Encapsulation of Bovine Serum Albumin in Temperature‐Programmed “Shell‐in‐Shell” Structures

A novel approach to load a hydrophilic bovine serum albumin into drug carriers was proposed in terms of temperature‐programmed “shell‐in‐shell” structures, which were fabricated with poly(N‐isopropylacrylamide), poly(lactide), poly(ethylene glycol), and Au nanoparticles. Spherically well‐defined “shell‐in‐shell” structures were constructed by a modified‐double‐emulsion method (MDEM). The lower critical solubility temperature of the structures was manipulated to 36.4 °C which was confirmed by UV/Vis spectroscopy and DSC (Differential Scanning Calorimetry).

TEM image of the Au@PLLA‐PEG@PNIPAAm‐PDLA structure.     

A “click” approach to ROMP block copolymers

Amphiphilic block copolymers can be conveniently prepared via convergent syntheses, allowing each individual polymer block to be prepared via the polymerization technique that gives the best architectural control. The convergent “click‐chemistry” route presented here, gives access to amphiphilic diblock copolymers prepared from a ring opening metathesis polymer and polyethylene glycol. Because of the high functional group tolerance of ruthenium carbene initiators, highly functional ring opening metathesis polymerization (ROMP) polymer blocks can be prepared. The described synthetic route allows the conjugation of these polymer blocks with other end‐functional polymers to give well‐defined and highly functional amphiphilic diblock copolymers. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2913–2921, 2008     

Synthesis and self‐assembly of novel amphiphilic copolymers poly(lactic acid)‐block‐poly(ascorbyl acrylate)

In this study, a novel type of amphiphilic block copolymers poly(lactic acid)‐block‐poly(ascorbyl acrylate) (PLA‐block‐PAAA) with biodegradable poly(lactic acid) as hydrophobic block and poly(ascorbyl acrylate) (PAAA) as hydrophilic block was successfully developed by a combination of ring‐opening polymerization and atom transfer radical polymerization, followed by hydrogenation under normal pressure. The chemical structures of the desired copolymers were characterized by ¹H NMR and gel permeation chromatography. The thermal physical properties and crystallinity were investigated by thermogravimetric analysis, differential scanning calorimetry, and wide angle X‐ray diffraction, respectively. Their self‐assembly behavior was monitored by fluorescence‐probe technique and turbidity change using UV–vis spectrometer, and the morphology and size of the nanocarriers via self‐assembly were detected by cryo‐transmission electron microscopy and dynamic light scattering. These polymeric micelles with PAAA shell extending into the aqueous solution have potential abilities to act as promising nanovehicles for targeting drug delivery. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Recent advances in the solution self‐assembly of amphiphilic “rod‐coil” copolymers

Solution self‐assembly of amphiphilic “rod‐coil” copolymers, especially linear block copolymers and graft copolymers (also referred to as polymer brushes), has attracted considerable interest, as replacing one of the blocks of a coil‐coil copolymer with a rigid segment results in distinct self‐assembly features compared with those of the coil‐coil copolymer. The unique interplay between microphase separation of the rod and coil blocks with great geometric disparities can lead to the formation of unusual morphologies that are distinctly different from those known for coil‐coil copolymers. This review presents the recent achievements in the controlled self‐assembly of rod‐coil linear block copolymers and graft copolymers in solution, focusing on copolymer systems containing conjugated polymers, liquid crystalline polymers, polypeptides, and polyisocyanates as the rod segments. The discussions concentrate on the principle of controlling over the morphology of rod‐coil copolymer assemblies, as well as their distinctive optical and optoelectronic properties or biocompatibility and stimuli‐responsiveness, which afford the assemblies great potential as functional materials particularly for optical, optoelectronic and biological applications. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 1459–1477     

Synthesis and aggregation of poly(valine)‐poly (ethylene glycol) block copolymers

The solubility nature of many medicines presents a challenge for successful delivery of these drugs to the body. Polymeric carriers are potentially viable as vessels for both the protection and transport of these medicinal substances. In an effort to generate polymeric materials for this desired application, A‐B‐A triblock copolymers have been synthesized with a central block composed of hydrophilic poly (ethylene glycol) (PEG) and flanking hydrophobic sequences composed of five valine units terminated with end groups of varying hydrophobicity. These copolymers were constructed by adding amino acids stepwise to the hydrophilic block using solution phase chemistry. The self‐assembly behavior of all polymers was investigated using fluorimetry with a pyrene probe. In general, copolymers with more hydrophobic end groups exhibited lower critical aggregation concentrations (CACs). Fmoc‐terminated copolymers displayed the lowest CAC of 0.032 mg/mL and demonstrated little cytotoxicity when exposed to SW620 colorectal cancer cells. Transmission electron micrographs show the presence of multiple compartments within these spherical assemblies, which may prove useful in encapsulating medicinal substances. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5381–5389, 2008     

“Clip” and “Click” Chemistries Combination: Toward Easy PEGylation of Degradable Aliphatic Polyesters

α‐Methoxy‐ω‐alkyne poly(ethylene glycol) (PEG) was tagged with pendent N‐hydroxy‐succinimidyl activated esters by photografting of a molecular clip. This easily synthesized heterofunctional PEG was found to be a versatile building block for (i) conjugation with an amino derivative and (ii) grafting to azido functional aliphatic polyesters backbone by Huisgen's 1,3‐dipolar cycloaddition. This original combination of “clip” and “click” reactions provides a versatile and straightforward pathway for the synthesis of functional amphiphilic and degradable copolymers valuable for biomedical applications such as in drug‐delivery.

     

Concurrent Block Copolymer Polymersome Stabilization and Bilayer Permeabilization by Stimuli‐Regulated “Traceless” Crosslinking

The fabrication of block copolymer (BCP) vesicles (polymersomes) exhibiting synchronized covalent crosslinking and bilayer permeabilization remains a considerable challenge as crosslinking typically leads to compromised membrane permeability. Herein it is demonstrated how to solve this dilemma by employing a stimuli‐triggered crosslinking strategy with amphiphilic BCPs containing photolabile carbamate‐caged primary amines. Upon self‐assembling into polymersomes, light‐triggered self‐immolative decaging reactions release primary amine moieties and extensive amidation reactions then occur due to suppressed amine pK_a within hydrophobic milieu. This leads to serendipitous vesicle crosslinking and the process is associated with bilayer hydrophobicity‐to‐hydrophilicity transition and membrane permeabilization.     

Dual Stimuli‐Responsive Polymeric Micelles Exhibiting “AND” Logic Gate for Controlled Release of Adriamycin

A new controlled release polymer micelle was designed and synthesized based on the concept of the “AND” logic with two orthogonal molecular triggers, namely pH and reduction, for intracellular drug delivery. Specifically, a hydrazine functionalized PEO‐b‐PMAA block copolymer was used to attach adriamycin (ADR) through the formation of hydrazone, then the as‐prepared ADR‐conjugated block copolymer micelles could be crosslinked by dithiodiethanoic acid. ADR was found to release most efficiently under both the low pH and the reductive conditions. This smart device is therefore equipped with two triggers with the “AND” logic for the releasing action, which is suitable for more complicated physiological conditions because the “ON” state is only realized under the simultaneous presence of the dual signal stimuli.

     

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

Dendritic polyglycerol‐co‐polycaprolactone (PG‐co‐PCL)‐derived block copolymers are synthesized and explored as nanoscale drug delivery platforms for a chemotherapeutic agent, gemcitabine (GEM), which is the cornerstone of therapy for pancreatic ductal adenocarcinoma (PDAC). Current treatment strategies with GEM result in suboptimal therapeutic outcome owing to microenvironmental resistance and rapid metabolic degradation of GEM. To address these challenges, physicochemical and cell‐biological properties of both covalently conjugated and non‐covalently stabilized variants of GEM‐containing PG‐co‐PCL architectures have been evaluated. Self‐assembly behavior, drug loading and release capacity, cytotoxicity, and cellular uptake properties of these constructs in monolayer and in spheroid cultures of PDAC cells are investigated. To realize the covalently conjugated carrier systems, GEM, in conjunction with a tertiary amine, is attached to the polycarbonate block grafted from the PG‐co‐PCL core. It is observed that pH‐dependent ionization properties of these amine side‐chains direct the formation of self‐assembly of block copolymers in the form of nanoparticles. For non‐covalent encapsulation, a facile “solvent‐shifting” technique is adopted. Fabrication techniques are found to control colloidal and cellular properties of GEM‐loaded nanoconstructs. The feasibility and potential of these newly developed architectures for designing carrier systems for GEM to achieve augmented prognosis for pancreatic cancer are reported.     

Synthesis of novel asymmetric dendritic‐linear‐dendritic block copolymers via “living” anionic polymerization of ethylene oxide initiated by dendritic macroinitiators

The first synthesis of asymmetric dendritic‐linear‐dendritic ABC block copolymers, that contain a linear B block and dissimilar A and C dendritic fragments is reported. Third generation poly(benzyl ether) monodendrons having benzyl alcohol moiety at their “focal” point were activated by quantitative titration with organometallic anions and the resulting alkoxides were used as initiators in the “living” ring‐opening polymerization of ethylene oxide. The reaction proceeded in controlled fashion at 40–50 °C affording linear‐dendritic AB block copolymers with predictable molecular weights (M_w = 6000–13,000) and narrow molecular weight distributions (M_w/M_n = 1.02–1.04). The propagation process was monitored by size‐exclusion chromatography with multiple detection. The resulting “living” copolymers were terminated by reaction either with HCl/tetrahydrofuran or with a reactive monodendron that differed from the initiating dendron not only in size, but also in chemical composition. The asymmetric triblock copolymers follow a peculiar structure‐induced self‐assembly pattern in block‐selective solvents as evidenced by size‐exclusion chromatography in combination with multi‐angle light scattering. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5136–5148, 2007     

A roadmap for poly(ethylene oxide)‐block‐poly‐ε‐caprolactone self‐assembly in water: Prediction,synthesis, and characterization

Numerical self‐consistent field (SCF) lattice computations allow a priori determination of the equilibrium morphology and size of supramolecular structures originating from the self‐assembly of neutral block copolymers in selective solvents. The self‐assembly behavior of poly(ethylene oxide)‐block‐poly‐ε‐caprolactone (PEO‐PCL) block copolymers in water was studied as a function of the block composition, resulting in equilibrium structure and size diagrams. Guided by the theoretical SCF predictions, PEO‐PCL block copolymers of various compositions have been synthesized and assembled in water. The size and morphology of the resulting structures have been characterized by small‐angle X‐ray scattering, cryogenic transmission electron microscopy, and multiangle dynamic light scattering. The experimental results are consistent with the SCF computations. These findings show that SCF is applicable to build up roadmaps for amphiphilic polymers in solution, where control over size and shape are required, which is relevant, for instance, when designing spherical micelles for drug delivery systems © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 330–339     

Amphiphilic diblock copolymers based on poly(2‐ethyl‐2‐oxazoline) and poly(4‐substituted‐ε‐caprolactone): Synthesis,characterization, and cellular uptake

Amphiphilic diblock copolymers with various block compositions were synthesized on poly(2‐ethyl‐2‐oxazoline) (PEtOz) as a hydrophilic block and poly(4‐methyl‐ε‐caprolactone) (PMCL) or poly(4‐phenyl‐ε‐caprolactone) (PBCL) as a hydrophobic block. These PEtOz‐b‐PMCL and PEtOz‐b‐PBCL copolymers consisting of soft domains of amorphous PEtOz and PM(B)CL had no melting endothermal peaks but displayed T_g. The lower critical solution temperature (LCST) values for the PEtOz‐b‐PMCL, and the PEtOz‐b‐PBCL aqueous solution were observed to shift to lower temperature than PEtOz homopolymers. Their aqueous solutions were characterized using fluorescence techniques and dynamic light scattering (DLS). The block copolymers formed micelles with critical micelle concentrations (CMCs) in the range 0.6–11.1 mg L^?1 in an aqueous phase. As the length of the hydrophobic PMCL or PBCL blocks elongated, lower CMC values were generated. The mean diameters of the micelles were between 127 and 318 nm, with PDI in the range of 0.06–0.21, suggesting nearly monodisperse size distributions. The drug entrapment efficiency and drug‐loading content of micelles depend on block polymer compositions. In vitro cell viability assay showed that PEtOz‐b‐PMCL has low cytotoxicity. Doxorubicin hydrochloride (DOX)‐loaded micelles facilitated human cervical cancer (HeLa) cell uptake of DOX; uptake was completed within 2 h, and DOX was able to reach intracellular compartments and enter the nuclei by endocytosis. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2769–2781     

Self‐assembly behavior of amphiphilic linear‐block‐dendritic copolymers with long subchains: Dependences on dendron generation and mixing dynamics

Block copolymers composed of acrylic acid and methyl methacrylate with three topologies of double linear blocks, poly(acrylic acid) (PAA) linear block/poly(methyl methacrylate) (PMMA) G1‐dendron and PAA linear block/PMMA G2‐dendron have been prepared by the combination of atom transfer radical polymerization and azide–alkyne click reaction. Proton nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and gel permeation chromatography have been adopted thoroughly to identify the chemical structure of those block copolymers with expected topologies. The self‐assembly of those block copolymers in the selective solvent has been performed through two mixing routes of gentle and abrupt variation in solvent selectivity, and the morphology of the obtained self‐assemblies/aggregates was observed by transmission electron microscopy. Because the abrupt variation route altered sharply the solvent quality during the mixing, the intermolecular association of polymer chains resulted in the smaller self‐assemblies but the further growth of smaller self‐assemblies was not observed. On the contrary, the gentle variation route changed gradually the solvent quality during the mixing, favoring not only the intermolecular association but also the further growth of self‐assemblies to result in larger aggregates. The final morphology of those assemblies/aggregates also exhibited the dependence of PMMA dendron generation. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1446–1456     

Synthesis of stable “gold nanoparticle–polymeric micelle” conjugates: A new class of star “molecular chimera” that self‐assemble into linear arrays of spherical micelles

Stable and aggregation‐free “gold nanoparticle–polymeric micelle” conjugates were prepared using a new and simple protocol enabled by the hydrogen bonding between surface‐capping ligands and polymeric micelles. Individual gold nanoparticles were initially capped using a phosphatidylthio–ethanol lipid and further conjugated with a star poly(styrene‐block‐glutamic acid) copolymer micelle using a one‐pot preparation method. The morphology and stability of these gold–polymer conjugates were characterized using transmission electron microscopy (TEM) and UV–vis spectroscopy. The self‐assembly of this class of polymer‐b‐polypeptide in aqueous an medium to form spherical micelles and further their intermicelle reorganization to form necklace‐like chains was also investigated. TEM and laser light scattering techniques were employed to study the morphology and size of these micelles. Polymeric micelles were formed with diameters in the range of 65–75 nm, and supermicellular patterns were observed. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 3570–3579, 2007     

“Raft” Formation by Two‐Dimensional Self‐Assembly of Block Copolymer Rod Micelles in Aqueous Solution

Block copolymers can form a broad range of self‐assembled aggregates. In solution, planar assemblies usually form closed structures such as vesicles; thus, free‐standing sheet formation can be challenging. While most polymer single crystals are planar, their growth usually occurs by uptake of individual chains. Here we report a novel lamella formation mechanism: core‐crystalline spherical micelles link up to form rods in solution, which then associate to yield planar arrays. For the system of poly(ethylene oxide)‐block‐polycaprolactone in water, co‐assembly with homopolycaprolactone can induce a series of morphological changes that yield either rods or lamellae. The underlying lamella formation mechanism was elucidated by electron microscopy, while light scattering was used to probe the kinetics. The hierarchical growth of lamellae from one‐dimensional rod subunits, which had been formed from spherical assemblies, is novel and controllable in terms of product size and aspect ratio.     

Synthesis of poly(propylene glycol)-block-polyethylenimine triblock copolymers for the delivery of nucleic acids

LPEIs, which are efficient DNA transfection agents, were found to be far less effective for the delivery of siRNAs. Here, two amphiphilic triblock copolymers LPEI(50) -b-PPG(36) -b-LPEI(50) (2) and LPEI(14) -b-PPG(68) -b-LPEI(14) (4) have been synthesized. The transfection assays showed that compound 2 was efficient for DNA transfection whilst it was almost inactive for siRNA delivery. In contrast, polymer 4 was inefficient for DNA transfection while it showed capabilities for siRNA delivery. Taken together, our results indicate that the properties required for DNA and siRNA delivery are different. Moreover, we show that introduction of a hydrophobic segment that allows self-assembly confers siRNA delivery capacities.     

Synthesis,characterization, and micellization of PCL‐g‐PEG copolymers by combination of ROP and “Click” chemistry via “Graft onto” method

Biodegradable and biocompatible PCL‐g‐PEG amphiphilic graft copolymers were prepared by combination of ROP and “click” chemistry via “graft onto” method under mild conditions. First, chloro‐functionalized poly(ε‐caprolactone) (PCL‐Cl) was synthesized by the ring‐opening copolymerization of ε‐caprolactone (CL) and α‐chloro‐ε‐caprolactone (CCL) employing scandium triflate as high‐efficient catalyst with near 100% monomer conversion. Second, the chloro groups of PCL‐Cl were quantitatively converted into azide form by NaN₃. Finally, copper(I)‐catalyzed cycloaddition reaction was carried out between azide‐functionalized PCL (PCL‐N₃) and alkyne‐terminated poly(ethylene glycol) (A‐PEG) to give PCL‐g‐PEG amphiphilic graft copolymers. The composition and the graft architecture of the copolymers were characterized by ¹H NMR, FTIR, and GPC analyses. These amphiphilic graft copolymers could self‐assemble into sphere‐like aggregates in aqueous solution with diverse diameters, which decreased with the increasing of grafting density. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Fluorescent Vesicles Consisting of Galactose‐based Amphiphilic Copolymers with a π‐Conjugated Sequence Self‐assembled in Water

Fluorescent vesicles considered as a mimic of natural primitive cells are prepared from poly(3‐hexylthiophene)‐block‐poly(3‐O‐methacryloyl‐D‐galactopyranose) P3HT‐b‐PMAGP copolymers. The unique characteristic of such vesicular nanostructures is their architecture, which comprises a hydrophobic π‐conjugated P3HT wall stabilized by a hydrophilic PMAGP interface featuring glucose units. The results of this work offer a very efficient and straightforward method for engineering well‐controlled fluorescent nanoparticles (without the addition of dyes), which provide an excellent support to the study of carbohydrate‐protein interactions.