Double Hydrophilic Block Copolymers Research Articles

Development of Double Hydrophilic Block Copolymer/Porphyrin Polyion Complex Micelles towards Photofunctional Nanoparticles

The electrostatic complexation between double hydrophilic block copolymers (DHBCs) and a model porphyrin was explored as a means for the development of polyion complex micelles (PICs) that can be utilized as photosensitive porphyrin-loaded nanoparticles. Specifically, we employed a poly(2-(dimethylamino) ethyl methacrylate)-b-poly[(oligo ethylene glycol) methyl ether methacrylate] (PDMAEMA-b-POEGMA) diblock copolymer, along with its quaternized polyelectrolyte copolymer counterpart (QPDMAEMA-b-POEGMA) and 5,10,15,20-tetraphenyl-21H,23H-porphine-p,p',p″,p'''-tetrasulfonic acid tetrasodium hydrate (TPPS) porphyrin. The (Q)PDMAEMA blocks enable electrostatic binding with TPPS, thus forming the micellar core, while the POEGMA blocks act as the corona of the micelles and impart solubility, biocompatibility, and stealth properties to the formed nanoparticles. Different mixing charge ratios were examined aiming to produce stable nanocarriers. The mass, size, size distribution and effective charge of the resulting nanoparticles, as well as their response to changes in their environment (i.e., pH and temperature) were investigated by dynamic and electrophoretic light scattering (DLS and ELS). Moreover, the photophysical properties of the complexed porphyrin along with further structural insight were obtained through UV-vis (200-800 nm) and fluorescence spectroscopy measurements.

Assembly of Poly(vinylphosphonic acid)-Based Double Hydrophilic Block Copolymers by Gadolinium Ions for the Formation of Highly Stable MRI Contrast Agents.

Mixing double-hydrophilic block copolymers containing a poly(vinylphosphonic acid) block with gadolinium ions in water leads to the spontaneous formation of polymeric nanoparticles. With an average diameter near 20 nm, the nanoparticles are stable after dilution or change of pH and ionic strength. High magnetic relaxivities were measured in vitro, and in vivo magnetic resonance imaging on rats demonstrates the high potential of such polymeric assemblies.

Amphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery Vehicles.

Self-assembly of amphiphilic block copolymers display a multiplicity of nanoscale periodic patterns proposed as a dominant tool for the 'bottom-up' fabrication of nanomaterials with different levels of ordering. The present review article focuses on the recent updates to the self-association of amphiphilic block copolymers in aqueous media into varied core-shell morphologies. We briefly describe the block copolymers, their types, microdomain formation in bulk and micellization in selective solvents. We also discuss the characteristic features of block copolymers nanoaggregates viz., polymer micelles (PMs) and polymersomes. Amphiphilic block copolymers (with a variety of hydrophobic blocks and hydrophilic blocks; often polyethylene oxide) self-assemble in water to micelles/niosomes similar to conventional nonionic surfactants with high drug loading capacity. Double hydrophilic block copolymers (DHBCs) made of neutral block-neutral block or neutral block-charged block can transform one block to become hydrophobic under the influence of a stimulus (physical/chemical/biological), and thus induced amphiphilicity and display self-assembly are discussed. Different kinds of polymer micelles (viz. shell and core-cross-linked, core-shell-corona, schizophrenic, crew cut, Janus) are presented in detail. Updates on polymerization-induced self-assembly (PISA) and crystallization-driven self-assembly (CDSA) are also provided. Polyion complexes (PICs) and polyion complex micelles (PICMs) are discussed. Applications of these block copolymeric micelles and polymersomes as nanocarriers in drug delivery systems are described.

Synthesis of Double Hydrophilic Block Copolymers Poly(2-isopropyl-2-oxazoline-b-ethylenimine) and their DNA Transfection Efficiency.

Gene delivery is now a part of the therapeutic arsenal for vaccination and treatments of inherited or acquired diseases. Polymers represent an opportunity to develop new synthetic vectors for gene transfer, with a prerequisite of improved delivery and reduced toxicity compared to existing polymers. Here, the synthesis in a two-step's procedure of linear poly(ethylenimine-b-2-isopropyl-2-oxazoline) block copolymers with the linear polyethylenimine (lPEI) block of various molar masses is reported; the molar mass of the poly(2-isopropyl-2-oxazoline) (PiPrOx) block has been set to 7kg mol-1 . Plasmid DNA condensation is successfully achieved, and in vitro transfection efficiency of the copolymers is at least comparable to that obtained with the lPEI of same molar mass. lPEI-b-PiPrOx block copolymers are however less cytotoxic than their linear counterparts. PiPrOx can be a good alternative to PEG which is often used in drug delivery systems. The grafting of histidine moieties on the lPEI block of lPEI-b-PiPrOx does not provide any real improvement of the transfection efficiency. A weak DNA condensation is observed, due to increased steric hindrance along the lPEI backbone. The low cytotoxicity of lPEI-b-PiPrOx makes this family a good candidate for future gene delivery developments.

Poly(acrylic acid)-b-Poly(vinylamine) Copolymer: Decoration with Silver Nanoparticles, Antibacterial Properties, Quorum Sensing Activity, and Cytotoxicity on Breast Cancer and Fibroblast Cell Lines

An elegant integration of primary amine-bearing segments into the acrylic acid-containing blocks and the subsequent addition of silver nanoparticles (Ag NPs) to this double hydrophilic block copolymer endowed the resulting well-defined self-assembled construct with promising antimicrobial and anti-quorum-sensing activity and high cytotoxicity against breast cancer cells. Poly(N-vinylformamide) (PNVF), precursor of amphoteric poly(vinyl amine) (PVAm), was chain-extended from pH-responsive poly(acrylic acid) (PAA) macro-chain-transfer agent synthesized via reversible addition–fragmentation chain transfer polymerization by the interchange of xanthates (RAFT/MADIX). PAA-b-PNVF block copolymers with molecular weights in the range of 12500–21800 Da and dispersities between 1.29 and 1.44 were characterized by FTIR, elemental analysis, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and size exclusion chromatography (SEC). PAA-b-PVAm copolymer was obtained by hydrolysis of the PNVF block. The decoration of PAA-b-PVAm with monodisperse Ag NPs to yield AgNPs@PAA-b-PVAm proceeded through a simple and green approach by amine-induced reduction of Ag ions in aqueous media. The formation of AgNPs@PAA-b-PVAm was characterized by UV/vis spectroscopy, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM). AgNPs@PAA-b-PVAm displayed superior antimicrobial and anti-QS activity. The cell proliferation was tested with an MTT assay on L929 and MCF-7 cell lines. Both the AgNP-decorated and the bare copolymer showed significantly higher cytotoxicity on cancer cells compared to healthy ones.

Protection of Double-Stranded RNA via Complexation with Double Hydrophilic Block Copolymers: Influence of Neutral Block Length in Biologically Relevant Environments.

Interaction between the anionic phosphodiester backbone of DNA/RNA and polycations can be exploited as a means of delivering genetic material for therapeutic and agrochemical applications. In this work, quaternized poly(2-(dimethylamino)ethyl methacrylate)-block-poly(N,N-dimethylacrylamide) (PQDMAEMA-b-PDMAm) double hydrophilic block copolymers (DHBCs) were synthesized via reversible addition–fragmentation chain-transfer (RAFT) polymerization as nonviral delivery vehicles for double-stranded RNA. The assembly of DHBCs and dsRNA forms distinct polyplexes that were thoroughly characterized to establish a relationship between the length of the uncharged poly(N,N-dimethylacrylamide) (PDMA) block and the polyplex size, complexation efficiency, and colloidal stability. Dynamic light scattering reveals the formation of smaller polyplexes with increasing PDMA lengths, while gel electrophoresis confirms that these polyplexes require higher N/P ratio for full complexation. DHBC polyplexes exhibit enhanced stability in low ionic strength environments in comparison to homopolymer-based polyplexes. In vitro enzymatic degradation assays demonstrate that both homopolymer and DHBC polymers efficiently protect dsRNA from degradation by RNase A enzyme.

Dual control of external surface and internal pore structure of small ordered mesoporous silica particles directed by mixed polyion complex micelles

A versatile approach has been developed to prepare small mesoporous silica particles with simultaneous control of the internal ordered pore structure and the external particle surface. Mixed polyion complex (PIC) micelles are used as silica structure-directing agents: they result from the complexation of a polybase with two polyacid double-hydrophilic block copolymers (DHBC) having either a poly(ethylene oxide) (PEO) based-block or a polyacrylamide (PAM) block. The ionizable block in both DHBC is poly(acrylic acid), which complexes oligochitosan to form the core of the electrostatic complex. By varying the architecture of the PEO-based block (linear or comb-shaped) and the synthesis parameters, it is possible to modulate the pore structure from 3D cage-like to 2D-hexagonal and lamellar mesostructures. Replacing a fraction of the PEO-based polymers with DHBC having a polyacrylamide block that has no affinity for silica is shown to affect silica-micelle interactions and material growth. While the PEO chains interact with silica to form the hybrid interface, the PAM chains act as capping agents and control the external surface of the particles. Increasing the relative amount of PAM-based DHBC leads to the formation of small discrete mesoporous silica particles that are reduced in size to 200 nm. The particle size reduction and particle surface stabilization by PAM chains can be explained by considering not only the existence of a mixed corona of PAM and PEO in PIC micelles but also the differentiated solubility of these two neutral blocks induced by silica condensation. Thus, the present strategy allows independent decrease of the particle size and tuning of its pore structure.

RAFT Polymerization of N-Methyl-N-vinylacetamide and Related Double Hydrophilic Block Copolymers

RAFT Polymerization of <i>N</i>-Methyl-<i>N</i>-vinylacetamide and Related Double Hydrophilic Block Copolymers

A deeper insight into the dual temperature- and pH-responsiveness of poly(vinylamine)-b-poly(N-isopropylacrylamide) double hydrophilic block copolymers

Block copolymers based on poly(vinylamine) and poly(N-isopropylacrylamide), PVAmm-b-PNIPAMn, were synthetized by hydrazinolysis of poly(N-vinylphthalimide) based copolymers, PVPIm-b-PNIPAMn, obtained by RAFT polymerization. The effect of molar mass and pH on the thermoresponsive and aggregation properties of these polymers in aqueous solution was studied with UV–vis spectroscopy, differential scanning calorimetry, NMR spectrometry, light and X-ray scattering experiments. For the first time it was demonstrated that at room temperature, these copolymers are prone to self-assemble and tend to form larger aggregates upon heating. Hence core-shell nanostructures with a dense PNIPAM core and a hydrophilic PVAm shell, were notably observed above Tc when pH < pKa.

Double hydrophilic poly(ethylene glycol)-block-poly(dehydroalanine) four-arm star block copolymers: synthesis and solution behavior

We report the synthesis and solution behavior of double hydrophilic star-shaped block copolymers featuring an ampholytic polydehydroalanine segment.

RAFT polymerisation of N-vinylformamide and the corresponding double hydrophilic block copolymers

Polyvinylamine-based double hydrophilic block copolymers are synthesised from RAFT polymerisation of N-vinylformamide.

Modulation of Double Zwitterionic Block Copolymer Aggregates by Zwitterion-Specific Interactions.

Transformable double hydrophilic block copolymer assemblies are valid as a biocompatible smart macromolecular system. The molecular mechanisms in the spontaneous assembly of double zwitterionic diblock copolymers composed of a poly(carboxybetaine methacrylate) (PCB2) and a poly(sulfobetaine methacrylate) (PSB4) chains (PCB2-b-PSB4) were investigated by the modulation of the aggregates in response to nondetergent zwitterions. The PCB2-b-PSB4 diblock copolymers with a high degree of polymerization PSB4 block produced aggregates in salt-free water through "zwitterion-specific" interactions. The PCB2-b-PSB4 aggregates were dissociated by the addition of nondetergent sulfobetaine (SB4) and carboxybetaine (CB2) molecules, while the aggregates showed different aggregation modulation processes for SB4 and CB2. Zwitterions with different charged groups from SB4 and CB2, glycine and taurine, hardly disrupted the PCB2-b-PSB4 aggregates. The PCB2-b-PSB4 aggregate modulation efficiency of SBs associated with the intercharge hydrocarbon spacer length (CSL) rather than the symmetry with the SB in the PSB chain. These zwitterion-specific modulation behaviors were rationalized based on the nature of zwitterions including partial charge density, dipole moment, and hydrophobic interactions depending on the charged groups and CSL.

Hybrid polymeric micelles stabilized by gallium ions: Structural investigation

The addition of gallium ions to a solution of a double-hydrophilic block copolymer, i.e. poly(ethylene oxide)-block-poly(acrylic acid), leads to the spontaneous formation of highly monodisperse micelles with a Hybrid PolyIon Complexes (HPICs) core. By combining several techniques, a precise description of the HPIC architecture was achieved. In particular and for the first time, NMR and anomalous small angle X-ray scattering (ASAXS) enable tracking of the inorganic ions in solution and highlighting the co-localization of the gallium and the poly(acrylic acid) blocks in a rigid structure at the core of the micelle. Such a core has a radius of ca 4.3 nm while the complete nano-object with its poly(ethylene oxide) shell has a total radius of ca 11 nm. The aggregation number was also estimated using the ASAXS results. This comprehensive structural characterization of the Ga HPICs corroborates the assumptions made for HPICs based on other inorganic ions and demonstrates the universality of the HPIC structure leading, for example, to new families of contrast agents in medical imaging.

Thermoresponsive Self-Assembly of Twofold Fluorescently Labeled Block Copolymers in Aqueous Solution and Microemulsions.

A nonionic double hydrophilic block copolymer with a long permanently hydrophilic and a small thermoresponsive block is synthesized by reversible addition-fragmentation chain-transfer polymerization (RAFT). By employing a specifically designed chain-transfer agent, the polymer is functionalized with complementary end groups which are suited for Förster resonance energy transfer (FRET). The end group attached to the permanently hydrophilic block of poly(N,N-dimethylacrylamide) pDMAm is designed as a permanently hydrophobic segment ("sticker") comprising a long alkyl chain and the 4-aminonaphthalimide fluorophore. The other end attached to the thermoresponsive block of poly(N-isopropylacrylamide) pNiPAm incorporates a coumarin fluorophore. The temperature-dependent self-assembly of the twofold fluorescently labeled copolymer is studied in pure aqueous solution as well as in an o/w microemulsion by several techniques including turbidimetry, dynamic light scattering (DLS), and fluorescence spectroscopy. It is compared to the behaviors of the analogous twofold-labeled pDMAm and pNiPAm homopolymer references. The findings indicate that the block copolymer behaves as a polymeric surfactant at low temperatures, with one relatively small hydrophobic end block and an extended hydrophilic chain forming "hairy micelles". At elevated temperatures above the LCST phase transition of the pNiPAm block, however, the copolymer behaves as an associative telechelic polymer with two nonsymmetrical hydrophobic end blocks, which do not mix. Thus, instead of a network of bridged "flower micelles", large dynamic aggregates are formed. These are connected alternatingly by the original micellar cores as well as by clusters of the collapsed pNiPAm blocks. This type of structure is even more favored in the o/w microemulsion than in pure aqueous solution, as the microemulsion droplets constitute an attractive anchoring point for the hydrophobic dodecyl sticker but not for the collapsed pNiPAm chains.

Encapsulation of a cationic antimicrobial peptide into self-assembled polyion complex nano-objects enhances its antitumor properties

Antimicrobial peptides, a large class of molecules synthetized by various organisms as an innate defense against pathogens are more and more used for their anticancer properties as well. In order to overcome some of their limitations and to enhance their therapeutic efficiency, the use of delivery systems was taken into consideration. In this study we describe an original delivery system for antimicrobial peptides based on its physico-chemical properties, namely the self-assembled polyion complexes (PIC) based on electrostatic interactions of cationic antimicrobial peptide P6 with negatively charged double hydrophilic block copolymers, the poly(ethylene oxide)-poly(acrylic acid) (PEO-PAA) in our study. The drug delivery system was tested on 3D human tumor HCT-116 spheroids. The spheroid evolution and cell viability were monitored at 24 and 48 h after the treatment was applied. Our study demonstrates for the first time the feasibility of forming a polyion complex PIC with an antimicrobial peptide and that this self-assembled organization provides added value in terms of anti-tumor therapeutic efficacy compared to the free form of the antimicrobial peptide.

A Unique Nano‐Capsule Possessing Inner Thermo‐Responsive Surface Prepared from a Toothbrush‐Like Comb−Coil Block Copolymer

Front Cover: In article number 2100174 by Haruka Takebuchi and Ren-Hua Jin, a double hydrophilic coil-brush block copolymer self-asssembles into core-corona micelles in water under heating. Via cross-linking the corona, the micelle is transformed into a nanocapsule which has an inner thermo-responsive surface. When heating step-by-step in a wide range of temperatures, the nanocapsule shrinks gradually, while when cooling step-by-step, the nanocapsule swells gradually back to its original size.

Effects of Polymer Block Length Asymmetry and Temperature on the Nanoscale Morphology of Thermoresponsive Double Hydrophilic Block Copolymers in Aqueous Solutions

By complementing small-angle neutron scattering (SANS) with Fourier transform infrared (FTIR) spectroscopy measurements, the influence of temperature as an external stimulus and block length asymmetry is studied on nanoscale assemblies of thermoresponsive double hydrophilic block copolymers in aqueous solutions. Morphologies and molecular hydration characteristics of two poly(N-isopropylacrylamide)-block-poly(oligo ethylene glycol methyl ether acrylate) (PNIPAM-b-POEGA) diblock copolymers, which differ in the length of the PNIPAM block, are compared. SANS provides insights into the nanostructure of the assemblies and FTIR probes vibrations of selected functional groups at the molecular level. Upon temperature increase, the solutions undergo transformations from hierarchical assemblies to more well-defined spherical morphologies. Variations in the block lengths lead to distinct morphological transformations. The variable morphological transformations originate from differences in the strength and/or amount of hydrogen bonding and hydrophobic interactions, as well as the chain density in the clusters formed and hydration. We identify transformations from hierarchical structures to fractal core–shell morphologies in the asymmetric block copolymer with the long PNIPAM block, while spherical and core–shell spherical morphologies are formed for the symmetric diblock copolymer with the short PNIPAM block. In these assemblies of PNIPAM-b-POEGA with the short PNIPAM block, the methyl side group hydration sensitively depends on the temperature increase at temperatures even beyond the nominal volume phase transition temperature. For both blocks, the evolution of the amide I band reflects that solvent–polymer interactions are still favorable even at the highest temperatures. Morphological variations after cooling to ambient temperature are reflected in both SANS and FTIR, pointing to remnant hydrogen bond interactions.

Hybrid Polymeric Nanostructures Stabilized by Zirconium and Gadolinium Ions for Use as Magnetic Resonance Imaging Contrast Agents

Nanostructures called hybrid polyion complexes (HPICs) are formed by adding metal ions to a solution of a double-hydrophilic block copolymer, leading to the spontaneous formation of highly monodisp...

Cholesterol-Functionalized Linear/Brush Block Copolymers for Metal-Incorporated Nanostructures with Modulated Core Density and Enhanced Self-Assembly Efficiency.

Metal-mediated self-assembly of chelating double-hydrophilic block copolymer has become a facile preparation strategy of great importance for the metal-chelated hybrid nanostructures. Herein, we present a delicate control over the morphology regulation of metal-chelated nanostructures by a terminal modification of polymer building blocks with mesogenic cholesterol. Such a molecular design motif at an end of chelating linear/brush-type block copolymer imparts not only additional hydrophobicity for enhanced cohesive force to facilitate the metal-mediated self-assembly, but also significant morphological alteration of a metal-chelated core that otherwise generally forms a spherical interior with cholesterol-free block copolymers. The presence of cholesterol entities localized at the central core further allows for the density modulation of the final PtII-chelated nanostructures while maintaining the colloidal stability, comparable to that of the cholesterol-free nanoparticles in physiological conditions. This metal-mediated assembly strategy with modified polymer building blocks can provide a potential platform for the delivery of inorganic agents.

Synthesis and self-assembly of polyzwitterionic phenylboronic acid-containing double hydrophilic block copolymers

Double hydrophilic block copolymers self-assemble into smart materials with promising applications in nanomedicine. However, such practical applications require thoroughly understanding the underlying mechanisms of this self-assembly process and the effects of external stimuli on the resulting materials. Thus, we report the post-polymerization modification of a pH-responsive double hydrophilic diblock copolymer (poly(ethylene oxide)-b-poly(4-vinyl pyridine)) by stimuli-responsive, diol-binding 2-bromomethyl-4-fluorophenylboronic acid and the comprehensive study of the self-assembly properties of this polyzwitterionic polymer for potential applications in the delivery of functional diols, including pharmaceutical drugs, steroids and sugars. For this purpose, we performed simple, robust and reproducible quaternization reactions at three different degrees (25, 50 and 100%) by varying the composition of the initial mixture and confirmed full control over the degree of quaternization by proton nuclear magnetic and infrared spectroscopy. Our results show that the degree of quaternization strongly affects the solubility of these polymers in basic solutions because PBA adopts a tetragonal conformation with a negative charge on boron at pH values higher than the pKA of PBA. Nevertheless, the specific PBA (anionic vs neutral) form of these polymers can be differentiated by 11B NMR, regardless of the degree of quaternization. In turn, the pH of the solvent affected the intensity of the NMR signals, thus suggesting the formation of kinetically frozen nanoparticles, in line with the results from both static and dynamic light scattering, with no indication of particle dissociation at low concentrations. Moreover, electrophoretic light scattering showed linear, albeit opposite (direct and inverse) correlations between the degree of quaternization and the zeta potential in water and 0.1 M HCl, respectively. When adsorbed to a mica surface, these nanoparticles predominantly displayed globular shapes under atomic force microscopy. Therefore, our high-throughput and low-cost nanofabrication method combining the stimuli-responsive behavior of a double hydrophilic block copolymer with the unique chemical properties of pH-responsive diol-binding phenylboronic acid functional groups establishes an experimental paradigm for preparing nanocarriers for biomedical applications, such as targeted drug delivery.