Formation of Structured Polygonal Nanoparticles by Phase‐Separated Comb‐Like Polymers

A simple approach using comb‐like polymers that undergo nanophase separation between the polyester backbone and the stearoyl side chains is proposed for the preparation of structured non‐spherical nanoparticles from a nanoemulsion. Depending on the degree of esterification of the OH groups of poly(glycerol adipate) differently ordered nanostructures is obtained. A perfect lamellar arrangement is obtained for polymers with a high degree of esterification and leads to spherical nanoparticles with an internal onion‐like structure. However, when the degree of esterification is only 20 mol%, polygonal nanoparticles with an internal pseudo‐hexagonal structure are obtained. The differences in the nanoparticle shapes are related to the volume fraction of the paraffinic pool.     

Preparation of Magnetite Nanoparticles Coated with an Amphiphilic Block Copolymer: A Potential Drug Carrier with a Core‐Shell‐Corona Structure for Hydrophobic Drug Delivery

Summary: The synthesis of magnetic magnetite nanoparticles coated with amphiphilic block copolymers of poly(ethyl methacrylate)‐block‐poly(2‐hydroxyethyl methacrylate) for use as new potential carriers for hydrophobic drug delivery is reported. The results show that a new core‐shell‐corona structural material is obtained with a very narrow molecular weight distribution of the hydrophobic segment (PDI = 1.10). UV‐Vis results show that 37% of progesterone is released from the nanoparticles after 22 h, much slower than free release (99% after 14 h), which demonstrates that the presence of the hydrophobic segment can effectively control the release of hydrophobic drugs.

Synthesis of an amphiphilic block polymer poly(ethyl methacrylate)‐block‐poly(2‐hydroxyethyl methacrylate) on magnetite nanoparticles and their use as potential drug carriers     

Amphiphilic Comb‐Like Poly(oxyethylene) and Its Complexes with LiClO4: Synthesis and Mesomorphic Behavior

Summary: We prepared an amphiphilic, comb‐like poly(oxyethylene) containing decyl‐tri(oxyethylene) amphiphiles in the side chain using a polymer analogous reaction to obtain a novel nonionic amphiphilic polymeric system with high molecular weight. The amphiphilic comb‐like poly(oxyethylene) itself only showed a side‐chain crystalline phase below its melting temperature of −31 °C. When the polymer was mixed with lithium perchlorate, a smectic liquid‐crystalline phase appeared. The ordered phases of the polymer and the polymer mixture were studied by differential scanning calorimetry, polarized optical microscopy, and X‐ray diffraction.

POM image (200 X) of D3OTP1 at room temperature.     

Synthesis of comb‐like polystyrene with poly(N‐phenyl maleimide‐alt‐p‐chloromethyl styrene) as macroinitiator

The copolymerization of N‐phenyl maleimide and p‐chloromethyl styrene via reversible addition–fragmentation chain transfer (RAFT) process with AIBN as initiator and 2‐(ethoxycarbonyl)prop‐2‐yl dithiobenzoate as RAFT agent produced copolymers with alternating structure, controlled molecular weights, and narrow molecular weight distributions. Using poly(N‐phenyl maleimide‐alt‐p‐chloromethyl styrene) as the macroinitiator for atom transfer radical polymerization of styrene in the presence of CuCl/2,2′‐bipyridine, well‐defined comb‐like polymers with one graft chain for every two monomer units of backbone polymer were obtained. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2069–2075, 2006     

Cationic Vesicles Based on Amphiphilic Pillar[5]arene Capped with Ferrocenium: A Redox‐Responsive System for Drug/siRNA Co‐Delivery

A novel ferrocenium capped amphiphilic pillar[5]arene (FCAP) was synthesized and self‐assembled to cationic vesicles in aqueous solution. The cationic vesicles, displaying low cytotoxicity and significant redox‐responsive behavior due to the redox equilibrium between ferrocenium cations and ferrocenyl groups, allow building an ideal glutathione (GSH)‐responsive drug/siRNA co‐delivery system for rapid drug release and gene transfection in cancer cells in which higher GSH concentration exists. This is the first report of redox‐responsive vesicles assembled from pillararenes for drug/siRNA co‐delivery; besides enhancing the bioavailability of drugs for cancer cells and reducing the adverse side effects for normal cells, these systems can also overcome the drug resistance of cancer cells. This work presents a good example of rational design for an effective stimuli‐responsive drug/siRNA co‐delivery system.     

Influence of molecular weight on the phase behaviors of comb‐like polymers with long n‐alkyl side chains based on mesogen‐jacketed liquid crystalline polymers

A series of comb‐like polymers, poly{2,5‐bis[(4‐octadecyloxyphenyl)oxycarbonyl]‐styrenes{ (P‐OC18s) with different molecular weights (M_n) and low molecular weight distributions have been successfully synthesized via atom transfer radical polymerization. The phase behaviors have been investigated by a combination of techniques including differential scanning calorimetry, polarized optical microscopy, wide‐angle X‐ray diffraction, and temperature‐variable FTIR spectroscopy. One hand, phase behaviors of the alkyl tails were strongly influenced by the mesogens of polymers, leading to the poor packing of the alkyl tails and the low melting. The other hand, the liquid crystalline phase structures of polymers were found to be strongly M_n dependent. The samples with M_n ≤ 4.6 × 10⁴ formed a smectic phase in low temperature and an isotropic phase in high temperature. The samples with M_n ≥ 5.2 × 10⁴ displayed a reentrant isotropic phase, which was separating the smectic phase and columnar nematic phase. Meantime, the experiment results showed that the glass temperature and the transition temperature from smectic phase to isotropic phase both slightly increased with the increase of M_nS; however, the transition temperature from isotropic phase to columnar phase sharply decreased with the M_nS improved. The reappearance of isotropic phase is due to the competing between the driving force of the enthalpy and the driving force of the entropy. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Galactose‐Functionalized Cationic Polycarbonate Diblock Copolymer for Targeted Gene Delivery to Hepatocytes

To mediate selective gene delivery to hepatocytes via the asialoglycoprotein receptors (ASGP‐Rs), we designed and synthesized well‐defined and narrowly dispersed galactose‐ and glucose‐functionalized cationic polycarbonate diblock copolymers (designated as Gal‐APC and Glu‐APC, respectively) using organocatalytic ring‐opening polymerization of functionalized carbonate monomers, with a subsequent quaternization step using bis‐tertiary amines to confer quaternary and tertiary amines for DNA binding and endosomal buffering, respectively. The sugar‐functionalized diblock copolymers effectively bound and condensed DNA to form positively charged nanoparticles (<100 nm in diameter and ≈30 mV zeta‐potential) that were stable under high physiological salt conditions. In comparison to the control Glu‐APC/DNA complexes, Gal‐APC/DNA complexes mediated significantly higher gene expression in ASGP‐R positive HepG2 cells with no significant difference observed in ASGP‐R negative HeLa cells. The co‐incubation of Gal‐APC/DNA complexes with a natural ASGP‐R ligand effectively led to a decrease in gene expression, hence providing evidence for the ASGP‐R mediated endocytosis of the polyplexes. Importantly, the Gal‐APC/DNA complexes induced minimal cytotoxicities in HepG2 cells at the N/P ratios tested. Taken together, the galactose‐functionalized cationic polycarbonate diblock copolymer has potential for use as a non‐viral gene vector for the targeted delivery of therapeutic genes to hepatocytes in the treatment of liver diseases.

     

Synthesis and self‐assembly of thymine‐ and adenine‐containing homopolymers and diblock copolymers

Atom transfer radical polymerizations (ATRPs) of 1‐(4‐methacryloyloxy‐benzyl)thymine (MAT) and 9‐(2‐methacryloyloxyethyl)adenine (MAA) were conducted for the synthesis of DNA‐base functionalized polymers. The association equilibrium constant K_asso between MAT and MAA and the complexation equilibrium constant K_comp between the corresponding polymers PMAT and PMAA were determined. A zipper‐like diblock copolymer, PMAT‐b‐PMAA, was prepared by anchoring the PMAT and PMAA blocks on the ortho‐positions of a pyridine ring via a successive two‐step ATRP. Dynamic light scattering and atom force microscopy confirmed that the block copolymer had a V‐shaped configuration in dimethylsulfoxide/N,N‐dimethylformamide. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5995–6006, 2006     

Crosslinked Redox‐Responsive Micelles Based on Lipoic Acid‐Derived Amphiphiles for Enhanced siRNA Delivery

Successful application of gene silencing approaches critically depends on systems that are able to safely and efficiently deliver genetic material such as small interfering RNA (siRNA). Due to their beneficial well‐defined dendritic nanostructure, self‐assembling dendrimers are emerging as promising nanovectors for siRNA delivery. However, these kinds of vectors are plagued with stability issues, especially when considered for in vivo applications. Therefore, in the present study, disulfide‐based temporarily fixed micelles are developed that can degrade upon reductive conditions, and thus lead to efficient cargo release. In detail, lipoic acid‐derived crosslinked micelles are synthesized based on small polymerizable dendritic amphiphiles. Particularly, one candidate out of this series is able to efficiently release siRNA due to its redox‐responsive biodegradable profile when exposed to simulated intracellular environments. As a result, the reduction‐triggered disassembly leads to potent gene silencing. In contrast, noncrosslinkable, structurally related constructs fails under the tested assay conditions, thereby confirming the applied rational design approach and demonstrating its large potential for future in vivo applications.

     

Amphiphilic polymer conetworks prepared by controlled radical polymerization using a nitroxide cross‐linker

Tandem atom transfer radical polymerization (ATRP) and nitroxide‐mediated radical polymerization (NMRP) were used to synthesize a polystyrene‐co‐poly(acrylic acid) (poly(St‐co‐AA)) network, in which the two components were interconnected by covalent bond. First, a specific cross‐linker, 1,4‐bis(1′‐(4″‐acryloyloxy‐2″,2″,6″,6″‐tetramethylpiperidinyloxy)ethyl)benzene (di‐AET), a bifunctional alkoxyamine possessing two acrylate groups, was copolymerized with tert‐butyl acrylate through ATRP to prepare a precursor gel. The gel was then used to initiate the NMRP of styrene to prepare poly(St‐co‐(t‐BA)) conetwork, in which the cross‐linkages are composed of polystyrene segments. Finally, the poly(St‐co‐(t‐BA)) conetwork was hydrolyzed to produce amphiphilic poly(St‐co‐AA) conetwork. The resulting gels show swelling ability in both organic solvent and water, which is characteristic of amphiphilic conetworks. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 4141–4149, 2010     

One‐Reactant Photografting of ATRP Initiators for Surface‐Initiated Polymerization

Self‐initiated photografting polymerization is used to couple the polymerizable initiator monomer 2‐(2‐chloropropanoyloxy)ethyl acrylate to a range of polymeric substrates. The technique requires only UV light to couple the initiator to surfaces. The initiator surface density can be varied by inclusion of a diluent monomer or via selection of initiator and irradiation parameters. The functionality of the initiator surface is demonstrated by subsequent surface‐initiated atom transfer radical polymerization. Surfaces are characterized by x‐ray photoelectron spectroscopy (XPS), ellipsometry, and atomic force microscopy (AFM), and UV‐induced changes to the initiator are assessed by ¹H NMR and gel permeation chromatography (GPC). This is the first time this one‐reactant one‐step technique has been demonstrated for creating an initiator surface of variable density.

     

Ultra‐pH‐Responsive and Tumor‐Penetrating Nanoplatform for Targeted siRNA Delivery with Robust Anti‐Cancer Efficacy

RNA interference (RNAi) gene silencing technologies have shown significant potential for treating various diseases, including cancer. However, clinical success in cancer therapy remains elusive, mainly owing to suboptimal in vivo delivery of RNAi therapeutics such as small interference RNA (siRNA) to tumors. Herein, we developed a library of polymers that respond to a narrow pH change (ultra‐pH‐responsive), and demonstrated the utility of these materials in targeted and deep tumor‐penetrating nanoparticle (NP) for in vivo RNAi. The new NP platform is mainly composed of the following key components: i) internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration; ii) polyethylene glycol (PEG) chains to prolong blood circulation; and iii) sharp pH‐responsive hydrophobic polymer to improve endosome escape. Through systematic studies of structure–function relationship, the optimized RNAi NPs (<70 nm) showed efficient gene silencing and significant inhibition of tumor growth with negligible toxicities in vivo.     

Codelivery for Paclitaxel and Bcl‐2 Conversion Gene by PHB‐PDMAEMA Amphiphilic Cationic Copolymer for Effective Drug Resistant Cancer Therapy

Antiapoptotic Bcl‐2 protein's upregulated expression is a key reason for drug resistance leading to failure of chemotherapy. In this report, a series of biocompatible amphiphilic cationic poly[(R)‐3‐hydroxybutyrate] (PHB)‐b‐poly(2‐(dimethylamino)ethyl methacrylate) (PDMAEMA) copolymer, comprising hydrophobic PHB block and cationic PDMAEMA block, is designed to codeliver hydrophobic chemotherapeutic paclitaxel and Bcl‐2 converting gene Nur77/ΔDBD with enhanced stability, due to the micelle formation by hydrophobic PHB segment. This copolymer shows less toxicity but similar gene transfection efficiency to polyethyenimine (25k). More importantly, this codelivery approach by PHB‐PDMAEMA leads to increased drug resistant HepG2/Bcl‐2 cancer cell death, by increased expression of Nur77 proteins in the Bcl‐2 present intracellular mitochondria. This work signifies for the first time that cationic amphiphilic PHB‐b‐PDMAEMA copolymers can be utilized for the drug and gene codelivery to drug resistant cancer cells with high expression of antiapoptosis Bcl‐2 protein and the positive results are encouraging for the further design of codelivery platforms for combating drug resistant cancer cells.     

PNIPAM‐b‐(PEA‐g‐PDMAEA) double‐hydrophilic graft copolymer: Synthesis and its application for preparation of gold nanoparticles in aqueous media

A series of well‐defined double‐hydrophilic graft copolymers, consisting of poly(N‐isopropylacrylamide)‐b‐poly(ethyl acrylate) (PNIPAM‐b‐PEA) backbone and poly(2‐(dimethylamino)ethyl acrylate) (PDMAEA) side chains, were synthesized by the combination of single‐electron‐transfer living radical polymerization (SET‐LRP) and atom‐transfer radical polymerization (ATRP). PNIPAM‐b‐PEA backbone was first prepared by sequential SET‐LRP of N‐isopropylacrylamide and 2‐hydroxyethyl acrylate at 25 °C using CuCl/tris(2‐(dimethylamino)ethyl)amine as catalytic system followed by the transformation into the macroinitiator by treating the pendant hydroxyls with 2‐chloropropionyl chloride. The final graft copolymers with narrow molecular weight distributions were synthesized by ATRP of 2‐(dimethylamino)ethyl acrylate initiated by the macroinitiator at 40 °C using CuCl/tris(2‐(dimethylamino)ethyl)amine as catalytic system via the grafting‐from strategy. These copolymers were employed to prepare stable colloidal gold nanoparticles with controlled size in aqueous solution without any external reducing agent. The morphology and size of the nanoparticles were affected by the length of PDMAEA side chains, pH value, and the feed ratio of the graft copolymer to HAuCl₄. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1811–1824, 2009     

Biodegradable Self‐Assembled Nanoparticles of Galactose‐Containing Amphiphilic Triblock Copolymers for Targeted Delivery of Paclitaxel to HepG2 Cells

Biodegradable self‐assembled polymeric nanoparticles (NPs) composed of poly(6‐O‐methacryloyl‐D‐galactopyranose)‐b‐poly(L‐lactide)‐b‐poly(6‐O‐methacryloyl‐D‐galactopyranose) (PMAGP‐b‐PLA‐b‐PMAGP) are prepared as carriers for the hydrophobic anticancer drug paclitaxel (PTX), to achieve target delivery to hepatoma cells. PTX can be encapsulated by the NPs with various molar ratios of L‐lactide (LA) and 6‐O‐methacryloyl‐D‐galactopyranose (MAGP) during the process of self‐assembly, and the resulting NPs exhibit high drug loading efficacy and substantial stability in aqueous solution. The size, size distribution, and morphology of the NPs are characterized using a Zetasizer Nano ZS and transmission electron microscopy. The hemolysis assay and cell cytotoxicity assay indicate that the polymeric NPs are biocompatible and non‐toxic. The cellular uptake assay demonstrates that the galactose‐containing NPs can be selectively recognized and subsequently accumulate in HepG2 cells. All of these results demonstrate that galactose‐containing polymeric NPs are potential carriers for hepatoma‐targeted drug delivery and liver cancer therapy in clinical medicine.

     

Synthesis of Novel Rod‐Coil Amphiphilic Block Copolymers PAA‐b‐DPS with Fréchet‐Type Dendronized Polystyrene and Poly(acrylic acid)

A series of well‐defined rod‐coil PAA‐b‐DPS block copolymers, containing Fréchet‐type dendronized polystyrene (DPS) with different generation as a rod‐like hydrophobic block and poly(acrylic acid) (PAA) as a hydrophilic coil were synthesized. The procedure included the following steps: the precursor PMA‐b‐DPS copolymer was prepared through ATRP of Fréchet‐type dendritic styrene macromonomer bearing the first to the third generation (G1–G3), respectively, initiated by poly(methyl acrylate) (PMA‐Br). Then, by converting PMA into PAA by subsequent hydrolysis, the targeted amphiphilic copolymers were obtained. Moreover, by using the rod‐coil amphiphiles as building blocks, large compound micelles and vesicles were formed in a binary solvent mixture of DMF/H₂O. Morphological changes in self‐assembly showed dependence on the length of the dendronized block.

     

Synthesis and SFM Study of Comb‐Like Poly(4‐vinylpyridinium) Salts and Their Complexes with Surfactants

Summary: Poly(4‐vinylpyridinium) bromides containing octyl and dodecyl pendant groups were synthesized. Bromide anions in these polymer salts were substituted with dodecylsulfate and bis(2‐ethylhexylsuccinate) anions using ion‐exchange reactions. Initially, P4VP and its derivatives loaded with hydrophobic groups were deposited on a mica surface from diluted solutions in chloroform for visualization. Images of single adsorbed macromolecules were obtained using scanning force microscopy. Original P4VP chains form partially compacted self‐intersecting coils. Loading the polymer chains with large hydrophobic groups and especially the increase in the number of alkyl tails (see Figure) per monomer unit of the polymer chain leads to the stretching of the coils, and the comb‐like macromolecules adopt more and more extended self‐avoiding 2D conformations when deposited on the substrate.

Polymer chains with large hydrophobic groups and increasing number of alkyl tails per monomer unit of the polymer chain.     

Synthesis,characterization, and fluorescence of pyrene‐containing eight‐arm star‐shaped dendrimer‐like copolymer with pentaerythritol core

Novel and well‐defined pyrene‐containing eight‐arm star‐shaped dendrimer‐like copolymers were successfully achieved by combination of esterification, atom transfer radical polymerization (ATRP), divergent reaction, ring‐opening polymerization (ROP), and coupling reaction on the basis of pentaerythritol. The reaction of pentaerythritol with 2‐bromopropionyl bromide permitted ATRP of styrene (St) to form four‐arm star‐shaped polymer (PSt‐Br)₄. The molecular weights of these polymers could be adjusted by the variation of monomer conversion. Eight‐hydroxyl star‐shaped polymer (PSt‐(OH)₂)₄ was produced by the divergent reaction of (PSt‐Br)₄ with diethanolamine. (PSt‐(OH)₂)₄ was used as the initiator for ROP of ε‐caprolactone (CL) to produce eight‐arm star‐shaped dendrimer‐like copolymer (PSt‐b‐(PCL)₂)₄. The molecular weights of (PSt‐b‐(PCL)₂)₄ increased linearly with the increase of monomer. After the coupling reaction of hydroxyl‐terminated (PSt‐b‐(PCL)₂)₄ with 1‐pyrenebutyric acid, pyrene‐containing eight‐arm star‐shaped dendrimer‐like copolymer (PSt‐b‐(PCL‐pyrene)₂)₄ was obtained. The eight‐arm star‐shaped dendrimer‐like copolymers presented unique thermal properties and crystalline morphologies, which were different from those of linear poly(ε‐caprolactone) (PCL). Fluorescence analysis indicated that (PSt‐b‐(PCL‐pyrene)₂)₄ presented slightly stronger fluorescence intensity than 1‐pyrenebutyric acid when the pyrene concentration of them was the same. The obtained pyrene‐containing eight‐arm star‐shaped dendrimer‐like copolymer has potential applications in biological fluorescent probe, photodynamic therapy, and optoelectronic devices. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2788–2798, 2008