Hyperbranched Block Copolymers Research Articles

Hyperbranched copolymer micelles as delivery vehicles of doxorubicin in breast cancer cells

AbstractFour types of drug nanoparticles (NPs) based on amphiphilic hyperbranched block copolymers were developed for the delivery of the chemotherapeutic doxorubicin (DOX) to breast cancer cells. These carriers have their hydrophobic interior layer composed of the hyperbranched aliphatic polyester, Boltorn® H30 or Boltorn® H40, that are polymers of poly 2,2‐bis (methylol) propionic acid (bis‐MPA), while the outer hydrophilic shell was composed of about 5 poly(ethylene glycol) (PEG) segments of 5 or 10 kDa molecular weight. A chemotherapeutic drug DOX, was further encapsulated in the interior of these polymer micelles and was shown to exhibit a controlled release profile. Dynamic light scattering and transmission electron microscopy analysis confirmed that the NPs were uniformly sized with a mean hydrodynamic diameter around 110 nm. DOX‐loaded H30‐PEG10k NPs exhibited controlled release over longer periods of time and greater cytotoxicity compared with the other materials developed against our tested breast cancer cell lines. Additionally, flow cytometry and confocal scanning laser microscopy studies indicated that the cancer cells could internalize the DOX‐loaded H30‐PEG10k NPs, which contributed to the sustained drug release, and induced more apoptosis than free DOX did. These findings indicate that the H30‐PEG10k NPs may offer a very promising approach for delivering drugs to cancer cells. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Tumor-Targeting, pH-Responsive, and Stable Unimolecular Micelles as Drug Nanocarriers for Targeted Cancer Therapy

A new type of multifunctional unimolecular micelle drug nanocarrier based on amphiphilic hyperbranched block copolymer for targeted cancer therapy was developed. The core of the unimolecular micelle was a hyperbranched aliphatic polyester, Boltorn H40. The inner hydrophobic layer was composed of random copolymer of poly(ε-caprolactone) and poly(malic acid) (PMA-co-PCL) segments, while the outer hydrophilic shell was composed of poly(ethylene glycol) (PEG) segments. Active tumor-targeting ligands, i.e., folate (FA), were selectively conjugated to the distal ends of the PEG segments. An anticancer drug, i.e., doxorubicin (DOX) molecules, was conjugated onto the PMA segments with pH-sensitive drug binding linkers for pH-triggered drug release. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis showed that the unimolecular micelles were uniform with a mean hydrodynamic diameter around 25 nm. The drug loading content was determined to be 14.2%. The drug release profile, cell uptake and distribution, and cytotoxicity of the unimolecular micelles were evaluated in vitro. The folate-conjugated micelles can be internalized by the cancer cells via folate-receptor-mediated endocytosis; thus, they exhibited enhanced cell uptake and cytotoxicity. At pH 7.4, the physiological condition of bloodstream, DOX conjugated onto the unimolecular micelles exhibited excellent stability; however, once the micelles were internalized by the cancer cells, the pH-sensitive hydrazone linkages were cleavable by the intracellular acidic environment, which initially caused a rapid release of DOX. These findings indicate that these unique unimolecular micelles may offer a very promising approach for targeted cancer therapy.

Hyperbranched Polyglycerols: From the Controlled Synthesis of Biocompatible Polyether Polyols to Multipurpose Applications

Dendritic macromolecules with random branch-on-branch topology, termed hyperbranched polymers in the late 1980s, have a decided advantage over symmetrical dendrimers by virtue of typically being accessible in a one-step synthesis. Saving this synthetic effort once had an unfortunate consequence, though: hyperbranching polymerization used to result in a broad distribution of molecular weights (that is, very high polydispersities, often M(w)/M(n) > 5). By contrast, a typical dendrimer synthesis yields a single molecule (in other words, M(w)/M(n) = 1.0), albeit by a labor-intensive, multistep process. But 10 years ago, Sunder and colleagues reported the controlled synthesis of well-defined hyperbranched polyglycerol (PG) via ring-opening multibranching polymerization (ROMBP) of glycidol. Since then, hyperbranched and polyfunctional polyethers with controlled molar mass and low polydispersities (M(w)/M(n) = 1.2-1.9) have been prepared, through various monomer addition protocols, by ROMBP. In this Account, we review the progress in the preparation and application of these uniquely versatile polyether polyols over the past decade. Hyperbranched PGs combine several remarkable features, including a highly flexible aliphatic polyether backbone, multiple hydrophilic groups, and excellent biocompatibility. Within the past decade, intense efforts have been directed at the optimization of synthetic procedures affording PG homo- and copolymers with different molecular weight characteristics and topology. Fundamental parameters of hyperbranched polymers include molar mass, polydispersity, degree of branching, and end-group functionality. Selected approaches for optimizing and tailoring these characteristics are presented and classified with respect to their application potential. Specific functionalization in the core and at the periphery of hyperbranched PG has been pursued to meet the growing demand for novel specialty materials in academia and industry. A variety of fascinating synthetic approaches now provide access to well-defined, complex macromolecular architectures based on polyether polyols with low polydispersity. For instance, a variety of linear-hyperbranched block copolymers has been reported. The inherent attributes of PG-based materials are useful for a number of individual implementation concepts, such as drug encapsulation or surface modification. The excellent biocompatibility of PG has also led to rapidly growing significance in biomedical applications, for example, bioconjugation with peptides, as well as surface attachment for the creation of protein-resistant surfaces.

Electroactive Linear–Hyperbranched Block Copolymers Based on Linear Poly(ferrocenylsilane)s and Hyperbranched Poly(carbosilane)s

A convenient two-step protocol is presented for synthesis of linear-hyperbranched diblock copolymers consisting of a linear, organometallic poly(ferrocenylsilane) (PFS) block and hyperbranched poly(carbosilane) (hbPCS) segments. Linear PFS diblock copolymers were synthesized through photolytic ring-opening polymerization of dimethyl[1]silaferrocenophane as the first block and methylvinyl[1]silaferrocenophane as the second. These block copolymers served as polyfunctional cores in a subsequent hydrosilylation polyaddition of different silane-based AB(2) monomers. Three AB(2) monomers (methyldiallylsilane; methyldiundecenylsilane, and ferrocenyldiallylsilane) were investigated; they introduced structural diversity to the hyperbranched block and showed variable reactivity for the hydrosilylation reaction. In the case with the additional ferrocene moiety in the ferrocenyldiallylsilane monomer, an electroactive hyperbranched block was generated. No slow monomer addition was necessary for molecular-weight control of the hyperbranching polyaddition, as the core had much higher functionality and reactivity than the carbosilane monomers. Different block ratios were targeted and hybrid block copolymers with narrow polydispersity (<1.2) were obtained. All the resulting polymers were investigated and characterized by size exclusion chromatography, NMR spectroscopy, cyclic voltammetry, and TEM, and exhibited strongly anisotropic aggregation.

Amphiphilic multi-arm-block copolymer conjugated with doxorubicin via pH-sensitive hydrazone bond for tumor-targeted drug delivery

Folate-conjugated unimolecular micelles based on amphiphilic hyperbranched block copolymer, Boltorn ® H40-poly( l-aspartate-doxorubicin)-b-poly(ethylene glycol)/FA-conjugated poly(ethylene glycol) (H40-P(LA-DOX)-b-PEG-OH/FA), were synthesized as a carrier for tumor-targeted drug delivery. The anticancer drug DOX was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms by pH-sensitive hydrazone linkage. The size of the unimolecular micelles was determined as ∼17–36 and 10–20 nm by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The release profiles of the DOX from the H40-P(LA-DOX)-b-PEG-OH/FA micelles showed a strong dependence on the environmental pH values. The DOX release rate increased in the acidic medium due to the acid-cleavable hydrazone linkage between the DOX and micelles. Cellular uptake of the H40-P(LA-DOX)-b-PEG-OH/FA micelles was found to be higher than that of the H40-P(LA-DOX)-b-PEG-OH micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. Degradation studies showed that the H40-P(LA-DOX)-b-PEG-OH/FA copolymer hydrolytically degraded into polymer fragments within six weeks. These results suggest that H40-P(LA-DOX)-b-PEG-OH/FA micelles could be a promising nanocarrier with excellent in vivo stability for targeting the drugs to cancer cells and releasing the drug molecules inside the cells by sensing the acidic environment of the endosomal compartments.

Folate-conjugated amphiphilic hyperbranched block copolymers based on Boltorn ® H40, poly( l-lactide) and poly(ethylene glycol) for tumor-targeted drug delivery

Folate-conjugated amphiphilic hyperbranched block copolymer (H40–PLA- b-MPEG/PEG–FA) with a dendritic Boltorn ® H40 core, a hydrophobic poly( l-lactide) (PLA) inner shell and a hydrophilic methoxy poly(ethylene glycol) (MPEG) and folate-conjugated poly(ethylene glycol) (PEG–FA) outer shell was synthesized as a carrier for tumor-targeted drug delivery. The block copolymer was characterized using 1H NMR and gel permeation chromatography (GPC) analysis. Due to its core–shell structure, this block polymer forms unimolecular micelles in aqueous solutions. The micellar properties of H40–PLA- b-MPEG/PEG–FA block copolymer were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). An anticancer drug, doxorubicin in the free base form (DOX) was encapsulated into H40–PLA- b-MPEG/PEG–FA micelles. The DOX-loaded micelles provided an initial burst release (up to 4 h) followed by a sustained release of the entrapped DOX over a period of about 40 h. Cellular uptake of the DOX-loaded H40–PLA- b-MPEG/PEG–FA micelles was found to be higher than that of the DOX-loaded H40–PLA- b-MPEG micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. In vitro degradation studies revealed that the H40–PLA- b-MPEG/PEG–FA block copolymer hydrolytically degraded into polymer fragments within six weeks. These results indicated that the micelles prepared from the H40–PLA- b-MPEG/PEG–FA block copolymer have great potential as tumor-targeted drug delivery nanocarriers.

Synthesis of well‐defined dendritic hyperbranched polymers by iterative methodologies using living/controlled polymerizations

AbstractThis review presents firstly the synthesis of various dendritic hyperbranched polymers with well‐defined structures by generation‐based growth methodologies using living/controlled polymerization. Secondly, the synthesis of dendritic hyperbranched poly(methyl methacrylate)s (PMMAs) and their functionalized block copolymers using a novel iterative methodology is described. The methodology involves a two‐reaction sequence in each iterative process: (a) a linking reaction of α‐functionalized living anionic PMMA with tert‐butyldimethylsilyloxymethylphenyl (SMP) groups with benzyl bromide (BnBr)‐chain‐end‐functionalized polymer and (b) a transformation reaction of the SMP groups into BnBr functions. This reaction sequence is repeated several times to construct high‐generation (maximum seventh generation) dendritic hyperbranched polymers. Similar branched architectural block copolymers have also been synthesized by the same iterative methodology using other α‐functionalized living anionic polymers. Surface structures of the resulting dendritic hyperbranched block copolymers composed of PMMA and poly(2‐(perfluorobutyl)ethyl methacrylate) segments have been characterized using X‐ray photoelectron spectroscopy and contact angle measurements. Solution behaviors of dendritic hyperbranched PMMAs with different generations and branch densities are discussed based on their intrinsic viscosities, g′ values and Rh values. Copyright © 2007 Society of Chemical Industry

Precise synthesis of dendron-like hyperbranched polymers and block copolymers by an iterative approach involving living anionic polymerization, coupling reaction, and transformation reaction

Dendritic hyperbranched poly(methyl methacrylate)s (PMMA)s, whose branched architectures resemble the “dendron” part(s) of dendrimer, were synthesized by an iterative methodology consisting of two reactions in each iteration process: (a) a coupling reaction of α-functionalized, living, anionic PMMA having twotert-butyldimethylsilyloxymethylphenyl (SMP) groups with benzyl bromide (BnBr)-chain-end-functionalized PMMA, and (b) a transformation reaction of the introduced SMP groups into BnBr functionalities. These two reactions, (a) and (b), were repeated three times to afford a series of dendron-like, hyperbranched (PMMA)s up to third generation. Three dendron-like, hyperbranched (PMMA)s different in branched architecture were also synthesized by the same iterative methodology using a low molecular weight, functionalized 1,1-diphenylalkyl anion prepared fromsec-BuLi and 1,1-bis(3-tert-butyldime-thylsilyloxymethylphenyl)ethylene in the reaction step (b) in each iterative process. Furthermore, structurally similar, dendron-like, hyperbranched block copolymers could be successfully synthesized by the iterative methodology using α-functionalized, living, anionic poly(2-(perfluorobutyl) ethyl methacrylate) (PRfMA) in addition to α-functionalized, living PMMA. Accordingly, the resulting block copolymers were comprised of both PMMA and PRfMA segments with different sequential orders. After the block copolymers were cast into films and annealed, their surface structures were characterized by angle-dependent XPS and contact angle measurements. All three samples showed significant segregation and enrichment of PRfMA segments at the surfaces.

Rheological and adhesive properties of new thermoresponsive hyperbranched poly[ethylene oxide-b-propylene oxide-b-ethylene oxide

Hydrogels are promising platforms for drug delivery, primarily due to the fact that many desirable physicochemical properties can be simultaneously conferred to such systems. In this respect thermoresponsive hydrogels are of interest. The adhesive and rheological properties of new hydrophilic thermoresponsive polymers are based on hyperbranched block copolymers of ethylene oxide and propylene oxide, EG35 and EG 40. EG 40 is constituted by the polycondensation of dihydroxytelechelic POE-PPO-POE triblocks linked together via carbanate, urea, allophanate and biuret bridges. The structure of EG35 is similar to EG40 if one accepts that EG35 exhibits acidic pendant groups. Oscillation stress sweep and creep recovery tests showed that EG35 and EG40 hydrogels were characterized by a remarkable elasticity. Temperature sweep tests and studies of the variation of viscosity at increasing temperatures have also proved the thermogelling character of these hydrogels. The gelling temperature was in the range of 30-37 °C. Furthermore, the adhesiveness of these hydrogels was shown to depend simultaneously on the intensity of the interfacial interactions developed between the hydrogel and the adhesion substrate, and the mechanical behavior of the hydrogel under mechanical solicitation. The mucoadhesion of the two hydrogels depended strongly on the temperature. Very interestingly, at 37 °C, thus over the gelling temperature, they exhibited considerable mucoadhesivity on rat intestinal mucosa compared to Carbopol 974P hydrogels, which were used as a positive control for mucoadhesion. These data suggested that EG35 and EG40 could be promising polymers for pharmaceutical applications, and particularly EG35, which had a considerable adhesiveness and a remarkable elasticity compared to Carbopol 974P.

Biodegradable cationic PEG–PEI–PBLG hyperbranched block copolymer: synthesis and micelle characterization

A novel amphiphilic biodegradable cationic hyperbranched poly(ethylene glycol)–polyethylenimine–poly( γ-benzyl l-glutamate) (PEG–PEI–PBLG) block copolymer was successfully synthesized by ring-opening polymerization (ROP) of N-carboxyanhydride of γ-benzyl- l-glutamate (BLG–NCA) with PEG–PEI as a macroinitiator. PEG–PEI was firstly prepared by coupling of PEG and PEI using hexamethylene diisocyanate (HMDI). The structural properties of PEG–PEI–PBLG copolymers were confirmed by 1H NMR and GPC. The copolymers were found to be self-assembled in water with critical micelle concentration (CMC) in the range of 0.00368–0.0125 g/l and high hydrophobic micelle core. The micelle size and CMC obviously depended on the hydrophobic block content in the copolymer and the ionic state of the PEI block. The CMC decreased with the increase in the PBLG block content. The decrease of micelle size and the increase of CMC simultaneously occurred with the protonated degree of PEI block by addition of HCl solution. ESEM and Gel retardation assay showed that the cationic micelles had ability to encapsulate plasmid DNA. The copolymer has potential medical applications in drug and gene delivery.

Application of Hyperbranched Block Copolymers as Templates for the Generation of Nanoporous Organosilicates

A general route to organic–inorganic hybrids with nanophase morphologies has been elaborated with the objective of ultimately generating nanoporosity in organosilicates. Hyperbranched block copolymers prepared by either the sequential or concurrent polymerization of an ABC monomer ( γ-( ∊-caprolactone) 2-bromo-2-dimethylpropionate) with a BCD monomer (2-hydroxyethyl methacrylate) were used as the macromolecular templates. The two monomers, each polymerizing by different chemistries, for example ring-opening polymerization and atom transfer radical polymerization, bear initiating centres that are targeted for the functionality located on the accompanying monomer. Consequentially, a branched polymer is obtained which avoids the traditional multistep procedures. The branching density was altered simply by the addition of the appropriate AB ( ∊-caprolactone) and/or CD (methyl methacrylate) comonomers. These polymers were readily soluble initially in the organosilicate prepolymer (methyl silsesquioxane), however, upon the onset of crosslinking, both the solubility parameters and molecular weight of the organosilicate (polymethylsilsesquioxane) change, causing the hyperbranched polymer to phase separate by a nucleation and growth process. The organic polymer was selectively removed by thermolysis, producing a nanoporous inorganic structure. The size and shape of the pores are identical to those of the initial hybrid morphology. A significant reduction in the dielectric constant was achieved by simply replacing a portion of the glass matrix with air, which has a dielectric constant of 1.0.

End functionalization of hyperbranched poly(siloxysilane): Novel crosslinking agents and hyperbranched–linear star block copolymers

End functionalization of hyperbranched poly(siloxysilane): Novel crosslinking agents and hyperbranched–linear star block copolymers

Preparation of branched polymer by radical polymerization using polymerizable chain transfer agent

Methyl methacrylate was polymerized in the presence of a polymerizable addition–fragmentation chain transfer agent consisting of methacryloyl and α-(benzylthiomethyl)acryloyl groups as dual functionality. The copolymers containing up to 3.1 mol% of the units from the transfer agent were prepared. The polymerizable chain transfer agent can connect up to three polymer chains as a result of copolymerization followed by chain transfer or vice versa as one step branching. Furthermore, each branch could also involve branching points for secondary branching. The unsaturated moieties from the chain transfer agent were subjected to addition of poly(styrene) radical to yield hyperbranched block copolymer consisting of poly(methyl methacrylate) and poly(styrene) segments without gelation. A side reaction of the unsaturated moiety was also shown.

Synthesis and polymerization of a self-condensable macromonomer

A novel self-condensable macromonomer that has a polymerizable group at one terminal and an initiator at the other was synthesized by the combination of the conventional macromonomer technique and the SmI2-induced transformation. Namely, living poly(tetrahydrofuran) [poly(THF)] carrying α-methacryloyl group was prepared by using methacryloyl chloride and silver trifluoromethanesulfonate. The living chain end was capped with sodium 2-bromoisobutyrate, and the sequential reduction of the terminal C-Br bond with SmI2 gave a terminating samarium enolate. The resulting samarium enolate copolymerized the α-methacryloyl group with methyl methacrylate, giving a hyperbranched block copolymer whose dendritic part consists of two kinds of polymer segments.