Self-assembled, pH-sensitive retinoate nanostructures ionically complexed with PEG-grafted cationic polyelectrolytes

All-trans-retinoic acids (ATRA) are ionically complexed with cationic polyelectrolytes containing tertiary amines and self-assembled into nanoscale colloidal structures. Poly(2-(dimethylamino)ethyl methacrylate) grafted with polyethylene glycol, poly(DMAEMA-g-PEG), is used as a double hydrophilic, cationic polyelectrolyte. The polyion/ATRA complexes are formed by adding ATRA in dimethyl sulfoxide into aqueous solution of poly(DMAEMA-g-PEG). This complexation effectively suppresses the formation of undesirable drug crystallites and produces stable colloidal nanostructures having a hydrodynamic diameter of about 15?nm at a neutral pH. However, as the pH decreases below about 6, they undergo dramatic structural change into large aggregates of about 250?nm in diameter presumably due to the dissociation of ATRA from the polyelectrolyte. We expect that this pH-sensitive response of the polyion/ATRA complexes is useful for intracellular translocation at a neutral pH followed by the endosomal escape of ATRA in an acidic condition.     

Synthesis of double-hydrophilic double-grafted copolymers PMA-g-PEG/PDMA and their protein-resistant properties

A series of double-hydrophilic double-grafted PMA-g-PEG/PDMA copolymers, which contained poly(methacrylate) (PMA) as backbone, poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide) (PDMA) as side chains synthesized successfully by using reversible addition-fragmentation chain transfer (RAFT) polymerization and atom transfer radical polymerization (ATRP), were used as physical coatings for the evaluation of protein-resistant properties by capillary electrophoresis (CE). Electroosmotic flow (EOF) measurement results showed that the PMA-g-PEG/PDMA copolymer coated capillaries could suppress electroosmotic mobility in a wide pH range (pH = 2.8–9.8) and EOF mobility decreased with the increase of copolymer molecular mass and PDMA content. At the same time, protein recovery, theoretical plate number of separation and repeatability of migration time demonstrated that antifouling efficiency was improved with the increase of molecular mass and PEG content.     

Multilayers and poly(allylamine hydrochloride)-graft-poly(ethylene glycol) modified bovine serum albumin nanoparticles: Improved stability and pH-responsive drug delivery

To improve the colloidal stability of bovine serum albumin(BSA) nanoparticles(NPs) in diverse mediums, poly(allylamine hydrochloride)(PAH)/sodium poly(4-styrene sulfonate)(PSS) multilayers and poly(allylamine hydrochloride)-graft-poly(ethylene glycol)(PAH-g-PEG) coating were coated on the surface of BSA NPs.Stabilities of the BSA NPs in diverse mediums with different surfaces were detected by dynamic light scattering(DLS).Multilayers and PAH-g-PEG coated BSA NPs can be well dispersed in various mediums with a narrow polydispersity index(PDI).The BSA NPs with the highest surface density of PEG show the best stability.The multilayers and PAH-g-PEG coating do not deter the pH-dependent loading and release property of BSA NPs.At pH 9,the encapsulation efficiency of doxorubicin reaches almost 99%,and the release rate at pH 5.5 is significantly higher than that at pH 7.4.     

Study on Self-assembly of Poly(ethylene glycol)- block-poly(γ-benzyl L -glutamate)-graft-poly(ethylene glycol) Copolymer and Poly(γ-benzyl L -glutamate)- block-poly(ethylene glycol) Copolymer in Ethanol

Poly(ethylene glycol)-block-poly(γ-benzyl L-glutamate)-graft-poly(ethylene glycol) (PEG-b-PBLG-g-PEG) copolymer was synthesized by the ester exchange reaction of poly(γ-benzyl L-glutamate)-block-poly(ethylene glycol) (PBLG-block-PEG) copolymer with PEG chain, and PBLG-block-PEG copolymer was prepared by a standard N-carboxyl-γ-benzyl-L-glutamate anhydride (NCA) method. Nuclear magnetic resonance (NMR) spectroscopy was used to confirm the components of PBLG-block-PEG and PEG-b-PBLG-g-PEG. The self-association behaviors of PBLG-block-PEG and PEG-b-PBLG-g-PEG in ethanol were investigated by transmission electron microscopy (TEM), dynamic laser scattering (DLS), and viscometry. The experimental results revealed that the different molecular structures could exert marked effects on the self-assembly behaviors of PBLG-block-PEG and PEG-b-PBLG-g-PEG in ethanol. PBLG-block-PEG and PEG-b-PBLG-g-PEG could self-assemble to form polymeric micelles with a core-shell structure in the shapes of plump spherical and regular rice-like, respectively. Effects of the introduction of PBLG homopolymer on the average particle diameter of the micelles of PBLG-block-PEG and PEG-b-PBLG-g-PEG and influence of testing temperature on the critical micelle concentration of different copolymers were studied.     

Fluorine-containing pH-responsive core/shell microgel particles: preparation,characterization, and their applications in controlled drug release

A kind of novel fluorine-containing pH-responsive core/shell microgels poly(DMAEMA-co-HFMA)-g-PEG were prepared via surfactant-free emulsion polymerization using water as the solvent. The well-defined chemical structure of the copolymers was characterized by FTIR, ¹H-NMR, ¹⁹F-NMR, and elemental analysis. The microgel particles were studied by florescence probe technique, dynamic light scattering, and zeta potential measurement; the microgels displayed a significant pH-responsive behavior. Furthermore, the cytotoxicity assay indicated that the copolymer microgels had low toxicity, and 5-FU-loaded microgels offered a certain killing potency against cancer cells. In addition, the drug loading and in vitro drug release demonstrated that 5-FU was successfully incorporated into polymeric microgels, and the drug-loaded microgels showed a marked pH-dependent drug release behavior. This study suggests that the poly(DMAEMA-co-HFMA)-g-PEG microgels play an important role in the release mechanism stimulated by the change in the pH and have potential applications as a controlled drug release carrier.     

Synthesis and drug release properties of novel pH- and temperature-sensitive copolymers based on a hyperbranched polyether core

Multi-arm star amphiphilic hyperbranched copolymers with poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) shell and hyperbranched poly(3-ethyl-3-(hydroxymethyl)oxetane) (HBPO) core were synthesized by reversible addition?Cfragmentation chain transfer method. The hyperbranched copolymers were further modified by succinic anhydride (SUC) to obtain the novel pH- and thermosensitive hyperbranched copolymer HBPO-star-PDMAEMAs-SUC. The composition and morphology of synthesized copolymers were investigated by ¹H NMR, dynamic light scattering, and transmission electron microscopy. These copolymers exhibited phase transitions in response to pH and temperature. The pH-dependent release properties of the drug-loaded micelles were also investigated using indomethacin (IND) as a model drug. The IND-loaded micelles displayed a rapid drug release at an alkaline pH.     

Fabrication of polymeric micelles with core–shell–corona structure for applications in controlled drug release

Thermo-responsive polymeric micelles of poly (ethylene glycol)-b-poly(2-hydroxyethyl methacrylate-g-lactide)-b-poly(N-isopropylacrylamide) (PEG-P(HEMA-PLA)-PNIPAM) with core–shell–corona structure were fabricated for applications in controlled drug release. The graft copolymer of PEG-P(HEMA-PLA)-PNIPAM was self-assembled into core–shell micelles with a densely PLA core and mixed PEG/PNIPAM shells at 25 °C in aqueous media. By increasing the temperature above the lower critical solution temperature of PNIPAM, these core–shell micelles could be converted into core–shell–corona micelles because of the collapse of PNIPAM block on the PLA core as the inner shell and the soluble PEG block stretching outside as the outer corona. Anticancer drug doxorubicin (DOX) was loaded in the polymeric micelles as a model drug. Compared with polymeric micelles formed by liner PEG-b-PLA-b-PNIPAM triblock copolymer, these polymeric micelles exhibited higher loading capacity, and release of DOX from the polymeric micelles with core–shell–corona structure was well-controlled.     

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 7 kg 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.     

Synthesis of poly(ethylene glycol)/polypeptide/poly(D,L‐lactide) copolymers and their nanoparticles

Core‐shell structured nanoparticles of poly(ethylene glycol) (PEG)/polypeptide/poly(D ,L ‐lactide) (PLA) copolymers were prepared and their properties were investigated. The copolymers had a poly(L ‐serine) or poly(L ‐phenylalanine) block as a linker between a hydrophilic PEG and a hydrophobic PLA unit. They formed core‐shell structured nanoparticles, where the polypeptide block resided at the interface between a hydrophilic PEG shell and a hydrophobic PLA core. In the synthesis, poly(ethylene glycol)‐b‐poly(L ‐serine) (PEG‐PSER) was prepared by ring opening polymerization of N‐carboxyanhydride of O‐(tert‐butyl)‐L ‐serine and subsequent removal of tert‐butyl groups. Poly(ethylene glycol)‐b‐poly(L ‐phenylalanine) (PEG‐PPA) was obtained by ring opening polymerization of N‐carboxyanhydride of L ‐phenylalanine. Methoxy‐poly(ethylene glycol)‐amine with a MW of 5000 was used as an initiator for both polymerizations. The polymerization of D ,L ‐lactide by initiation with PEG‐PSER and PEG‐PPA produced a comb‐like copolymer, poly(ethylene glycol)‐b‐[poly(L ‐serine)‐g‐poly(D ,L ‐lactide)] (PEG‐PSER‐PLA) and a linear copolymer, poly(ethylene glycol)‐b‐poly(L ‐phenylalanine)‐b‐poly(D ,L ‐lactide) (PEG‐PPA‐PLA), respectively. The nanoparticles obtained from PEG‐PPA‐PLA showed a negative zeta potential value of ?16.6 mV, while those of PEG‐PSER‐PLA exhibited a positive value of about 19.3 mV. In pH 7.0 phosphate buffer solution at 36 °C, the nanoparticles of PEG/polypeptide/PLA copolymers showed much better stability than those of a linear PEG‐PLA copolymer having a comparable molecular weight. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Multicompartmental Microcapsules with Orthogonal Programmable Two‐Way Sequencing of Hydrophobic and Hydrophilic Cargo Release

Multicompartmental responsive microstructures with the capability for the pre‐programmed sequential release of multiple target molecules of opposite solubility (hydrophobic and hydrophilic) in a controlled manner have been fabricated. Star block copolymers with dual‐responsive blocks (temperature for poly(N‐isopropylacrylamide) chains and pH for poly(acrylic acid) and poly(2‐vinylpyridine) arms) and unimolecular micellar structures serve as nanocarriers for hydrophobic molecules in the microcapsule shell. The interior of the microcapsule can be loaded with water‐soluble hydrophilic macromolecules. For these dual‐loaded microcapsules, a programmable and sequential release of hydrophobic and hydrophilic molecules from the shell and core, respectively, can be triggered independently by temperature and pH variations. These stimuli affect the hydrophobicity and chain conformation of the star block copolymers to initiate out‐of‐shell release (elevated temperature), or change the overall star conformation and interlayer interactions to trigger increased permeability of the shell and out‐of‐core release (pH). Reversing stimulus order completely alters the release process.     

四臂星型聚苯乙烯-聚4-乙烯基吡啶嵌段共聚物纤维状胶束及负载金纳米粒子的研究

通过两步原子转移自由基聚合,制备了4种不同嵌段长度的四臂星型嵌段共聚物苯乙烯-聚4-乙烯基吡啶嵌段共聚物(PS-b-P4VP)4.在选择性溶剂甲苯中,随着嵌段长度的变化,自组装胶束的形态从球型到短棒状和纤维状的转变,其中(PS25-b-P4VP90)4自组装形成的以P4VP为核,以PS为花瓣型壳的纤维状胶束.以这种纤维状胶束作为模板,制备了金纳米粒子均匀分布的一维纳米材料     

Innovative amphiphilic cellulose nanobiostructures: Physicochemical,spectroscopic, morphological,and hydrophilic/lipophilic properties

The amphiphilic character of cellulosic copolymers offers the opportunity to employ their derivatives as novel bio-friendly stable amphiphilic agents. It can be speculated that the synthesized nanobiostructures with hydrophilic and hydrophobic segments will have micellar features. Our investigations, for the first time, demonstrate that the amphiphilic nature of the synthesized macromolecules based on hydrophobic cellulose triacetate (CTA) and hydroxyl terminated oligomeric species of CTA (HCTA) by using hydrophilic polyethylene glycol (PEG) with M_n 600 and 2000 D as CTA-g-PEG, 600; CTA-g-PEG, 2000; HCTA-b-PEG, 600; and HCTA-b-PEG, 2000. The characteristic features of the copolymers were determined by XRD, differential scanning calorimeter, ¹H NMR, FTIR, GPC, dynamic light scattering measurements, and transmission electron microscopy. In addition, their critical micelle concentrations were evaluated. The obtained results indicated that the hydrophobic blocks make a significant influence on the micellar characteristics of the surfactants. A comparison of the micellar behavior of a hydrophobic species, like pyrene, incorporated in the synthesized systems indicated that the incorporation content of the surfactants is influenced by the hydrophobic and hydrophilic chain lengths. Therefore, it is possible to design the diversity of the surfactants based on various hydrophilic/lipophilic balance.     

Copolymer of poly(4-vinylpyridine)-g-poly(ethylene oxide) respond sharply to temperature, pH and ionic strength

The stimuli-responsive copolymers with poly(ethylene oxide) (PEO) as side chain were prepared by free-radical copolymerization of methacrylamide end-capped PEO macromonomer and 4-vinylpyridine (4VP). Phase transition behavior of these copolymers of poly(4-vinylpyridine)-g-poly(ethylene oxide) (P4VP-g-PEO) was investigated as a function of polymer concentration, temperature, pH and ionic strength by monitoring the turbidity of the polymer solutions. The copolymers displayed sharp response to temperature and pH. The LCST of P4VP-g-PEO copolymer increased with the increase of PEO content and decreased with increasing pH due to the deprotonation of the pyridine ring, indicating well-tunable LCST. In addition, the LCST of P4VP-g-PEO9 presented a unique phase transition behavior with varying salt concentration, showing a minimum with 1 M NaCl solution at pH 6.0.     

Aggregation Behavior of Poly(ethylene glycol)-block-poly (γ-benzyl L-glutamate)-graft-poly(ethylene glycol) Copolymer and its Blends with Poly(γ-benzyl L-glutamate) Homopolymer in Mixed Solvents

Poly(ethylene glycol)-block-poly(γ-benzyl L-glutamate)-graft-poly(ethylene glycol) (PEG-b-PBLG-g-PEG) copolymer was synthesized by the ester exchange reaction of PBLG-block-PEG copolymer with mPEG. The self-association behaviors of PEG-b-PBLG-g-PEG and its blends with PBLG homopolymer in the mixtures of ethanol and dimethylformamide (DMF) were investigated by transmission electron microscopy (TEM), dynamic light scattering (DLS), and viscometry. Effects of the introduction of PBLG homopolymer, the grafting ratio, and the DMF content on the self-association behaviors of PEG-b-PBLG-g-PEG copolymer in the mixtures of ethanol and DMF were mainly researched. It was revealed that PEG-b-PBLG-g-PEG copolymer could self-assemble to form polymeric micelles with a core-shell structure in various shapes from different preparation conditions. The critical micelle concentration (CMC) and the average particle diameter of the micelles formed by PEG-b-PBLG-g-PEG copolymer in the mixed solvents also changed with different preparation conditions.     

Ring-opening polymerization of l-lactide in supercritical carbon dioxide using PDMS based stabilizers

Ring-opening suspension polymerization of l-lactide in supercritical CO₂ (scCO₂) was investigated in the presence of different stabilizer architectures based on poly(dimethyl siloxanes) (PDMS). Two amphiphilic AB type block copolymers, a graft copolymer, and an ester-capped PDMS were selected to find their efficacy as stabilizers for the synthesis of poly(l-lactide) (PLLA) in scCO₂. The stabilizer’s efficiency was analyzed in terms of the molecular weight, yield, and particle morphology of PLLA. The block copolymers, poly(dimethylsiloxane)-b-poly(acrylic acid) (PDMS-b-PAA) and poly(dimethylsiloxane)-b-poly(methacrylic acid) (PDMS-b-PMA) were found to be effective, leading to the formation of fine, discrete PLLA microparticles. On the other hand, the graft copolymer, poly(dimethylsiloxane-g-pyrrolidonecarboxylic acid) (PDMS-g-PCA) and acetylated PDMS (PDMS-OAc) failed to give an enough stabilization to the PLLA due to their short polymer-philic chains, resulting in hard agglomerates.     

Multifunctional covalently stabilized vesicles acting simultaneously as the template of gold nanoparticle cluster and the nanocarrier of guest molecules

The terminal hydroxyl groups of amphiphilic multiarm star copolymers with a hydrophilic hyperbranched polyethylenimine (PEI) core and hydrophobic poly(ε-caprolactone) (PCL) arms were partially or completely transformed into the radical-crosslinkable methacrylate (MA) groups (PEI-b-PCL-MA). The resulting PEI-b-PCL-MA polymers with 100% MA substitution self-assembled in water into simple vesicles, whereas those with partial MA substitution aggregated into complex vesicles. These structures could be proved by transmission electron microscopy and dynamic light scattering only after crosslinking the intra-vesicular MA groups that generated the covalently stabilized vesicles (CSVs). The obtained CSVs could be used as host for the formation of gold nanoparticle (AuNP) cluster, and the AuNP clusters stabilized by the CSVs were stable under a wider range of CSV/AuNP feed ratio than those stabilized by the uncrosslinked precursors. The diameter of AuNPs in the clusters was in the range of 4-6 nm, and the distance of adjacent AuNPs could be modulated through altering the feed ratio of CSV/AuNP. The color of the solutions of AuNPs with CSV could be tuned from brown to red, purple, even blue. The composites of CSV and AuNPs could be further used as nanocarriers to accommodate hydrophobic guest of pyrene, and a higher amount of AuNPs in the nanocarriers led to a lower encapsulation capacity for pyrene guests.     

Biodegradable amphiphilic block copolymers containing functionalized PEO blocks: Controlled synthesis and biomedical potentials

A series of controllable amphiphilic block copolymers composed of poly(ethylene oxide) (PEO) as the hydrophilic block and poly(?-caprolactone) (PCL) as the hydrophobic block with the amino terminal group at the end of the PEO chain (PCL-b-PEO-NH₂) were synthesized. Based on the further reaction of reactive amino groups, diblock copolymers with functional carboxyl groups (PCL-b-PEO-COOH) and functional compounds RGD (PCL-b-PEO-RGD) as well as the triblock copolymers with thermosensitive PNIPAAm blocks (PCL-b-PEO-b-PNIPAAM) were synthesized. The well-controlled structures of these copolymers with functional groups and blocks were characterized by gel permeation chromatography (GPC) and ¹H NMR spectroscopy. These copolymers with functionalized hydrophilic blocks were fabricated into microspheres for the examination of biofunctions via cell culture experiments and in vitro drug release. The results indicated the significance of introducing functional groups (e.g., NH₂, COOH and RGD) into the end of the hydrophilic block of amphiphilic block copolymers for biomedical potentials in tissue engineering and controlled drug release.     

Liquid Crystalline Period Variations in Self‐Assembled Block Copolypeptides–Surfactant Ionic Complexes

We investigate the complexation of ampholytic poly(N‐isopropylacylamide)‐block‐poly‐ (L ‐glutamic acid)‐block‐poly(L ‐lysine) (PNiPAM‐b‐PLG‐b‐PLLys) triblock copolymers and PNiPAM‐block‐(PLG‐co‐PLLys) diblock copolymers with counter charged anionic and cationic surfactants. Both triblock and diblock copolymers are able to selectively form complexes through either L ‐glutamic acid–cationic surfactant or L ‐lysine–anionic surfactant ionic pairs, depending on the protonated or deprotonated states of the ampholytic peptide units. The complexes show ordering at multiple length scales: i) the block copolymer length scale (10¹ nm), ii) the liquid crystalline length scale (10⁰ nm), and, iii) the peptidic secondary structures length scale (10⁰ nm). We show that the liquid crystalline period can be tuned by varying the random/block copolypeptide architectures and the composition of the ampholytic amino acid species.

     

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Amphiphilic Copolymers for Long-Acting Injectables: Synthesis,Non-Acylating Performance and In Vivo Degradation

This article presents the evaluation of diblock and triblock poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) amphiphilic copolymers (PEG-PTMCs) as excipients for the formulation of long-acting injectables (LAIs). Copolymers were successfully synthesised through bulk ring-opening polymerisation. The concomitant formation of PTMC homopolymer could not be avoided irrespective of the catalyst amount, but the by-product could easily be removed by gel chromatography. Pure PEG-PTMCs undergo faster erosion in vivo than their corresponding homopolymer. Furthermore, these copolymers show outstanding stability compared to their polyester analogues when formulated with amine-containing reactive drugs, which makes them particularly suitable as LAIs for the sustained release of drugs susceptible to acylation.     

Biocompatible and pH‐responsive triblock copolymer mPEG‐b‐PCL‐b‐PDMAEMA: Synthesis,self‐assembly,and application

A series of well‐defined amphiphilic triblock copolymers [polyethylene glycol monomethyl ether]‐block‐poly(ε‐caprolactone)‐block‐poly[2‐(dimethylamino)ethyl methacrylate] (mPEG‐b‐PCL‐b‐PDMAEMA or abbreviated as mPEG‐b‐PCL‐b‐PDMA) were prepared by a combination of ring‐opening polymerization and atom transfer radical polymerization. The chemical structures and compositions of these copolymers have been characterized by Fourier transform infrared spectroscopy, ¹H NMR, and thermogravimetric analysis. The molecular weights of the triblock copolymers were obtained by calculating from ¹H NMR spectra and gel permeation chromatography measurements. Subsequently, the self‐assembly behavior of these copolymers was investigated by fluorescence probe method and transmission electron microscopy, which indicated that these amphiphilic triblock copolymers possess distinct pH‐dependent critical aggregation concentrations and can self‐assemble into micelles or vesicles in PBS buffer solution, depending on the length of PDMA in the copolymer. Agarose gel retardation assays demonstrated that these cationic nanoparticles can effectively condense plasmid DNA. Cell toxicity tests indicated that these triblock copolymers displayed lower cytotoxicity than that of branched polyethylenimine with molecular weight of 25 kDa. In addition, in vitro release of Naproxen from these nanoparticles in pH buffer solutions was conducted, demonstrating that higher PCL content would result in the higher drug loading content and lower release rate. These biodegradable and biocompatible cationic copolymers have potential applications in drug and gene delivery. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1079–1091, 2010