Pentablock Copolymers Research Articles

Single dose combination nanovaccine provides protection against influenza A virus in young and aged mice.

Immunosenescence poses a formidable challenge in designing effective influenza vaccines for aging populations. While approved vaccines against influenza viruses exist, their efficacy in older adults is significantly decreased due to the diminished capabilities of innate and adaptive immune responses. In this work, the ability of a combination nanovaccine containing both recombinant hemagglutinin and nucleoprotein to provide protection against seasonal influenza virus infection was examined in young and aged mice. Vaccine formulations combining two nanoadjuvants, polyanhydride nanoparticles and pentablock copolymer micelles, were shown to enhance protection against challenge compared to each adjuvant alone in young mice. Nanoparticles were shown to enhance in vitro activation of dendritic cells isolated from aged mice, while both nanoadjuvants did not induce proinflammatory cytokine secretion which may be detrimental in aged individuals. In addition, the combination nanovaccine platform was shown to induce demonstrable antibody titers in both young and aged mice that correlated with the maintenance of body weight post-challenge. Collectively, these data demonstrate that the combination nanovaccine platform is a promising technology for influenza vaccines for older adults.

Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer

A polymeric dual delivery nanoscale device (DDND) was designed for combined delivery of microRNA (miR-345) and gemcitabine (GEM) to treat pancreatic cancer (PC). This temperature and pH-responsive pentablock copolymer system was able to restore miR-345, making xenograft tumors more susceptible to GEM, the standard therapy for PC. Restoration using DDND treatment results in sonic hedgehog signaling down regulation, which decreases desmoplasia, thereby resulting in improved GEM perfusion to the tumor and better therapeutic outcomes. The release of miR-345 and GEM could be tuned by using the DDND in the form of micelles or in the form of thermoreversible gels, based on polymer concentration. The DDNDs enabled miR-345 stability and sustained co-release of miR-345 and GEM, thereby facilitating dose-sparing use of GEM. Further, enhanced in vitro cellular uptake due to amphiphilic character, and endosomal escape because of the cationic end blocks led to efficient transfection with DDNDs. The combined DDND treatment enabled efficient reduction in cell viability of Capan-1 and CD18/HPAF cells in vitro compared with either GEM or miR-345 treatment alone. Mice carrying xenograft tumors treated with DDNDs carrying both miR-345 and GEM combination therapy displayed reduced tumor growth and less metastasis in distant organs compared to individual drug treatments. Immunohistochemical analysis of the xenograft tissues revealed significant down regulation of desmoplastic reaction, SHH, Gli-1, MUC4, and Ki67 compared to control groups.

Systematic Approaches To Tailor the Morphologies and Transport Properties of Solution-Cast Sulfonated Pentablock Copolymers

Sulfonated block polymers are widely studied for applications in water management and electrochemical devices because they combine the properties of ionomers and thermoplastic elastomers in a singl...

Amino acid functionalized pH- and temperature-sensitive biodegradable injectable hydrogels: synthesis, physicochemical characterization and in vivo degradation kinetics

In recent years, injectable hydrogels that undergo sol-to-gel phase transition in response to the physiological pH- and temperature have attracted increasing attention in therapeutics delivery. In this study, we developed a biodegradable pH- and temperature-sensitive pentablock copolymers by chemical conjugation of L-cysteine oligomer to the backbone of poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) (PCLA-PEG-PCLA) copolymers. A series of pentablock copolymers with various chain lengths were prepared by tuning the reaction time and temperature. These copolymers were freely soluble in water at high pH and low temperature; whereas, they could form a stable gel at the physiological condition (pH 7.4, 37 °C). An in vivo injectable study in the back of Sprague-Dawley (SD) rats indicated that the copolymer could form an in situ gel. In addition, an in vivo biodegradation study of the hydrogels showed controlled degradation of the gel matrix without inflammation at the injection site. Overall, our results show that biodegradable pH- and temperature-responsive hydrogel prepared in this study found to be bioresorbable and could be used as a controlled therapeutics delivery vehicle.

Polyamide-based pH and temperature-responsive hydrogels: Synthesis and physicochemical characterization

The pH- and temperature-responsive pentablock copolymers that could form in situ hydrogels, composed of pH-responsive polyamide and temperature-responsive poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone) (PCL-b-PEG-b-PCL), have been synthesized. The pH-responsive polyamide blocks containing diamide linkages were synthesized using condensation polymerization of adipic acid dihydrazide and phthalic anhydride; whereas, temperature-responsive PCL-b-PEG-b-PCL was synthesized by ring-opening polymerization of e-caprolactone in the presence of bifunctional PEG macroinitiator. Pentablock copolymer was then synthesized by the chemical conjugation of carboxylic acid-terminated pH-responsive copolymer to the chain end of temperature-responsive triblock copolymer through ester bond formation. The pKa values of pH-sensitive polyamide, measured using titration method, varied depending on the average molecular weight of polymers. In aqueous solutions, the pentablock and triblock copolymers formed spherical micelles and their particle sizes were found to be 55 to 100 nm. The pentablock copolymer exhibited pH- and temperature-induced sol-to-gel phase transition. At high pH and low temperature, the copolymers were freely soluble even at 20 wt% concentration and form stable hydrogel at the physiological condition (pH 7.4, 37 °C). Furthermore, the sol-to-gel window of the pentablock copolymers was controlled by varying the composition of polyamide to PCL/PEG and covers the physiological region. Overall, these results suggest that the sharp physicochemical change of the pentablock copolymers may be exploited in controlled delivery applications.

Highways for water molecules: Interplay between nanostructure and water vapor transport in block copolymer membranes

Water vapor removal is a crucial process for several industries (e.g., air conditioning systems, flue gas dehydration, compressed air drying etc.). An effective dehumidification has the potential to drastically reduce the energy consumption and the overall cost of a process stream. Membranes with high water permeance and selectivity are promising candidates to achieve an energy-efficient water removal. We propose self-assembled membranes with interconnected and ordered hydrophilic domains that act as extremely fast water transport highways (water channels). We used a commercial amphiphilic pentablock copolymer (Nexar™), which has the ability to form long-range, self-ordering nanoscale morphologies with rigid end-blocks and a flexible molecular network where polar and non-polar solvents regulated the final morphologies of the membranes. Our results demonstrate how well-defined periodic morphology allow for molecular level control in effective removal of water vapor. The membranes with ordered hydrophilic nanochannels present a 6-fold improvement in water vapor permeability and a 14-fold increase in water vapor/N2 selectivity compared to Nexar™ membranes with disordered domains.Molecular dynamics stimulations are carried out on the self-assembly behavior of block copolymer solution in different solvents. In addition, sorption and desorption kinetics studies for Nexar™ films were correlated to the different morphologies imaged by transmission electron, atomic force and environmental scanning electron microscopy.

On-demand Microfluidic Manipulation of Thermally Stable Water-in-Perfluorocarbon Emulsions

Monodispersed thermally stable aqueous emulsions were generated in perfluorocarbon oil with penta-block copolymers of fluorocarbon and poly(ethylene oxide-b-propylene oxide-b-ethylene oxide), which are controlled in guided channels of microfluidic devices, which were essentially the protrusion on top of microfluidic channels. Aqueous emulsions could stably follow the guide channels and sequentially stored at dead ends of guide channels. Depending on the size ratio of emulsion to trapping region, one or two emulsions were stored in two-dimensional arrays on demand. By adding pneumatic valve actuators on top of guide channel, they could be stored or released on demand or as programmed. Furthermore, by encapsulating colloidal particles and Hela cells in the thermally stable water-in-perfluorocarbon emulsions, we demonstrated that particle-laden and cellladen emulsions could be manipulated in controlled and programmed manner.

Degradable and Injectable Hydrogel for Drug Delivery in Soft Tissues.

Injectable hydrogels are promising platforms for tissue engineering and local drug delivery as they allow minimal invasiveness. We have here developed an injectable and biodegradable hydrogel based on an amphiphilic PNIPAAm- b-PLA- b-PEG- b-PLA- b-PNIPAAm pentablock copolymer synthesized by ring-opening polymerization/nitroxide-mediated polymerization (ROP/NMP) combination. The hydrogel formation at around 30 °C was demonstrated to be mediated by intermicellar bridging through the PEG central block. Such a result was particularly highlighted by the inability of a PEG- b-PLA- b-PNIPAAm triblock analog of the same composition to gelify. The hydrogels degraded through hydrolysis of the PLA esters until complete mass loss due to the diffusion of the recovered PEG and PNIPAAm/micelle based residues in the solution. Interestingly, hydrophobic molecules such as riluzole (neuroprotective drug) or cyanine 5.5 (imaging probe) could be easily loaded in the hydrogels' micelle cores by mixing them with the copolymer solution at room temperature. Drug release was correlated to polymer mass loss. The hydrogel was shown to be cytocompatible (neuronal cells, in vitro) and injectable through a small-gauge needle (in vivo in rats). Thus, this hydrogel platform displays highly attractive features for use in brain/soft tissue engineering as well as in drug delivery.

PSMA Antibody-Conjugated Pentablock Copolymer Nanomicellar Formulation for Targeted Delivery to Prostate Cancer.

The main purpose of this study was to develop a prostate-specific membrane antigen (PSMA) antibody-conjugated drug-loaded nanomicelles using MPEG--PLA-PCL-PLA-PEG-NH2 pentablock copolymer for targeted delivery of hydrophobic anticancer drugs to prostate cancer cells. During this experiment, monomers of L-lactide, ε-caprolactone, poly(ethylene glycol)-methyl ether, and poly(ethylene glycol)-NH2 were used to prepare pentablock copolymer using the ring opening technique. The pentablock nanomicellar (PBNM) formulation was prepared by the evaporation-rehydration method. The resultant pentablock nanomicelles were then conjugated with PSMA antibody resulting in PSMA-Ab-PTX-PBNM. Both the block copolymers and the nanomicelles were analyzed by hydrogen nuclear magnetic resonance (H-NMR), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The obtained nanomicelles (NM) were then analyzed for size and zeta potential using dynamic light scattering-dynamic laser scattering (DLS) and then further submitted to H-NMR and TEM analyses. The XRD, FTIR, and the H-NMR analyses confirmed the structure of the pentablock copolymers. The average size for conjugated nanomicellar was 45nm ± 2.5nm. The average (ζ-potential) was around - 28mV. H-NMR and FTIR analysis done on PSMA-coupled paclitaxel-loaded PBNM showed peaks characteristic of the drug (paclitaxel) and the polymer, confirming the successful encapsulation. TEM analysis showed well-defined spherical morphology and confirmed the size range obtained by the DLS. In vitro release studies revealed sustained slow of PTX in phosphate buffer solution (PBS). Confocal scanning microscopy (TEM) of coumarin6-loaded in PBNM indicated that pentablock nanomicelles were internalized into the prostate cancer (PC-3) cells. Cell proliferation assay showed that nanomicelles ferried paclitaxel into the PC-3 cells and subsequently reduced the cell proliferation. The results depict PTX-PBNM-Ab as a suitable carrier for targeted delivery of drugs to prostate cancer cells.

Strategic Pentablock Copolymer Nanomicellar Formulation for Paclitaxel Delivery System.

Nanomicelles (NM) enhance solubility and absorption of active pharmaceutical ingredients (APIs). Various polymers and non-polymers are utilized to prepare nanomicellar formulations to achieve high absorption and delivery of drugs. The main purpose of this study was to develop drug-loaded nanomicelles with pentablock copolymers for paclitaxel delivery. Monomers of lactide, ε-caprolactone, and polyethylene-glycol were utilized to prepare pentablock copolymer by ring opening technique. The pentablock nanomicelles (PBNM) were formulated by evaporation and rehydration. Both copolymers and nanomicelles were analyzed by H-NMR, FTIR, and XRD. Nanomicelles were further analyzed for size and zeta potential using dynamic light scattering (DLS) and by H-NMR and TEM. The XRD, FTIR, and H-NMR analyses confirmed the structures of the pentablock copolymers. Average size was 20nm ± 5.00nm, and ζ-potential is around zero. H-NMR and FTIR analyses for Paclitaxel-PBNM indicated peaks of paclitaxel and the polymer, confirming successful encapsulation. TEM showed spherical morphology and size range similar to that obtained by DLS. In vitro release studies revealed slow first-order paclitaxel release rate from pentablock nanomicelles in phosphate buffer solution (PBS). Confocal laser scanning microscopy analysis with coumarin-6-loaded in PBNM indicated that pentablock nanomicelles were efficiently taken into prostate cancer (PC-3) cells. Cell proliferation assay showed that nanomicelles were able to ferry adequate amounts of paclitaxel drug into PC-3 cells and subsequently inhibiting PC-3 cell proliferation significantly. Results confirmed that pentablock copolymer can generate drug-loaded nanomicelles with desirable sizes and zeta potential. These demonstrate potentiality of pentablock nanomicelles as carrier for anticancer delivery.

Microbial otitis media: recent advancements in treatment, current challenges and opportunities

Otitis media (OM) is a common disease affecting humans, especially paediatric populations. OM refers to inflammation of the middle ear and can be broadly classified into two types, acute and chronic. Bacterial infection is one of the most common causes of OM. Despite the introduction of vaccines, the incidence of OM remains significantly high worldwide. In this mini-review article, we discuss the recent treatment modalities for OM, such as suspension gel, transcutaneous immunization, and intranasal and transtympanic drug delivery, including therapies that are currently undergoing clinical trials. We provide an overview of how these recent advancements in therapeutic strategies can facilitate the circumvention of current treatment challenges involving preadolescence soft palate dysfunction, biofilm formation, tympanic membrane (ear drum) barrier and the attainment of efficacious drug concentrations in the middle ear. While traditional first-line immunization strategies are generally not very efficacious against biofilms, new technologies that use transdermal or intranasal drug delivery via chitosan-PsaA nanoparticles have shown promising results in experimental animal models of OM. Sustained drug delivery systems such as penta-block copolymer poloxamer 407-polybutylphosphoester (P407-PBP) or poloxamer 407 (e.g. OTO-201, with the brand name 'OTIPRIO') have demonstrated that treatments can be reduced to a single topical application. The emergence of effective new treatment modalities opens up promising new avenues for the treatment of OM that could lead to improved quality of life for many children and their families.

Pentablock Copolymer from Tetracomponent Monomer Mixture Using a Switchable Dizinc Catalyst

Well-defined pentablock copolymers are prepared using a single catalyst, in one pot, from four different monomers: anhydride, epoxide, lactone, and CO2. The dizinc catalyst bridges three distinct polymerization cycles and performs a double switch in polymerization mechanism to produce pentablock copolymers. The new materials are hydroxyl-telechelic and are efficiently postfunctionalized to introduce polar and nonpolar side-chains.

Preparation of an ethylene glycol-based block copolymer consisting of six different temperature-responsive blocks

An ethylene glycol-based hexa-block copolymer with six different temperature-responsive blocks was prepared via a reversible addition-fragmentation chain transfer (RAFT) polymerization. 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) were selected as the ethylene glycol-based monomers. Each block of the hexa-block copolymer has a different OEGMA content and thus exhibits a different lower critical solution temperature (LCST). The structures of the block copolymers are similar to gradient copolymers. The molecular weights of the copolymers increased with the number of blocks (first block (P(MEO2MA)): 2800 g/mol, di-block copolymer: 7400 g/mol, tri-block copolymer: 12,000 g/mol, tetra-block copolymer: 18,500 g/mol, penta-block copolymer: 26,800 g/mol, and hexa-block copolymer: 40,400 g/mol) with relatively narrow molecular weight distributions (1.18–1.42). Each block exhibits a different LCST in aqueous solution owing to their different OEGMA contents. To the best of our knowledge, this is the first report of a block copolymer containing more than four types of temperature-responsive blocks. The temperature-responsive properties of the prepared block copolymers were investigated by UV-vis spectroscopy, micro-differential scanning calorimetry, and scanning electron microscopy. An ethylene glycol-based hexa-block copolymer with six different temperature-responsive blocks was prepared via a reversible addition-fragmentation chain transfer (RAFT) polymerization. 2-(2-Methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) were selected as the ethylene glycol-based monomers. Each block exhibits a different LCST in aqueous solution owing to their different OEGMA contents.

Palmitic Acid-Pluronic F127-Palmitic Acid Penta-Block Copolymer as a Novel Nanocarrier for Oral Delivery of Glipizide

Palmitic Acid-Pluronic F127-Palmitic Acid Penta-Block Copolymer as a Novel Nanocarrier for Oral Delivery of Glipizide

Hollow mesoporous organosilica nanospheres templated with flower-like micelles of pentablock copolymers

We present a facile preparation of hollow mesoporous organosilica nanospheres with well-defined, uniform mesopores by controlling the morphology of pentablock copolymer templates under acidic conditions. The CBABC type poly(lactic acid-co-glycolic acid)-b-poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-b-poly(lactic acid-co-glycolic acid) (PLGA-b-PEO-b-PPO-b-PEO-b-PLGA) pentablock copolymers were synthesized via a step-growth and ring-opening polymerization method using Pluronic F68 and F108 as macro-initiators. Two kinds of pentablock copolymers, (LA45GA12)EO75PO30EO75(LA45GA12) and (LA28GA9)EO141PO54 EO141(LA28GA9), were used as single soft templates to prepare mesoporous ethane-silica and benzene-silica hollow nanospheres by sol-gel chemistry in acidic aqueous solutions. The inner cavity diameter was controlled up to ∼20 nm by varying acidity and the chain length of the hydrophobic PLGA block without using additional swelling agents. The evolution of hollow nanospheres could be explained by single flower-like micelle template mechanism and the variation of morphology of pentablock copolymers upon solution acidity. Moreover, the amine-functionalized hollow benzene-silica nanospheres showed high carbon dioxide adsorption at ambient conditions. The hollow organosilica nanospheres were characterized by small-angle X-ray scattering, nitrogen adsorption-desorption, solid-state 13C- and 29Si nuclear magnetic resonance, and scanning and transmission electron microscopy and so on.

Amphiphilic comb-like pentablock copolymers of Pluronic L64 and poly(ethylene glycol)methyl ether methacrylate: synthesis by ATRP, self-assembly, and clouding behavior

Well-defined amphiphilic comb-like pentablock copolymers based on Pluronic L64 (PEO13-b-PPO30-b-PEO13) and poly(ethylene glycol)methyl ether methacrylate (PEGMA) have been successfully synthesized via atom transfer radical polymerization (ATRP). The L64 is transformed into ATRP macroinitiator and chain extended with PEGMA under typical ATRP conditions to achieve comb-like pentablock copolymers of various compositions. Due to their amphiphilic nature, the block copolymers could form self-assembled structures in aqueous solutions as confirmed by dynamic light scattering. At higher PEGMA content in the synthesized copolymer, however, the critical aggregation concentration (CAC) is less pronounced that could be attributed to the increased hydrophilicity and steric hindrance of PEG side chains of the PEGMA, thus preventing the formation of well-defined micellar aggregates, and probably leads to open-shell aggregation mechanism. The lower critical solution temperature (LCST) of the synthesized block copolymers is found higher than the neat L64 and increased with increasing the PEGMA content. Further, tuning the clouding behavior could be achieved with inorganic additives (KBr and K2SO4). The influence of SO42− and Br1− on LCST is according to their position in Hofmeister series. Interestingly, the effect of additives is more pronounced above the CAC of the copolymer, suggesting that the nanoaggregates in solution induce the macrophase separation.

PH-responsive polymeric micelles self-assembled from amphiphilic copolymer modified with lipid used as doxorubicin delivery carriers.

In the present study, a novel pH-responsive amphiphilic copolymer, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] conjugated poly(β-amino esters) (DSPE-b-PEG-b-PAE-b-PEG-b-DSPE), was designed and successfully synthesized via Michael-type step polymerization. The chemical structure of the pentablock copolymer was confirmed with proton nuclear magnetic resonance (1H-NMR) and Fourier transform infrared (FT-IR) spectroscopy. The copolymer was able to self-assemble into core/shell polymeric micelles in aqueous solution at low concentrations, and its critical micelle concentration (CMC) value was 4.5 mg l−1 determined by fluorescence spectrophotometry. The pKb value of the copolymer was about 6.5, confirmed by acid–base titration, indicating the pH-sensitivity of the polymeric micelle. The hydrodynamic diameter, distribution and zeta potential of the polymeric micelles at different pH conditions were monitored by dynamic light scattering (DLS). Doxorubicin (DOX) was encapsulated into the core of the micelles with a high drug loading content (15.9%) and entrapment efficacy (60.4%). In vitro experiments demonstrated that the release behaviour of DOX from the DOX-loaded polymeric micelles (DOX-PMs) was pH-triggered. When the pH decreased from 7.4 to 5.0, the drug release rate was markedly accelerated. MTT assay showed that the copolymer had negligible cytotoxicity whereas the DOX-PMs displayed high toxicity for tumour cells such as B16F10, HepG2 and HeLa cell lines. The results demonstrated that these pH-sensitive polymeric micelles could be used as potential anti-cancer drug carriers for cancer chemotherapy with controlled release.

Tailoring Pore Size, Structure, and Morphology of Hierarchical Mesoporous Silica Using Diblock and Pentablock Copolymer Templates

Mesoporous materials of tailored pore size, structure, and morphology are of interests for a wide range of applications. It is important to develop synthetic methods that will allow for easy proces...

Ordering and Grain Growth in Charged Block Copolymer Bulk Films: A Comparison of Solvent‐Related Processes

AbstractWhile prior efforts have demonstrated that the morphologies of block copolymer (BC) bulk films can be controlled through judicious chemical design and thermal annealing, recent interest has focused on regulating the orientation of BC nanostructures and minimizing defects. Thermal processes developed to achieve this purpose for nonpolar BCs are not, however, suitable for orienting microphase‐ordered BCs composed of at least one block with charged moieties that can form thermally stable ionic clusters. To overcome this challenge, we have previously applied solvent‐vapor (SV) annealing to block ionomer (BI) bulk films composed of midblock‐sulfonated pentablock copolymers and established that this approach yields highly ordered morphologies that display evidence of improved in‐plane orientation. Here, we employ small‐angle X‐ray scattering to compare the effectiveness of three solvent‐related processes–SV annealing, SV permeation, and SV sorption–on BI ordering and grain growth, and offer explanations for observed differences on the basis of thermodynamic‐ and transport‐related considerations. Differences in the experimental design of these solvent‐related processes are found to affect nanostructural development, as evidenced by the extent of in‐plane grain growth.

Preparation of multiblock copolymers via step-wise addition of l-lactide and trimethylene carbonate.

Poly(l-lactide) (PLA) is a bioderived and biodegradable polymer that has limited applications due to its hard and brittle nature. Incorporation of 1,3-trimethylene carbonate into PLA, in a block copolymer fashion, improves the mechanical properties, while retaining the biodegradability of the polymer, and broadens its range of applications. However, the preparation of 1,3-trimethylene carbonate (TMC)/l-lactide (LA) copolymers beyond diblock and triblock structures has not been reported, with explanations focusing mostly on thermodynamic reasons that impede the copolymerization of TMC after lactide. We discuss the preparation of multiblock copolymers via the ring opening polymerization (ROP) of LA and TMC, in a step-wise addition, by a ferrocene-chelating heteroscorpionate zinc complex, {[fc(PPh2)(BH[(3,5-Me)2pz]2)]Zn(μ-OCH2Ph)}2 ([(fcP,B)Zn(μ-OCH2Ph)]2, fc = 1,1'-ferrocenediyl, pz = pyrazole). The synthesis of up to pentablock copolymers, from various combinations of LA and TMC, was accomplished and the physical, thermal, and mechanical properties of the resulting copolymers evaluated.