Linear-dendritic Copolymers Research Articles

Supramolecular Linear-Dendritic Nanoreactors: Synthesis and Catalytic Activity in “Green” Suzuki-Miyaura Reactions

This study describes the synthesis of novel amphiphilic linear-dendritic block copolymers and their self-assembly in water to form supramolecular nanoreactors capable of catalyzing Suzuki-Miyaura coupling reactions under "green" conditions. The block copolymers were formed through copper(I)-catalyzed alkyne-azide cycloaddition between azide functionalized poly(benzyl ether) dendrons as the perfectly branched blocks, as well as bis-alkyne modified poly(ethylene glycol), PEG, as the linear block. A first-generation poly(benzyl ether) dendron (G1) was coupled to a bis-alkyne modified PEG with molecular mass of 5 kDa, forming an ABA copolymer (G1)2-PEG5k-(G1)2 (yield 62%), while a second-generation dendron (G2) was coupled to a 11 kDa bis-alkyne modified PEG to produce (G2)2-PEG11k-(G2)2 (yield 49%). The structural purity and low dispersity of the linear-dendritic copolymers were verified by size-exclusion chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Their self-assembly was studied by dynamic light scattering, showing that (G1)2-PEG5k-(G1)2 and (G2)2-PEG11k-(G2)2 formed single populations of micelles (17 nm and 37 nm in diameter, respectively). The triazole rings located at the boundaries between the core and the corona are efficient chelating groups for transition metals. The ability of the micelles to complex Pd was confirmed by 1H NMR, transmission electron microscopy, and inductively coupled plasma. The catalytic activity of the supramolecular linear-dendritic/Pd complexes was tested in water by model Suzuki-Miyaura reactions in which quantitative yields were achieved within 3 h at 40 °C, while, at 17 °C, a yield of more than 70% was attained after 17 h.

Dumbbell-like polyionic complexes of dendronized poly(ethylene glycol): synthesis and self-assembly studies

Synthesis and self-organization studies of polyionic complexes of linear–dendritic copolymers based on polyethylene glycols bearing aspartic dendrons with terminal amino and carboxylic groups.

Dendritic-Linear Copolymer and Dendron Lipid Nanoparticles for Drug and Gene Delivery.

Polymers constitute a diverse class of macromolecules that have demonstrated their unique advantages to be utilized for drug or gene delivery applications. In particular, polymers with a highly ordered, hyperbranched structure─"dendrons"─offer significant benefits to the design of such nanomedicines. The incorporation of dendrons into block copolymer micelles can endow various unique properties that are not typically observed from linear polymer counterparts. Specifically, the dendritic structure induces the conical shape of unimers that form micelles, thereby improving the thermodynamic stability and achieving a low critical micelle concentration (CMC). Furthermore, through a high density of highly ordered functional groups, dendrons can enhance gene complexation, drug loading, and stimuli-responsive behavior. In addition, outward-branching dendrons can support a high density of nonfouling polymers, such as poly(ethylene glycol), for serum stability and variable densities of multifunctional groups for multivalent cellular targeting and interactions. In this paper, we review the design considerations for dendron-lipid nanoparticles and dendron micelles formed from amphiphilic block copolymers intended for gene transfection and cancer drug delivery applications. These technologies are early in preclinical development and, as with other nanomedicines, face many obstacles on the way to clinical adoption. Nevertheless, the utility of dendron micelles for drug delivery remains relatively underexplored, and we believe there are significant and dramatic advancements to be made in tumor targeting with these platforms.

Multimolecular Structure Formation with Linear Dendritic Copolymers

The formation of complex macromolecular structures can be achieved by harnessing self-assembly of well-defined macromolecular building blocks in solution. In this work, we investigate linear-dendritic copolymers, which are dendrimers with chemically different linear chains grafted to their terminal groups. We consider the case of a selective solvent, which is a good solvent for the grafted linear chains and a poor solvent for the dendritic core, so that single molecules also form micelles with a brushlike shell of linear chains. An example could be PEGylated PAMAM dendrimers in aqueous solution. We develop a mean-field model to predict the size of multimolecular micelles formed under equilibrium conditions and at finite concentration of the linear-dendritic copolymers. Out of the combination of the many molecular parameters, which characterizes the linear-dendritic copolymers with flexible spacers, we identify two scaling parameters, which control the free energy of the multimolecular micellar state, and we provide an analytical solution for the most probable number of molecules per micelle in the limit of large micelles. The theoretical model is compared with simulation results using the bond fluctuation model with explicit solvent. The simulations also provide the time evolution of the micelle populations, and we derive the free energy of fusion for a two-molecular state both based on the reaction equation and from the calculation of the potential of mean force between two molecules. Our work provides a systematic concept how to control size and shape of the multimolecular dendritic structures by tuning their molecular parameters. The particular property of linear-dendritic copolymers is well defined in terms of small number of molecules per micelle, which can be switched in a discrete way by changing the solvent properties.

Synthesis and direct assembly of linear–dendritic copolymers via CuAAC click polymerization-induced self-assembly (CPISA)

A one-pot method was developed for in situ preparation of linear–dendritic copolymer assemblies via click polymerization-induced self-assembly (CPISA).

Preparation of core-crosslinked linear-dendritic copolymer micelles with enhanced stability and their application for drug solubilisation

In this study we explore the preparation of core-crosslinked micelles of linear-dendritic methoxy-poly(ethylene glycol) (MPEG)-co-poly(ester-sulfide) (PES) polymers to improve the stability of such polymeric micelle systems against premature disintegration and drug release. A series of MPEG-PES copolymers were synthesised via stepwise reactions of acetylation and thiol-ene photoreaction. Surface tension measurement showed that the copolymers with ethenyl surface groups could self-associate in dilute aqueous solutions to form micelles. Crosslinking within the micelle cores in the presence of dithioerythritol (DTT) linker was initiated under UV radiation. The formation of core-crosslinked micelles was confirmed by HPLC in combination with charged aerosol detection (CAD). The copolymers were found to readily hydrolyse under acidic conditions due to the ester-containing dendrons. Drug solubilisation capacities of the micellar solutions were determined using griseofulvin as a poorly water-soluble model drug. The solubility of griseofulvin showed a 10-fold enhancement in 1% w/v micelle solution and increased with the concentration of the copolymers. Drug release studies indicated that a more sustained release of griseofulvin was achieved for the core-crosslinked micelles compared to the non-crosslinked micelles, attributable to greater stability of the crosslinked core structure. The findings of this study present a new pathway towards developing biodegradable polymeric nanocarriers.

A Facile and Efficient Approach for the Production of Reversible Disulfide Cross-linked Micelles.

Nanomedicine is an emerging form of therapy that harnesses the unique properties of particles that are nanometers in scale for biomedical application. Improving drug delivery to maximize therapeutic outcomes and to reduce drug-associated side effects are some of the cornerstones of present-day nanomedicine. Nanoparticles in particular have found a wide application in cancer treatment. Nanoparticles that offer a high degree of flexibility in design, application, and production based on the tumor microenvironment are projected to be more effective with rapid translation into clinical practice. The polymeric micellar nano-carrier is a popular choice for drug delivery applications. In this article, we describe a simple and effective protocol for synthesizing drug-loaded, disulfide cross-linked micelles based on the self-assembly of a well-defined amphiphilic linear-dendritic copolymer (telodendrimer, TD). TD is composed of polyethylene glycol (PEG) as the hydrophilic segment and a thiolated cholic acid cluster as the core-forming hydrophobic moiety attached stepwise to an amine-terminated PEG using solution-based peptide chemistry. Chemotherapy drugs, such as paclitaxel (PTX), can be loaded using a standard solvent evaporation method. The O2-mediated oxidation was previously utilized to form intra-micellar disulfide cross-links from free thiol groups on the TDs. However, the reaction was slow and not feasible for large-scale production. Recently, an H2O2-mediated oxidation method was explored as a more feasible and efficient approach, and it was 96 times faster than the previously reported method. Using this approach, 50 g of PTX-loaded, disulfide cross-linked nanoparticles have been successfully produced with narrow particle size distribution and high drug loading efficiency. The stability of the resulting micelle solution is analyzed using disrupting conditions such as co-incubation with a detergent, sodium dodecyl sulfate, with or without a reducing agent. The drug-loaded, disulfide cross-linked micelles demonstrated less hemolytic activity when compared to their non-cross-linked counterparts.

Dendritic macromolecules supported Ag nanoparticles as efficient catalyst for the reduction of 4-nitrophenol

Polymer supported Ag nanoparticles, generated in situ by silver nitrate (AgNO3) reduction under reaction conditions, catalyzed the hydrogenation of 4-nitrophenol with high efficiency in water at room temperature in the presence of an excess amount of NaBH4. Amphiphilic linear-dendritic copolymers containing a poly(ethylene glycol) (PEG) core and poly(2-ethyl-2-oxazoline)-poly(ε-caprolactone) arms were able to load the Ag nanoparticles. The Ag nanoparticles with a diameter of 8–10 nm were found to show a comparable catalytic activity towards formation of the aromatic amine as single product with short reaction time.

Facile Synthesis of Temperature- and pH-responsive Dendritic–Linear–Dendritic Copolymer

Dendritic–linear–dendritic triblock copolymers have attracted much attention due to their unique topology and special features. However, facile methods are still necessary to synthesize uniform dendritic–linear–dendritic copolymers. Here, we report an effective strategy for the synthesis of a temperature- and pH-responsive dendritic–linear–dendritic poly(amido amine)-poly(N-isopropylacrylamide)-poly(amido amine) (PAMAM-PNIPAM-PAMAM), and evaluate the temperature- and pH-responsive properties of PAMAM-PNIPAM-PAMAM.

Affinity-controlled protein encapsulation into sub-30nm telodendrimer nanocarriers by multivalent and synergistic interactions.

Novel nanocarriers are highly demanded for the delivery of heterogeneous protein therapeutics for disease treatments. Conventional nanoparticles for protein delivery are mostly based on the diffusion-limiting mechanisms, e.g., physical trapping and entanglement. We develop herein a novel linear-dendritic copolymer (named telodendrimer) nanocarrier for efficient protein delivery by affinitive coating. This affinity-controlled encapsulation strategy provides nanoformulations with a small particle size (<30nm), superior loading capacity (>50% w/w) and maintained protein bioactivity. We integrate multivalent electrostatic and hydrophobic functionalities synergistically into the well-defined telodendrimer scaffold to fine-tune protein binding affinity and delivery properties. The ion strength and density of the charged groups as well as the structure of the hydrophobic segments are important and their combinations in telodendrimers are crucial for efficient protein encapsulation. We have conducted a series of studies to understand the mechanism and kinetic process of the protein loading and release, utilizing electrophoresis, isothermal titration calorimetry, Förster resonance energy transfer spectroscopy, bio-layer interferometry and computational methods. The optimized nanocarriers are able to deliver cell-impermeable therapeutic protein intracellularly to kill cancer cells efficiently. Invivo imaging studies revealed cargo proteins preferentially accumulate in subcutaneous tumors and retention of peptide therapeutics is improved in an orthotopic brain tumor, these properties are evidence of the improved pharmacokinetics and biodistributions of protein therapeutics delivered by telodendrimer nanoparticles. This study presents a bottom-up strategy to rationally design and fabricate versatile nanocarriers for encapsulation and delivery of proteins for numerous applications.

A comparative study of linear, Y-shaped and linear-dendritic methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) block copolymers for doxorubicin delivery in vitro and in vivo

The linear, Y-shaped, and linear-dendritic block copolymers of methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) (MPEG-b-PAMAM-b-PGA) with one, two, four, and eight PGA arms but similar MPEG/PGA weight ratios (W/W) (named as P1PA, P2PA, P4PA and P8PA, respectively) were synthesized and comparatively investigated for doxorubicin hydrochloride (DOX) delivery. All the obtained block copolymers were highly biocompatible and could efficiently load DOX into nanoparticles (NPs) through electrostatic interaction. The NPs formed by linear (P1PA) or Y-shaped (P2PA) block copolymers and DOX were spherically shaped with smaller sizes, while the NPs formed from linear-dendritic block copolymers (P4PA and P8PA) were irregular in shape and larger in size. The P1PA/DOX and P2PA/DOX NPs exhibited better DOX protection and slower DOX release profile. However, cell cytotoxicity assays indicated that all the DOX-loaded NPs exhibited similar cytotoxicities with free DOX, indicating effective DOX release after cellular uptake. The NPs from linear and Y-shaped block copolymers greatly extended the blood circulation time, and displayed more accumulation in tumor site and less accumulation in the liver and kidney compared with the linear-dendritic counterparts. In addition, the P1PA/DOX and P2PA/DOX NPs also exhibited higher anti-tumor efficacy and less toxicity than the other DOX formulations. All these results indicated that the linear and Y-shaped MPEG-b-PAMAM-b-PGA block copolymers displayed better DOX delivery ability in anti-tumor treatment than the linear-dendritic copolymers. Statement of SignificancePolymeric NPs derived from block copolymers have emerged as effective vehicles for drug delivery. However, the majority of the researches in this field have involved simple linear block copolymers and there are very few comparative studies on the self-assembly, in vitro, and in vivo drug delivery by the block copolymers with similar composition but different architectures. In this study, a series of linear, Y-shaped, and linear-dendritic polypeptide-based block copolymers were prepared and thoroughly investigated for DOX delivery. These block polymers loaded DOX into NPs with different sizes and morphologies, and exhibited different anti-tumor capabilities both in vitro and in vivo. The results indicated that the architecture of the block copolymers played an important role in their drug delivery behaviors.

Photoresponsive assemblies of linear-dendritic copolymers containing azobenzene in the dendron interior: the effect of the dendron structure on dye encapsulation and release

Linear-dendritic copolymers show differential dye encapsulation and photoinduced dye release based on the number and positions of azobenzenes in the dendritic backbone as well as substituents on the dendron periphery.

Synthesis and self-assembly of polypeptide- and lipid-glycosylated dendron hybrids into glyconanoparticles

Event Abstract Back to Event Synthesis and self-assembly of polypeptide- and lipid-glycosylated dendron hybrids into glyconanoparticles John F. Trant1*, Ariane Peyret2*, Colin V. Bonduelle2*, Khalid Ferji2*, Namrata Jain1*, Sebastien Lecommandoux2* and Elizabeth Gillies1, 3* 1 The University of Western Ontario, Chemistry, Canada 2 Université Bordeaux/IPB, ENSCBP, Laboratoire de Chimie des Polymères Organique, France 3 The University of Western Ontario, Chemical and Biochemical Engineering, Canada Introduction: Glycolsylated nanoparticles hold promise in targeted delivery, inhibition of viral or bacterial infection, and in immunotherapy through their ability to mimic or intercept the functions of carbohydrates in biological systems[1],[2]. Different approaches have been developed to prepare glycosylated polymer assemblies including the conjugation of glycans to preformed assemblies[3] and the formation of assemblies from macromolecules comprising carbohydrate-based hydrophilic blocks[4],[5]. Presented here is an alternative new approach involving the use of carbohydrate-functionalized dendrons as the hydrophilic block and poly(gamma-benzyl-L-glutamate) (PBLG) or distearoyl glycerol (DSG) as the hydrophobic block. Assembly of the resulting linear-dendritic copolymers into glyconanoparticles is described. Materials and Methods: The synthetic approach involved the conjugation of an azide-terminated PBLG (Figure 1)[6] or azide-functionalized DSG (Figure 2) to an alpha-galactose-functionalized dendron with a focal point alkyne. Using PBLG with degrees of polymerization (DP) of 14, 28, and 54 as well as 2nd, 3rd, and 4th generation dendrons, amphiphilies with varying hydrophilic fractions were prepared. Self-assembly was performed by a nanoprecipitation procedure involving the dissolution of the copolymer in dimethylsulfoxide (DMSO) and the addition of water to the organic solution or the rapid injection of the organic solution into water. The organic solvent was then removed by dialysis. Results and Discussion: It was found that a copolymer comprising PBLG with a DP of 28 and a 4th generation dendron with 16 peripheral galactose moieties assembled into well-defined micelles with a diameter of 20 nm when a DMSO solution was added to water, as measured by transmission electron microscopy (TEM) (Figure 3A) and 40 nm as measured by dynamic light scattering (DLS). While the sizes of these assemblies could be tuned by the addition of PBLG homopolymer or by changing the organic solvent, the assemblies tended to aggregate in salt solutions and aggregates were observed for the other copolymers. This was attributed to the competition between the tendency of the dendron to form curved interfaces between the blocks versus the tendency of PBLG to behave as a rod due to its alpha-helical structure, which favors lamellar assemblies[7]-[9]. Use of DSG as a hydrophobic block provides greater conformational flexibility and a lower hydrophobic volume fraction. Indeed, assemblies of the lipid-dendron amphiphilies were less susceptible to aggregation with the 2nd generation hybrid forming vesicles (Figure 3B) and the 3rd and 4th generation systems forming stable micelles in both water and buffer. Conclusion: A series of amphiphiles composed of hydrophobic PBLG or DSG and hydrophilic glycolsylated dendrons were synthesized and their self-assembly behavior was studied. A copolymer composed of PBLG-28 and a 4th generation dendron assembled into micelles. Lipid-dendron hybrids composed of 3rd and 4th generation dendrons provided micelles, whereas the 2nd generation system provided vesicles. These glyconanoparticles serve as new platforms for biomedical applications, in particular as immunotherapeutics due to the important role of alpha-galactose in immunostimulation and pathogenesis[10].

A drug-specific nanocarrier design for efficient anticancer therapy.

The drug-loading properties of nanocarriers depend on the chemical structures and properties of their building blocks. Here, we customize telodendrimers (linear-dendritic copolymer) to design a nanocarrier with improved in vivo drug delivery characteristics. We do a virtual screen of a library of small molecules to identify the optimal building blocks for precise telodendrimer synthesis using peptide chemistry. With rationally designed telodendrimer architectures, we then optimize the drug binding affinity of a nanocarrier by introducing an optimal drug-binding molecule (DBM) without sacrificing the stability of the nanocarrier. To validate the computational predictions, we synthesize a series of nanocarriers and evaluate systematically for doxorubicin delivery. Rhein-containing nanocarriers have sustained drug release, prolonged circulation, increased tolerated dose, reduced toxicity, effective tumor targeting and superior anticancer effects owing to favourable doxorubicin-binding affinity and improved nanoparticle stability. This study demonstrates the feasibility and versatility of the de novo design of telodendrimer nanocarriers for specific drug molecules, which is a promising approach to transform nanocarrier development for drug delivery.

Linear-dendritic copolymer composed of polyethylene glycol and all-trans-retinoic acid as drug delivery platform for paclitaxel against breast cancer.

A new linear-dendritic copolymer composed of poly(ethylene glycol) (PEG) and all-trans-retinoic acid (ATRA) was synthesized as the anticancer drug delivery platform (PEG-G3-RA8). It can self-assemble into core-shell micelles with a low critical micelle concentration (CMC) at 3.48 mg/L. Paclitaxel (PTX) was encapsulated into PEG-G3-RA8 to form PEG-G3-RA8/PTX micelles for breast cancer treatment. The optimized formulation had high drug loading efficacy (20% w/w of drug copolymer ratio), nanosized diameter (27.6 nm), and narrow distribution (PDI = 0.103). Compared with Taxol, PEG-G3-RA8/PTX remained highly stable in the serum-containing cell medium and exhibited 4-fold higher cellular uptake. Besides, near-infrared fluorescence (NIR) optical imaging results indicated that fluorescent probe loaded micelle had a preferential accumulation in breast tumors. Pharmacokinetics and biodistribution studies (10 mg/kg) showed the area under the plasma concentration-time curve (AUC0-∞) and mean residence time (MRT0-∞) for PEG-G3-RA8/PTX and Taxol were 12.006 ± 0.605 mg/L h, 2.264 ± 0.041 h and 15.966 ± 1.614 mg/L h, 1.726 ± 0.097 h, respectively. The tumor accumulation of PEG-G3-RA8/PTX group was 1.89-fold higher than that of Taxol group 24 h postinjection. With the advantages like efficient cellular uptake and preferential tumor accumulation, PEG-G3-RA8/PTX showed superior therapeutic efficacy on MCF-7 tumor bearing mice compared to Taxol.

Supramolecular anticancer drug delivery systems based on linear–dendritic copolymers

The combination of two generations of polymers as linear–dendritic copolymers leads to hybrid systems with unique properties, which are of great interest for many applications. Herein, recent advances in anticancer drug delivery systems based on linear–dendritic copolymers have been reviewed.

Controlled micellar disassembly of photo- and pH-cleavable linear-dendritic block copolymers

A biocompatible linear-dendritic copolymer comprising photo and pH-cleavable groups at the junction was synthesised and controlled release of drug into cells was demonstrated.

The self-assembly of linear–dendritic and lipid-like copolymers investigated by computer simulations

Amphiphiles have long been attractive for their spontaneous formation of diverse structures and potential applications. Here, the self-assembly of binary mixtures with various hydrophilic/hydrophobic ratios is systematically investigated by dissipative particle dynamics simulations. On increasing the proportion of linear–dendritic copolymers, the self-assembled structure changes from a compound vesicle to a netlike micelle. Additionally, more structures including the high-genus vesicle, toroidal vesicle, oblate vesicle, and the perforated vesicle are obtained at different mixing ratios. The spontaneous curvature of self-assembling morphologies is the critical factor for shaping their final structures. Furthermore, stress is released as much as possible via the intelligent distribution of two amphiphiles, which makes the structures more stable than those obtained in pure amphiphile systems. Moreover, the slow release of the potential energy stored in the initially self-assembled components may induce the system into a metastable state and the self-assembly can be kinetically controlled by a pathway-directing process.

"Green" synthesis of unnatural poly(Amino Acid)s with Zwitterionic character and pH-responsive solution behavior, mediated by linear-dendritic laccase complexes.

This article describes the enzyme-catalyzed "green" synthesis of an unnatural poly(amino acid). dl-Tyrosine was polymerized under environmentally friendly conditions using linear-dendritic laccase complexes as initiators and water as solvent. The influence of the dendron generation in the linear-dendritic copolymers, the monomer concentration, and time and temperature on the polymer yields and molecular masses was investigated. Depending on the reaction conditions poly(tyrosine) with molecular mass (Mw) up to 82 kDa could be obtained in yields ranging between 45 and 69%. It was found that the linear-dendritic laccase complexes can induce further chain growth upon addition of fresh monomer to the preformed poly(tyrosine) in a fashion resembling the classic "living" polymerization. The structure of the poly(tyrosine) was investigated by NMR, FT-IR, and MALDI-TOF and it was discovered that the polymer chains consist of phenol repeating units linked together by C-C and C-O bonds randomly distributed along the backbone of the polymers. The materials formed are completely water-soluble and behave as typical poly(zwitterions) changing charge and size with the medium pH. DLS measurements reveal that the zeta potential of the polymers can vary between +15 mV at pH 1.2 with hydrodynamic diameter (Dh) = 6.7 nm to -35 mV at pH 11.8 and Dh = 10 nm. The isoelectric point was found at pH = 2.3-2.6, where Dh of the polymer is at the minimum (2.4 nm).

Linear-dendritic copolymers/indoxacarb supramolecular systems: biodegradable and efficient nano-pesticides.

Photodegradable and biocompatible nano-indoxacarb was prepared successfully by encapsulation of indoxacarb with poly(citric acid)-poly(ethylene glycol)-poly(citric acid) (PCA-PEG-PCA) ABA type linear-dendritic copolymers both with (nano-IND/TiO2) and without (nano-IND) TiO2 nanoparticles via supramolecular interactions. Preparation of nano-indoxacarb by both formulae was confirmed using spectroscopy and microscopy analyses. TEM images showed small particles with average sizes of 10 nm for nano-IND and 12 nm for nano-IND/TiO2. Interestingly, the rate of degradation of indoxacarb in both nano-IND/TiO2 and nano-IND exposed to UV and natural light was higher than that for free indoxacarb in the presence of TiO2 nanoparticles. Furthermore, results of bioassay experiments on the model pest showed that the essential dosage of pesticide for pest control significantly decreased when nano-IND and nano-IND/TiO2 were used. Because of the higher loading capacity and slower release rate for indoxacarb from nano-IND than from nano-IND/TiO2, and because TiO2 nanoparticles show toxicity in bioassay experiments, nano-IND is introduced as a promising and eco-friendly pesticide system.