Dendritic Copolymers Research Articles

Synthesis of dendritic urethane acrylates for fabricating a robust honeycomb-like structure acting for SERS detection

In this study, novel dendritic urethane acrylate polymers were developed for the fabrication of robust honeycomb-like surfaces after exposure to a UV-crosslinking process. Through iterative synthesis based on a highly selective intermediate of 4-isocyanate-4′-(3,3-dimethyl-2,4-dioxo-azetidine)-diphenylmethane, poly(urea/malonamide) dendrons bearing peripheral methyl methacrylate end groups with well-defined structures were realized. A coating solution was prepared by the combined use of 30–70 wt% UA dendron acting as dendritic diluents and dendritic UA copolymers acting as amphiphiles that can fabricate honeycomb-like surfaces via a breath figure self-assembly process using water droplets as templates. The resulting film can be cured under UV light to achieve a robust honeycomb-like structure with a hexagonal structure exhibiting solvent-resistant properties in ethanol. Consequently, this solvent-resistant porous array can act as a substrate for the detection of vanishingly low concentrations of analytes that are aqueous insoluble via surface-enhanced Raman scattering analysis.

Dendritic copolymers from P-, N- and Si-based monomer and melamine phosphate generate thermal deformation toughening and a rapid charring flame retardant effect in polypropylene

In this work, a novel dendritic copolymer PNSi-co-MP as an intumescent flame retardant was fabricated using a silicon-, phosphorus- and nitrogen-containing monomer (PNSi) and melamine phosphate (MP). Random copolymerization way disrupted the regularity of monomer arrangement, resulting in the thermal deformation behavior of PNSi-co-MP being different from the self-polymerized macromolecule (MPNSi) / melamine polyphosphate (MPP) system. Consequently, PNSi-co-MP was distributed reasonably evenly in the polypropylene (PP) matrix, and some of the PNSi-co-MP particles deformed to 200–300 nm from 5 to 10 μm. More importantly, the toughness of PNSi-co-MP/PP was dramatically increased compared with MPNSi/MPP/PP. Specifically, 16PNSi-co-4MP/PP exhibited a 278% higher elongation at break and a 33.3% higher unnotched impact strength compared to 16MPNSi/4MPP/PP. Furthermore, PNSi-co-MP exhibited a rapid charring effect in PP. In a cone calorimeter test, the maximum combustion intensity of the composite was inhibited in only 17 s by the PNSi-co-MP molecule. Compared with the pure PP, the composite with 20 wt% 12PNSi-co-8MP showed a 93.6% lower peak heat release rate and an 87.2% lower smoke production rate, indicating its excellent flame retardancy. The composites containing copolymer molecules also performed much higher flame retardancy than MPNSi/MPP/PP sample, although their chemical composition was almost the same except for the linking form of flame-retardant monomers. PNSi-co-MP simultaneously endowed PP with a higher limited oxygen index, glow wire flammability index, glow wire ignition temperature, residue yield, and fire safety performance than MPNSi/MPP. The reason for this was that the copolymerization strategy aggregated the flame-retardant monomers into one molecule, thus effectively promoting the charring reaction. Accordingly, this work provided a new method for preparing flame-retardant molecules with comprehensive performance through molecular composition and structural design.

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.

Cross-linking Poly(caprolactone)–Polyamidoamine Linear Dendritic Block Copolymers for Theranostic Nanomedicine

This study represents a comparative analysis of the solution behavior and self-assembly pattern of two linear dendritic block copolymers (LDBCs) composed of a generation 3 polyamidoamine (PAMAM) dendron as the dendritic block and poly(caprolactone) (PCL) as the linear block, the latter of which is modified with pendant phenyl groups. Phenyl substituents were introduced to induce physical cross-linking in LDBC nanoparticles via π–π stacking. A synthetic strategy was developed to access phenyl substituted LDBCs through an ε-caprolactone monomer derivative followed by ring-opening polymerization to form a library of LDBCs with yields above 83%. Polymersome-like nanoparticles were observed in water with a 74.4 nm average diameter. Cross-linked LDBC nanoparticles demonstrated a 37.1% relative decrease in the critical aggregation concentration (CAC) and a 27.3–41.2% relative increase of hydrophobic loading efficiency relative to unsubstituted LDBCs. Nanoparticles loaded with a potential photothermal agent (phenyl indolizine-C5 (C5)) showed a photothermal efficiency of 49.4% with a heating temperature of 44.4 °C. These nanoparticles were efficiently loaded into HEK293 cells with cell viability above 87.5% at the highest concentration. Upon illumination with red light, nanoparticles loaded with photothermal agent were able to induce cell death in cancer cells. This work suggests that the phenyl substituted LDBCs form nanoparticles with enhanced stability and loading efficiencies compared to conventional nonphenylated systems and display a greater potential to be used as nanocarriers in theranostic nanomedicine.

Cathepsin B and thermal dual‐stimuli responsive linear‐dendritic block copolymer micelles for anticancer drug delivery

AbstractIn this study, two linear poly(N‐vinylcaprolactam)s (PNVCLs) with different molecular weights were first synthesized as polymeric supporters by reversible addition‐fragmentation chain transfer polymerization and then were used to prepare cathepsin B and thermal dual‐stimuli responsive amphiphilic linear–dendritic block copolymers (LDBCs) PNVCLn‐b‐d(Phe‐Lys)1–3 (n = 66, 100) with linear PNVCL and dendritic phenylalanyl‐lysine (Phe‐Lys) dipeptides via stepwise peptide chemistry. The copolymers were characterized by 1H NMR spectra and gel permeation chromatography and exhibited a controlled molecular weight and a narrow molecular weight distribution (polydispersity index ≤ 1.27). They self‐assemble into stable micelles at relatively low critical micelle concentrations (0.007–0.019 mg mL−1) in aqueous solution. These micelles are capable of dissociating to release the encapsulated anticancer drug doxorubicin upon cathepsin B treatment. The doxorubicin release rates from PNVCLn‐b‐d(Phe‐Lys)1–3 micelles decreased with increasing generation of Phe‐Lys dipeptide dendrons and decreasing molecular weight of PNVCL. In addition, the lower critical solution temperatures of the copolymers increased with an extension of the enzyme incubation time. The results of in vitro cytotoxicity and cell uptake experiments showed that LDBCs show no cytotoxicity even at a high LDBC concentration of 0.4 mg mL−1 and the drug‐loaded micelles can be enriched in tumor cells. Such smart copolymers could be efficiently used in targeted therapy systems. © 2021 Society of Industrial Chemistry.

Physicochemical properties and bio‐interfacial interactions of surface modified PDLLA‐PAMAM linear dendritic block copolymers

AbstractHere, we demonstrate the applicability of self‐assembling linear‐dendritic block copolymers (LDBCs) and their nanoaggregates possessing varied surfaces as therapeutic nanocarriers. These LDBCs are comprised of a hydrophobic, linear polyester chemically coupled to a hydrophilic dendron polyamidoamine (PAMAM)—the latter of which acts as the surface of the self‐assembled nanoaggregate in aqueous media. To better understand how surface charge density affects the overall operability of these nanomaterials, we modified the nanoaggregate surface to yield cationic (NH3+), neutral (OH), and anionic (COO−) surfaces. The effect of these modifications on the physicochemical properties (i.e., size, morphology, and surface charge density), colloidal stability, and cellular uptake mechanism of the polymeric nanocarrier were investigated. This comparative study demonstrates the viability of nanoaggregates formed from PDLLA‐PAMAM LDBCs to serve as nanocarriers for applications in drug delivery.

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.

Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic-Linear-Dendritic Block Copolymers.

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic® F127 hybrid dendritic–linear–dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2′-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2′-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.

Supramolecular Functionalizable Linear-Dendritic Block Copolymers for the Preparation of Nanocarriers by Microfluidics.

Hybrid linear–dendritic block copolymers (LDBCs) having dendrons with a precise number of peripheral groups that are able to supramolecular bind functional moieties are challenging materials as versatile polymeric platforms for the preparation of functional polymeric nanocarriers. PEG2k-b-dxDAP LDBCs that are based on polyethylene glycol (PEG) as hydrophilic blocks and dendrons derived from bis-MPA having 2,6-diacylaminopyridine (DAP) units have been efficiently synthesized by the click coupling of preformed blocks, as was demonstrated by spectroscopic techniques and mass spectrometry. Self-assembly ability was first checked by nanoprecipitation. A reproducible and fast synthesis of aggregates was accomplished by microfluidics optimizing the total flow rate and phase ratio to achieve spherical micelles and/or vesicles depending on dendron generation and experimental parameters. The morphology and size of the self-assemblies were studied by TEM, Cryogenic Transmission Electron Microscopy (cryo-TEM), and Dynamic Light Scattering (DLS). The cytotoxicity of aggregates synthesized by microfluidics and the influence on apoptosis and cell cycle evaluation was studied on four cell lines. The self-assemblies are not cytotoxic at doses below 0.4 mg mL−1. Supramolecular functionalization using thymine derivatives was explored for reversibly cross-linking the hydrophobic blocks. The results open new possibilities for their use as drug nanocarriers with a dynamic cross-linking to improve nanocarrier stability but without hindering disassembly to release molecular cargoes.

Nanogel Encapsulated Hydrogels As Advanced Wound Dressings for the Controlled Delivery of Antibiotics

AbstractBiocompatible and degradable dual‐delivery gel systems based on hyperbranched dendritic−linear−dendritic copolymers (HBDLDs) is herein conceptualized and accomplished via thiol‐ene click chemistry. The elasticity of the hydrogels is tunable by varying the lengths of PEG (2, 6, 10 kDa) or the dry weight percentages (20, 30, 40 wt%), and are found to range from 2–14.7 kPa, comparable to human skin. The co‐delivery of antibiotics is achieved, where the hydrophilic drug novobiocin sodium salt (NB) is entrapped within the hydrophilic hydrogel, while the hydrophobic antibiotic ciprofloxacin (CIP) is encapsulated within the dendritic nanogels (DNGs) with hydrophobic cores (DNGs‐CIP). The DNGs‐CIP with drug loading capacity of 2.83 wt% are then physically entrapped within the hybrid hydrogels through UV curing. The hybrid hydrogels enable the quick release of NB and prolonged released of CIP. In vitro cell infection assays showed that the antibiotic‐loaded hybrid hydrogels are able to treat bacterial infections with significant bacterial reduction. Hybrid hydrogel band aids are fabricated and exhibited better antibacterial activity compared with commercial antimicrobial band aids. Remarkably, most hydrogels and hybrid hydrogels show enhanced human dermal cell proliferation and could be degraded into non‐toxic constituents, showing great promise as wound dressing materials.

Enhancing Long‐Term Thermal Stability of Non‐Fullerene Organic Solar Cells Using Self‐Assembly Amphiphilic Dendritic Block Copolymer Interlayers

AbstractHerein, interfacial engineering is demonstrated to improve the thermal stability of non‐fullerene bulk‐heterojunction (BHJ) OPVs to a practical level. An amphiphilic dendritic block copolymer (DBC) is developed through a facile coupling method and employed as the surface modifier of ZnO electron‐transporting layer in inverted OPVs. Besides showing distinct self‐assembly behavior, the synthesized DBC possesses high compatibility with plasmonic gold nanoparticles (NPs) due to the constituent malonamide and ethylene oxide units. The hybrid DBC@AuNPs interlayer is shown to improve device's performance from 14.0% to 15.4% because it enables better energy‐level alignment and improves interfacial compatibility at the ZnO/BHJ interface. Moreover, the DBC@AuNPs interlayer not only improves the interfacial thermal stability at the ZnO/BHJ interface but also endows a more ideal BHJ morphology with an enhanced thermal robustness. The derived device reserves 77% of initial PCE after thermal aging at 65 °C for 3000 h and yields an extended T80 lifetime of >1100 h when stored at a constant thermal condition at 65 °C, outperforming the control device. Finally, the device is evaluated to possess a T80 lifetime of over 1.79 years at room temperature (298 K) when stored in an inert condition, showing great potential for commercialization.

Biocompatible antibacterial nanoparticles prepared by assembling polycaprolactone-lysine-dendrimers

Novel dendritic antibacterial copolymer (PCL20-KG5) mimicking antimicrobial peptide features is synthesized by using Polycaprolactone (PCL) and BOC-Lysine(BOC)-OSu. PCL20-NH2 is designed as the core, and BOC-lysine(BOC)-OSu reacts with amino groups generation by generation to form dendritic structures. The properties and morphologies of PCL20-KG5 and their assemblies are characterized via the plate counting method, hemolytic analysis, transmission electron microscopy, dynamic light scattering, and drug release experiment. Results showed that PCL20-KG5 has excellent broad-spectrum antibacterial activity and extremely low hemolytic toxicity. It achieves antibacterial effect via membrane destruction without inducement of drug resistance. In addition, PCL20-KG5 dendrimer copolymer can self-assemble into uniform stable vesicles. Drug release experiments showed that the vesicles possess efficient drug loading capacity and are beneficial to realize continuous drug release in clinical treatment.

Self-Assembling PCL-PAMAM Linear Dendritic Block Copolymers (LDBCs) for Bioimaging and Phototherapeutic Applications.

This study represents a successful approach toward employing polycaprolactone-polyamidoamine (PCL-PAMAM) linear dendritic block copolymer (LDBC) nanoparticles as small-molecule carriers in NIR imaging and photothermal therapy. A feasible and robust synthetic strategy was used to synthesize a library of amphiphilic LDBCs with well-controlled hydrophobic-to-hydrophilic weight ratios. Systems with a hydrophobic weight ratio higher than 70% formed nanoparticles in aqueous media, which show hydrodynamic diameters of 51.6 and 96.4 nm. These nanoparticles exhibited loading efficiencies up to 21% for a hydrophobic molecule and 64% for a hydrophilic molecule. Furthermore, successful cellular uptake was observed via trafficking into endosomal and lysosomal compartments with an encapsulated NIR theranostic agent (C3) without inducing cell death. A preliminary photothermal assessment resulted in cell death after treating the cells with encapsulated C3 and exposing them to NIR light. The results of this work confirm the potential of these polymeric materials as promising candidates in theranostic nanomedicine.

The Introduction of the Radical Cascade Reaction into Polymer Chemistry: A One-Step Strategy for Synchronized Polymerization and Modification.

SummaryPolymerization and modification play central roles in polymer chemistry and are generally implemented in two steps, which suffer from the time-consuming two-step strategy and present considerable challenge for complete modification. By introducing the radical cascade reaction (RCR) into polymer chemistry, a one-step strategy is demonstrated to achieve synchronized polymerization and complete modification in situ. Attributed to the cascade feature of iron-catalyzed three-component alkene carboazidation RCR exhibiting carbon-carbon bond formation and carbon-azide bond formation with extremely high efficiency and selectivity in one step, radical cascade polymerization therefore enables the in situ synchronized polymerization through continuous carbon-carbon bond formation and complete modification through carbon-azide bond formation simultaneously. This results in a series of α, β, and γ poly(amino acid) precursors. This result not only expands the methodology library of polymerization, but also the possibility for polymer science to achieve functional polymers with tailored chemical functionality from in situ polymerization.

DOX-loaded peptide dendritic copolymer nanoparticles for combating multidrug resistance by regulating the lysosomal pathway of apoptosis in breast cancer cells.

Multidrug resistance (MDR) is a common phenomenon in clinical oncology and is a major obstacle to cancer chemotherapy. Many nanoparticle (NP)-based drug delivery systems have been developed to overcome MDR depending on increasing intracellular drug concentrations via increased cellular uptake and rapid drug release. The objective of this work was to investigate the performance and possible mechanisms of enzyme-sensitive mPEGylated dendron-GFLG-DOX conjugate based nanoparticles for blockading the MDR phenotype of MCF-7/ADR. In vitro, mPEGylated dendron-GFLG-DOX conjugate based nanoparticles could significantly promote cellular uptake and accumulation, potent cytotoxicity and apoptosis compared to free DOX in resistant cells. mPEGylated dendron-GFLG-DOX conjugate based nanoparticles were found to translocate across the membranes of resistant cells via active endocytic pathways leading to more DOX accumulating in the nuclei of MCF-7/ADR cells. Importantly, we found that mPEGylated dendron-GFLG-DOX conjugate based nanoparticles could induce cathepsin B in the cytoplasm and enhance lysosomal-mediated cell death compared to free DOX. Furthermore, mPEGylated dendron-GFLG-DOX conjugate based nanoparticles enhanced the drug's penetration, toxicity, and growth inhibition compared to free DOX in the three-dimensional multicellular tumor spheroid model. In vivo, mPEGylated dendron-GFLG-DOX conjugate based nanoparticles significantly improved the therapeutic efficacy against MDR xenograft tumors, and showed better biocompatibility than free DOX. These results indicated that mPEGylated dendron-GFLG-DOX conjugate based nanoparticles could be used as an alternative drug delivery system for MDR tumor treatment through initiating the lysosomal apoptosis pathway.

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).

Norbornadienes: Robust and Scalable Building Blocks for Cascade "Click" Coupling of High Molecular Weight Polymers.

Herein, we report the development of a scalable and synthetically robust building block based on norbornadiene (NBD) that can be broadly incorporated into a variety of macromolecular architectures using traditional living polymerization techniques. By taking advantage of a selective and rapid deprotection with tetrazine, highly reactive "masked" cyclopentadiene (Cp) functionalities can be introduced into synthetic polymers as chain-end groups in a quantitative and efficient manner. The orthogonality of this platform further enables a cascade "click" process where the "unmasked" Cp can rapidly react with dienophiles, such as maleimides, through a conventional Diels-Alder reaction. Coupling proceeds with quantitative conversions allowing high molecular weight star and dendritic block copolymers to be prepared in a single step under ambient conditions.

Nonionic Amphiphilic Linear Dendritic Block Copolymers. Solvent-Induced Self-Assembly and Morphology Tuning

In this article, we report the solution self-assembly of a series of amphiphilic linear–dendritic block copolymers (LDBCs), which are composed of hydrophilic dendritic poly(ether-ester), PEE, blocks based on 2,2-bis(hydroxymethyl)propionic acid and hydrophobic linear poly(styrene), PSt, blocks. The investigated LDBCs have narrow dispersity with three PEE generations (1–3) and a broad range of PSt molecular masses and are produced by dendron-initiated atom transfer radical polymerization of styrene followed by deprotection of the peripheral dendron hydroxyl groups. The solution self-assembly of the copolymers is performed by slowly adding water to the polymer solution in tetrahydrofuran (THF) as the common solvent for both blocks of the copolymers. The morphologies of the supramolecular assemblies are preserved either by diluting their dispersion by excess of water or by THF evaporation. It is found that the micellar morphology (sphere, wormlike, and/or vesicle) depends on the hydrophilic block fraction (F...

Synthesis and characterization of polylactide‐PAMAM “Janus‐type” linear‐dendritic hybrids

ABSTRACTHerein, we present a facile and comprehensive synthetic methodology for the preparation of polyester‐polyamidoamine (PAMAM) (i.e., polyester: polylactide [PLA] (hydrophobic) and polyamidoamine, PAMAM [hydrophilic]) polymers. A library of PLA‐PAMAM linear dendritic block copolymers (LDBCs) in which both l and d, l polylactide were employed in mass ratios of 30:70, 50:50, 70:30, and 90:10 (PLA:PAMAM) were synthesized and analyzed. When placed in aqueous media, the immiscibility of the hydrophilic and hydrophobic segments leads to nanophase‐segregation exhibited as the formation of aggregates (e.g., vesicles, worms, and/or micelles). By employing both stereochemical configurations of PLA, the differentiation in mass ratios of PLA‐PAMAM aided in elucidating the structure–property relationships of the LDBC system and provided a means toward the control of nanoparticle morphology. Transmission electron microscopy and dynamic light scattering afford the size and shape of the nanoparticles with diameters ranging from 10.6 for low mass ratios to 122.4 nm for high mass ratios of PLA‐PAMAM and positive zeta‐potential values between +24.7 mV and +48.2 mV. Furthermore, small‐angle X‐ray scattering (SAXS) studies were employed to obtain more detailed information on the morphological assemblies constructed via direct dissolution. Such insights provide a pathway toward nanomaterials with unique morphologies and tunable properties deemed relevant in the development of next generation biomaterials. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1448–1459

Self-Assembly of Linear-Dendritic and Double Dendritic Block Copolymers: From Dendromicelles to Dendrimersomes

Nanostructures formed upon self-assembly of amphiphilic block copolymers with linear and dendronized blocks are promising as nanocarriers for targeted drug and gene delivery. We propose a theoretical framework to predict how dimensions and morphologies of such nanostructures as well as the number of potentially functionalized terminal groups exposed to surrounding media can be controlled by adjusting molecular architecture parameters of dendronized blocks (i.e., number of generations and branching functionality). We demonstrate that dendronization of the soluble block stabilizes spherical micelles with a dendritic corona, whereas block copolymers with dendritic insoluble blocks give rise to cylindrical wormlike micelles or polymersomes even if homologous linear-linear block copolymers assemble into spherical micelles. Spherical micelles with a dendronized corona combine smaller hydrodynamic dimensions with a larger number of terminal groups as compared to micelles formed by homologous linear diblock copol...