphilic state, as well as “schizophrenic” behavior, where the core- and shell-forming blocks are inverted. The exchange of the roles of the hydrophilic and hydrophobic block in the amphiphilic states is possible through a homogeneous intermediate state or a heterogeneous one.

Distinct Morphological Transitions of Photoreactive and Thermoresponsive Vesicles for Controlled Release and Nanoreactors

The construction of intelligent vesicular nanocarriers and nanoreactors has received increasing interests due to their potential in mimicking natural counterparts such as cells and organelles. Herein, we report thermoresponsive and photoreactive vesicles could be fabricated from amphiphilic block copolymers (BCPs), poly(N-isopropylacrylamide)-b-poly(2-((((2-nitrobenzyl)oxy)carbonyl)amino)ethyl acrylate) (PNIPAM-b-PNBOCA), which were synthesized via consecutive reversible addition–fragmentation chain transfer (RAFT) polymerizations. The resulting BCPs self-assembled into vesicles when temperatures were lower than the lower critical solution temperature (LCST) of PNIPAM blocks (defined as LCST0). However, the resulting vesicles irreversibly formed collapsed vesicles upon temperature rise (T > LCST0), and a further temperature increase (T > Tagg,0) led to the formation of irregular aggregates of collapsed vesicles. On the other hand, upon UV irradiation, the initially hydrophobic PNBOCA bilayers underwent am...

Effect of Molecular Architecture of PDMAEMA-POEGMA Random and Block Copolymers on Their Adsorption on Regenerated and Anionic Nanocelluloses and Evidence of Interfacial Water Expulsion.

Block copolymers of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) with varying block sizes were synthesized by consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization and then exposed to cellulose substrates with different anionic charge density. The extent and dynamics of quaternized PDMAEMA-b-POEGMA adsorption on regenerated cellulose, cellulose nanofibrils (CNF), and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)-oxidized cellulose nanofibrils (TOCNF) was determined by using electromechanical and optical techniques, namely, quartz crystal microbalance (QCM-D) and surface plasmon resonance (SPR), respectively. PDMAEMA-b-POEGMA equilibrium adsorption increased with the anionic charge of cellulose, an indication of electrostatic interactions. Such an observation was further confirmed by atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). Depending on their architecture, adsorption on TOCNF of some of the PDMAEMA-b-POEGMA copolymers produced a significant reduction in QCM frequency, as expected from large mass uptake, while surprisingly, other copolymers induced the opposite effect. This latter, remarkable behavior was ascribed to coupled water expulsion from the interface upon charge neutralization of anionic surface sites with adsorbing cationic polymer segments. These observations were further investigated with SPR and QCM-D measurements using deuterium oxide solvent exchange to determine the amount of coupled water at the TOCNF-block copolymer interface. Finally, random copolymers with similar composition adsorbed to a larger extent compared to the respective block copolymers, revealing the effect of adsorbed loops and tails as well as hydration.

Chain Length Dependence of Non-Surface Activity and Micellization Behavior of Cationic Amphiphilic Diblock Copolymers

The cationic and anionic amphiphilic diblock copolymers with a critical chain length and block ratio do not adsorb at the air/water interface but form micelles in solution, which is a phenomenon called "non-surface activity". This is primarily due to the high charge density of the block copolymer, which creates a strong image charge effect at the air/water interface preventing adsorption. Very stable micelle formation in bulk solution could also play an important role in the non-surface activity. To further confirm these unique properties, we studied the adsorption and micellization behavior of cationic amphiphilic diblock copolymers of poly(n-butyl acrylate)-b-poly(3-(methacryloyloxy)ethyl)trimethylammonium chloride) (PBA-b-PDMC) with different molecular weights of hydrophobic blocks but with the same ionic block length. These block copolymers were successfully prepared via consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization. The block copolymer with the shortest hydrophobic block length was surface-active; the solution showed surface tension reduction and foam formation. However, above the critical block ratio, the surface tension of the solution did not decrease with increasing polymer concentration, and there was no foam formation, indicating lack of surface activity. After addition of 0.1 M NaCl, stable foam formation and slight reduction of surface tension were observed, which is reminiscent of the electrostatic nature of the non-surface activity. Fluorescence and dynamic and static light scattering measurements showed that the copolymer with the shortest hydrophobic block did not form micelles, while the block copolymers formed spherical micelles having radii of 25-30 nm. These observations indicate that micelle formation is also important for non-surface activity. Upon addition of NaCl, cmc did not decrease but rather increased as observed for non-surface-active block copolymers previously studied. The micelles formed were very stable, and their size decreased by only ∼5 nm after addition of 0.1 M NaCl.

Thermomechanical Properties of Bimodal Brush Modified Nanoparticle Composites

The enthalpic incompatibility of organic polymer matrices and high surface energy inorganic nanoparticles often leads to phase separation in polymer nanocomposites (PNC) precluding the realization of anticipated property enhancements. The grafting of polymer chains to nanoparticles holds promise as a means for controlling dispersion. A single population of polymer chains with tunable graft density (σ) and molecular weight (N) is observed to have antithetical enthalpic and entropic effects on interface compatibility. We report the use of bimodal polymer brushes with fundamentally decoupled enthalpic and entropic parameters. Bimodal polystyrene brushes were grafted from 15 nm colloidal silica nanoparticles by a previously reported consecutive RAFT (reversible addition–fragmentation chain transfer) polymerization technique. The combination of a high graft density short brush and a low graft density long brush was found to cause improved nanoparticle dispersion in a polystyrene matrix when compared to single populations of long and short brushes of corresponding graft densities and molecular weights. A new quantitative model was developed to understand these results and was found capable of predicting dispersions in grafted nanoparticle composites in the allophobic dewetting regime. The bimodal-brush-graft particles were also found to be remarkably well dispersed in an entropically unfavorable higher molecular weight matrix. This facilitated a study of the role of matrix–brush entanglement on the thermomechanical properties of PNCs, isolated from the effects of particle dispersion. The best enhancements in glassy properties resulted from improved matrix–brush entanglement, attained by lowering the long chain graft density and increasing the long chain to matrix molecular weight ratio.

A Bifunctional Diblock Copolymer from Consecutive RAFT Polymerizations and its Functionalization

AbstractPoly(glycidyl methacrylate)‐block‐poly(4‐vinylbenzyl chloride), or P(GMA)‐b‐P(VBC), is synthesized via consecutive reversible addition‐fragmentation chain transfer (RAFT) polymerizations. Subsequent functionalization via atom‐transfer radical polymerization (ATRP) of methyl methacrylate (MMA) and styrene (St) gives rise to two functional brush‐type diblock graft copolymers, P(GMA)‐b‐(P(VBC)‐g‐P(MMA)) and P(GMA)‐b‐(P(VBC)‐g‐PS). These graft copolymers are further functionalized by a ring‐opening reaction of the P(GMA) block with diethylamine (DEA) to produce two diblock copolymer brushes, P(DEAHPMA)‐b‐(P(VBC)‐g‐P(MMA) and P(DEAHPMA)‐b‐(P(VBC)‐g‐PS (Brush‐2A). Single molecules of the copolymers are imaged by atomic force microscopy (AFM). Brush‐2A can be cast into porous membranes with well‐defined micropores from tetrahydrofuran (THF) solutions by phase inversion in an aqueous medium.

Self-assembly behavior of pH- and thermo-responsive hydrophilic ABCBA-type pentablock copolymers synthesized by consecutive RAFT polymerization

A multi-responsive hydrophilic ABCBA-type pentablock copolymer, consisting of poly(ethylene glycol), poly(N-isopropylacrylamide), and poly(2-(diethylamino)ethyl methacrylate), PDEA-b-PNIPAM-b-PEG-b-PNIPAM-b-PDEA, was synthesized by consecutive reversible addition–fragmentation chain transfer (RAFT) polymerization. The polymerization showed all of the expected features of living radical polymerization and allowed the synthesis of copolymers with controlled lengths of the PNIPAM and PDEA blocks. Due to the multi-component and multi-functional nature of the pentablock copolymer, the solution properties can be manipulated by the changing of parameters such as temperature, pH etc. For example, the copolymer could be dissolved in acidic aqueous solution at room temperature, since the pH was below the pKa of the PDEA block, and the temperature was below the lower critical solution temperature (LCST) of the PNIPAM block. While in alkaline solution at room temperature, the copolymer self-assembled into core–shell–corona micelles, with the hydrophobic PDEA block as the core, the thermoresponsive PNIPAM block as the shell and the hydrophilic PEG block as the corona. At elevated temperatures in acidic media, the copolymer self-assembled into PNIPAM-core micelles with mixed hydrophilic PEG and pH-responsive PDEA coronas. Moreover, the self-assembly behavior of the pentablock copolymers in aqueous solution was investigated by varying the length of PDEA blocks.

Bionanoparticles of amphiphilic copolymers polyacrylate bearing cholesterol and ascorbate for drug delivery

In this study, a series of amphiphilic polymers with poly(ascorbyl acrylate) (PAAA) as hydrophilic blocks and polyacrylate bearing side-chain cholesteryl mesogens (PCholDEGA) as hydrophobic blocks were prepared using a combination of four-step reactions consisting of two consecutive reversible addition-fragmentation chain transfer (RAFT), desulfurization, and hydrogenolysis under normal pressure. The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) as well as wide-angle X-ray diffraction (WAXD) studies showed that the copolymers with PCholDEGA as major block had relatively high stability and clear isotropization temperature (Ti). Small-angle X-ray diffraction (SAXD) investigation exhibited that the copolymers had bilayer smectic A structure. Their self-assembly behavior was monitored by turbidity change using UV–vis spectrometer, and the morphology and size of the nanoparticles via self-assembly were detected using transmission electron microscopy (TEM) and dynamic light scattering (DLS). The entrapment efficiency and loading capacity of these amphiphilic copolymers were investigated using nile red and drug molecule Ibuprofen. These polymeric micelles with PAAA shell extending into the aqueous solution and strong hydrophobic PCholDEGA core have potential abilities to act as promising nanovehicles with high loading and targeting delivery.

Ultrasensitive ratiometric fluorescent pH and temperature probes constructed from dye-labeled thermoresponsive double hydrophilic block copolymers

We report on the fabrication of highly sensitive ratiometric fluorescent pH and temperature probes based on thermoresponsive double hydrophilic block copolymers (DHBCs) with the two blocks labeled with two types of dyes possessing different pH-switchable emission characteristics. P(NIPAM-co-FITC)-b-P(OEGMA-co-RhBAM) DHBCs were synthesized via consecutive reversible addition–fragmentation chain transfer (RAFT) polymerizations in combination with post-modifications, where NIPAM, OEGMA, FITC, and RhBAM are N-isopropylacrylamide, oligo(ethylene glycol) monomethyl ether methacrylate, fluorescein isothiocyanate, and rhodamine B-based derivatives, respectively. Due to that FITC and RhBAM moieties exhibit prominent decrease and increase in emission intensities with decreasing solution pH, respectively, intensity ratios of characteristic RhBAM and FITC emission bands, I582/I522, of P(NIPAM-co-FITC)-b-P(OEGMA-co-RhBAM) unimers at 25 °C exhibit ∼39-fold changes in the range of pH 2–10. At elevated temperatures, thermo-induced formation of PNIPAM-core micelles enables effective fluorescence resonance energy transfer (FRET) between FITC and RhBAM moieties respectively located within micellar cores and coronas, and I582/I522 exhibits ∼52.5-fold changes in the same pH range. The reported dually modulated multicolor-emitting P(NIPAM-co-FITC)-b-P(OEGMA-co-RhBAM) DHBCs are capable of ultrasensitive fluorometric detection of solution pH and temperature in a ratiometric manner, which augurs well for their practical applications in sensing, imaging, and the fabrication of new generation of theranostic systems.

Facile synthesis of fluorescent ABA type amphiphilic triblock copolymers via RAFT polymerization and their aggregation behavior in a selective solvent

AbstractWell-defined naphthalene end-capped poly(styrene)-block-poly(Nisopropyl- acrylamide)-block-poly(styrene) (PS-b-PNIPAM-b-PS) amphiphilic triblock copolymers with different molecular weights and block copolymer compositions were successfully prepared via consecutive reversible additionfragmentation chain transfer (RAFT) polymerizations using a novel RAFT reagent, S,S'-bis(1-naphthylmethyl) trithiocarbonate (BNTTC). The aggregation behaviour of the prepared PS-b-PNIPAM-b-PS in water/DMF mixture was studied by transmission electron microscopy (TEM). The effect of the copolymer concentration, PNIPAM block length and the irradiation of UV-light on the sizes and morphologies of micelles were also investigated.

Synthesis of Miktoarm Dumbbell-Like Amphiphilic Triblock Copolymer by Combination of Consecutive RAFT Polymerizations and ATRP

A novel synthetic route, combining three reversible addition-fragmentation chain transfer (RAFT) and one atom transfer radical polymerization (ATRP) processes, for the preparation of a miktoarm dumbbell-like amphiphilic triblock copolymer, poly(poly(ethylene glycol) methyl ether methacrylate)-b-polystyrene-b-(poly(4-vinylbenzyl chloride)-g-polystyrene) (PPEGMA-b-PS-b-(PVBC-g-PS)), was developed using 2-cyanoprop-2-yl 1-dithionaphthalate (CPDN) as a RAFT agent, and the benzyl chloride group of the VBC units in the PVBC block as active ATRP macroinitiators, respectively. The structures of the obtained (co)polymers were characterized by 1H NMR spectroscopy. The obtained PPEGMA-b-PS-b-(PVBC-g-PS) amphiphilic triblock graft copolymer could self-assemble into spherical micelles with 100-300 nm diameters in a selective solvent.

Cononsolvency-Induced Micellization of Pyrene End-Labeled Diblock Copolymers of N-Isopropylacrylamide and Oligo(ethylene glycol) Methyl Ether Methacrylate

Pyrene end-labeled double hydrophilic diblock copolymers, poly(N-isopropylacrylamide)-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (Py-PNIPAM-b-POEGMA), were synthesized via consecutive reversible addition-fragmentation chain transfer polymerization using a pyrene-containing dithioester as the chain transfer agent. These diblock copolymers molecularly dissolve in pure methanol and water, but form well-defined and nearly monodisperse PNIPAM-core micelles in an appropriate mixture of them due to the cononsolvency of PNIPAM block. 1H NMR, laser light scattering, fluorescence spectroscopy, and transmission electron microscopy were employed to characterize the cononsolvency-induced PNIPAM-core micelles. When the volume fraction of water, phi water, in the methanol/water mixture is in the range of 0.5-0.8, the sizes of micelles are in the range of 20-30 nm in radius for Py-PNIPAM50-b- POEGMA18. At phi water = 0.5, the formed micelles possess the highest overall micelle density and the largest molar mass. The effects of varying the block lengths of Py-PNIPAM-b-POEGMA diblock copolymers on the structural parameters of PNIPAM-core micelles have also been explored. Although we can observe the immediate appearance of bluish tinge upon mixing the diblock copolymer solution in methanol with equal volume of water (phi water = 0.5), which is characteristic of the formation of micellar aggregates, the whole micellization process apparently takes a relatively long time to complete, as revealed by monitoring the time dependence of fluorescence emission spectra. The excimer/monomer fluorescence intensity ratios, IE/IM, continuously decrease with time and then reach a plateau value after approximately 20 min. The decrease of IE/IM after the initial formation of pseudo-equilibrium micelles should be ascribed to the structural rearrangement and further packing of PNIPAM segments within the micelle core, restricting the mobility of pyrene end groups and decreasing the probability of contact between them. Compared to the conventional cosolvent approach employed for the micellization of block copolymers in selective solvents, the reported cononsolvency-induced unimer-micelle-unimer transition of Py-PNIPAM-b-POEGMA in methanol/water mixtures has been unprecedented.