A Robust Strategy for Precise Fabrication of Rigid–Flexible Coupling Dendrimers toward Self-Coordinated Hierarchical Assembly

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE1 Apr 2021A Robust Strategy for Precise Fabrication of Rigid–Flexible Coupling Dendrimers toward Self-Coordinated Hierarchical Assembly Xing Wang, Peiyuan Gao, Juan Wang, Yanyu Yang, Yezi You and Decheng Wu Xing Wang Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 , Peiyuan Gao Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Juan Wang Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Yanyu Yang *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 College of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450001 , Yezi You *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026. and Decheng Wu *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 https://doi.org/10.31635/ccschem.020.202000238 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Advances in nanotechnology depend upon expanding the ability to create biologically inspired complex materials with well-defined multidimensional structures. Fabrication of hybrid hierarchical structures by combining colloidal organic and inorganic building blocks remains a challenge due to the difficulty in preparing a diverse spectrum of rigid–flexible coupling units of precise shape and size. Here we report a general strategy for crafting a myriad of uniform aggregates via manipulating self-assembly of distinct dendrimers with precisely controlled polyhedral oligomeric silsesquioxane (POSS)-embedded cores integrating stiffness and ductility. The rigidity of POSS units exerts steric effects on self-amplification of hydrophobic domains while the flexibility from internally ductile linkages provides ideal scenarios in establishing self-adaptive structural optimization, which subsequently drive the assemblies to proceed into hierarchical self-assembly via multiple coordination effects, generating highly complex multicompartment micelles (MCMs) without any preprocessing. Our facile approach enables a robust modular nanofabrication of well-organized dendrimers toward artificial functional systems with defined geometric architectures and intriguing functions for advanced biological applications. Download figure Download PowerPoint Introduction Nature uses a hierarchy of self-assembly steps to construct functional hybrid structures from inorganic and organic building blocks. Many examples from nature have demonstrated the power of hierarchical self-assembly in constructing structurally complex and functional architectures such as DNA and proteins, in which multiple components are brought together through a stepwise process driven by multiple coordination interactions. Aiming to obtain a better understanding of such biological processes in nature, a great deal of effort has been devoted toward investigating artificial functional systems. Current synthetic approaches are beginning to reach similar levels of exquisite control in the creation of nanoscale and mesoscale architectures using well-defined nanomaterials as building blocks. Among this large variety of dendritic chemical structures, amphiphilic dendrimers, due to their well-defined architectures and shape persistence, have attracted considerable attention in the field of bottom-up hierarchical self-assembly for decades and found great applications in myriad fields, including supramolecular chemistry, gene transfection, drug delivery, and catalysis, to name but a few.1–10 Unfortunately, a grand challenge to yield the delicate dendrimers requires tedious multistep reactions, purification processes, and stringent experimental conditions, which significantly limit the varieties and scopes of dendritic self-assembly. According to the anatomy of core–shell-type architectures and rigidity of interior kernels, dendrimers could be mainly divided into two categories: (1) rigid core dendrimers, based on the traditional horizontal periodic elemental features associated with conducting or semiconducting properties,11–16 tend to form crystalline or rigid 3D lattices with uniform size and fixed shape. For example, Au NP cores possess uniform nanometer size and shape that could prevent adjacent rigid cores from deforming in the self-assembly process, thus limiting the multiformity of assembled morphologies;17–19 (2) flexible core dendrimers, including those materials with organic-like structures in correlation with pliable abilities, possess a variety of interchangeable chain conformations, which are apt to curl and entangle with each other to facilitate the hydrophobic areas, forming a series of random heterogeneous aggregates.20–22 Among them, regulation protocols that enable the simple production and convenient tailoring of dendritic building blocks with specific geometry and symmetry are of key general importance, but most of the techniques are subject to limited syntheses, monotone structures, and sophisticated controls.23–29 Thus, to realize the precise design of uniform rigid–flexible coupling core dendrimers (integrating high rigidity and limited freedom to distort), rigorous control of well-organized aggregates and systematic achievement of more well-worth exploring hierarchical self-assembly are particularly challenging and fascinating. Polyhedral oligomeric silsesquioxane (POSS) is a classic type of cube-shaped core that is better for the growth of multiple generations in three dimensions, which is beneficial for the preparation of different kinds of dendrimers with a POSS core.30–34 Due to their relatively globular conformations, rigid 3D structures, few entangled branches, and high proportion of terminal functional groups, self-assembed POSS-cored amphiphilic dendrimers have gained popularity as important building blocks and shown much advantageous versatility and functionalities.35–38 However, most relevant works concentrate on tuning the species and length of hydrophilic chains positioned on the exterior of dendrimers to control hydrophobic/hydrophilic ratio, but little attention is devoted to adjusting POSS moieties with diverse shape, size, and spatial arrangement in solutions.39 Here, we demonstrate a facile and general strategy for fabrication of a category of rigid–flexible coupling core dendrimers ( Cx-G1, Supporting Information Figure S1) and corresponding Cx-POSSm-PEGn polymers with variant stiff skeletons and explicit geometries via a combination of 1 → 7 divergent approach and thiol–ene click reaction (Figure 1).40 Variously extended polyethylene glycol (PEG) length and precisely defined geometry have vital roles in the diversiform rigid–flexible coupling POSS-embedded cores in aqueous solutions. The rigidity from POSS units exerts steric effects on the self-amplification of hydrophobic domains while the flexibility of ductile chains provides ideal scenarios in establishing a library of self-adaptive capacity with virtually unlimited possibilities for structural variations. These continuous self-adjustments subsequently drive the selective assemblies to perform a multiple-coordination-driven hierarchical self-assembly by strong phase separation, contributing to the hierarchical evolution without any idiosyncratic controls. Thus, this work reveals a versatile strategy for elaborate design of rigid–flexible coupling core dendrimers for exploring a wide diversity of hierarchical self-assemblies with tailor-made composition, shape, and multifunction. Figure 1 | Synthetic route of POSS-embedded dendrimers. Synthesis of four topological Cx-G1 POSS-embedded dendrimers and amphiphilic Cx-POSSm-PEGn polymers from a monohydroxyl 1 → 7 branching (AB7) monomer and four different starting cores (C2, C3, C4, and C8). Download figure Download PowerPoint Experimental Method Materials Octavinyl POSS (98%; Hybrid Plastics, USA), trifluoromethanesulfonic acid (99%; Aldrich, USA), 1,4-butanedicarboxylic acid (99%; Energy Chemical), 4-(2-aminoethyl) diethylenetriamine (99%; Energy Chemical, Shanghai, China), 2-mercaptoethylamine hydrochloride (99%; Energy Chemical), pentaerythritol (99%; J&K, Beijing, China), 4-(dimethyl-amino)-pyridine (DMAP; 99%; Aldrich), succinic anhydride (99%; J&K), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 99%; Energy Chemical), 2,2-dimethoxy-2-phenylacetophenone (DMPA; 99%; J&K), PEG-SH (Mn = 160, 350, 550, and 750) were prepared according to our previous work.41 Triethylamine (TEA; 99%; Beijing Chemical Works, Beijing, China), methanol, acetone, hydrochloric acid, hexane and diethyl ether (reagent grade; Beijing Chemical Works), tetrahydrofuran (THF), N,N-dimethyl formamide (DMF), chloroform (CHCl3), and dichloromethane (CH2Cl2) were purified by stirring over calcium hydride for 24 h followed by distillation. Hydrophobic content The hydrophobic/hydrophilic ratio of amphiphilic polymers is a well-known and important criterion to predict self-assembly behaviors. Here the hydrophobic content (Hc) was firstly used to assess the hydrophobic/hydrophilic balance of amphiphilic dendrimers and further determine their self-assembly behaviors in water. This parameter has been successfully applied in the hydrophobicity estimation of some amphiphilic dendrimers.42 The Hc was defined as follows: H c = ( M A / M T ) × 100 % (1)where MA is molecular weight of hydrophobic POSS contents and MT is the total molecular weight. Molecular mechanics calculation method To further understand the structures and dimensions of the topological C2-, C3-, C4-, and C8-G1 POSS molecules, a molecular mechanics simulation method was employed in this work. The condensed-phase (no solvent molecules) optimized molecular potential for atomistic simulation studies (COMPASS) force field was adopted to perform energy minimization. The branches of the POSS molecule should be extended because of the steric hindrance in the equilibrium state. In this simulation, the conformation of the POSS molecule was obtained by the molecular mechanics calculation method. It should be noted that the conformation energy may not be minimum globally but locally due to the limited phase space that was explored. In other words, the branches of POSS molecule in our simulation may not all be extended. However, we knew that the extended branch represented the real state for the POSS molecule in equilibrium. So we calculated the radial distribution function (RDF) of the center in the POSS molecule and the outside carbon atoms after the molecular mechanics run. And the largest distance in the RDF plot, or the greatest distance between two sorts of atoms, would be the maximum radius of the POSS molecule. RDF was calculated with the equation: g a b ( r ) = 1 N a N b ∑ i = 1 N a ∑ j = 1 N b 〈 δ | r i j | − r 〉 (2)where a, b represent two sorts of atoms, and they also could be the same. The operator 〈 〉 represents the ensemble average. δ is the delta function. Dissipative particle dynamics simulation method In general, a dissipative particle dynamics (DPD) bead could represent a group of atoms. The force on bead i was calculated by the sum of three sorts of forces, that is, the conservative force, the dissipative force, and the random force. Full details of the implementation of the DPD method were given elsewhere.43,44 F i = Σ j ≠ i F i j C + F i j D + F i j R (3) F i j C = a i j ( 1 − r i j r c ) r ^ i j (4) F i j D = − γ ω 2 ( r i j ) ( r ^ i j · v → i j ) r ^ i j (5) F i j R = σ ω ( r i j ) θ i j r ^ i j (6)where γ was the friction coefficient governing the magnitude of the dissipative force, σ was the noise amplitude controlling the intensity of random force, and θij was a randomly fluctuating variable with zero mean and unit variance. Within the coarse-grained (CG) model, the neighboring CG beads were bonded to each other by a harmonic spring potential, Ub = 0.5kb(r − r0)2, where kb was the spring constant and r0 was the equilibrium bond length. In this study for POSS molecule, kb = 100 and for other bonded interaction kb = 25. The bond length r0 was equal to 0.7. The fractional concentration of POSS dendrimer in the solution φ was 0.05, which was calculated by the following formula φ = N P V P + N G V G + N J V J N P V P + N G V G + N J V J + N W V W (7)where NP, NG, NJ, and NW were the numbers of POSS, PEG, joint, and water beads while VP, VG, VJ, and VW were the volumes of one bead of POSS, PEG, joint, and solvent, respectively. The size of simulation box was 30 × 30 × 30. The simulation was performed in the canonical ensemble with periodic boundary conditions applied in all three dimensions and at a fixed system number density of 3.0. All the CG beads had the same mass as m = 1. The interaction cutoff radius was set to 1 as the unit of length. The size of POSS was three times that of PEG or water beads in model 1 and two times in the refined model. The reduced temperature was 1.0. In the CG simulation, the modified velocity Verlet algorithm was used to integrate the equations of motion with a time step of 0.03. We started simulations from isotropic configurations, which were constructed by equilibrating the systems under a thermal condition, that is, by setting aij = 25 and T = 1.0 for all DPD beads and running 1 × 106 steps for equilibrium. Then we performed 1 × 107 steps to observe the morphology of aggregates at equilibrium. All-atom molecular dynamics simulations All-atom molecular dynamics (MD) simulations were performed by GROMACS. The TIP3P water model was used for water. In MD simulations, one C4-POSS4-PEG28 dendrimer with PEG side chains of different molecular weights (160, 350, 550, and 750) was solvated in water, which was employed as a typical example to illustrate the important relationships between the spatial geometry and the hydrophilic PEG length. The simulation box length was 5 nm. These systems were firstly simulated at 300 K and 1 atm for 20 ns. Then 1 μs production simulations were performed. The time step was 2 fs. The temperature and pressure were maintained by the Berendsen thermostat and barostat in equilibrium, and in the production simulation the Nose–Hoover thermostat and Parrinello–Rahman barostat were used. Electrostatic interactions were calculated using particle mesh Ewald and a real space cutoff of 1.2 nm. Van der Waals interactions were switched to zero between 1 and 1.2 nm. Results and Discussion Dendrimer syntheses One simple esterification by the varied carboxyl modified ( C2, C3, C4, and C8, Supporting Information Figures S2–S5) cores and (vinyl)7-POSS-OH (AB7 monomer) ( Supporting Information Figure S6) could produce C2-, C3-, C4-, and C8-G1 POSS dendrimers with various topologies and terminal groups. IR analyses ( Supporting Information Figure S7) and NMR spectra (Figure 2a) verified the complete substitutions of end-functional groups by the merged resonances of vinyl groups and accurate integrated areas of corresponding peaks. Gel permeation chromatography (GPC) coupled with a triple detector array was employed to verify their high level of efficiency and associated purity of symmetrical Cx-G1 POSS dendrimers (PDIs = 1.02∼1.13, Supporting Information Figure S8 and Table S1). In addition, thermal gravimetric analysis (TGA) was also a useful technique to evaluate inorganic POSS contents by burning out organic segments in air; the results exhibited inorganic POSS constituents identical to the theoretical contents in all POSS dendrimers and proved their uniform frameworks ( Supporting Information Figure S9). The most convincing evidence was provided by the matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectra of the proposed products (Figure 2b). These representative narrow mass peaks all agreed with their respectively calculated molecular weights, unambiguously confirming uniformity of POSS dendrimers. The unimolecular diameters were 3.5 ± 0.1, 4.3 ± 0.2, 3.8 ± 0.2, and 5.3 ± 0.1 nm by transmission electron microscopy (TEM) in Figure 2c, which were coincident with their theoretical sizes (3.2, 4.2, 4.0, and 5.6 nm) after structural optimization by MMC (Figure 2dand Supporting Information Table S1). These results provided confirmative proof of the various molecular integrities of Cx-G1 POSS dendrimers. Figure 2 | Structural characterizations and size measurements of POSS-embedded dendrimers. (a) NMR spectra, (b) MALDI-TOF mass spectra, (c) TEM images, and (d) MMC models of four Cx-G1 POSS dendrimers. Download figure Download PowerPoint From the aforementioned analysis, it was well grounded that the modular nature of this 1 → 7 divergent approach was facile and convenient to prepare well-defined POSS dendrimers with multitopologies and huge peripheral active groups. These dendrimers possessed robust physical properties (e.g., nanoscale monodispersity, moderate thermal stability, and strong rigidity) and flexible chemical functional modifications originating from a number of vinyl groups on the periphery. In this case, it was concluded that more and more multiarchitectural and functional POSS dendrimers could be easily tailored only by selecting the various kinds of inner starting cores, which would open a new and universal avenue for constructing multiarmed dendrimers with unitary nanosized structures and plentiful terminal groups in applications of functional self-assembly. Effect of external PEG length on the geometry and rigidity–flexibility of POSS-embedded core By employing the simple, efficient thiol-ene click reaction, various hydrophilic segments of PEG-SH (Mn = 160, 350, 550, and 750) were readily attached onto the periphery of POSS cages, generating four kinds of Cx-POSSm-PEGn polymers, as verified by NMR and GPC measurements ( Supporting Information Figures S10–S13 and Table S2). Notably, installation of various lengths of PEG chains not only affected the hydrophobic/hydrophilic balance of these amphiphiles in water, but also produced great effects on the geometry of internal cores. Taking the C4-POSS4-PEG28 (Mn,PEG = 160, 350, 550, and 750) as examples, Figure 3ashows that four intuitive C4-POSS4-PEG28 molecules presented diversiform PEG extended conformations (all-atom MD simulations) that could occupy the excluded volume of hydrophobic areas and exert a strong effect on the outstretched or curly conformations of inner flexible chains. Their radii of gyration (Rg) and distances (D) between any two adjacent POSS units were distinctive in aqueous solutions (Figure 3band Supporting Information Table S3) and shorter than the size of the pure C4-G1 dendrimer, which suggested the influences of extended PEG chains on the and of flexible linkages the POSS from to to of but the size of the POSS-embedded core was the capacity of the flexible chains or interior linkages and the important effects of PEG lengths on the geometry in aqueous solutions. various PEG lengths not only had on the amphiphilic but also the geometry and of inner cores. this it was that these unimolecular Cx-POSSm-PEGn molecules, employed as structural units for would diversiform as a function of the of PEG length. Figure | Effect of external PEG length on the geometry of C4-POSS4-PEG28 polymers using MD (a) conformations of C4-POSS4-PEG28 molecule with of 160, 350, 550, and in water. The water beads are for (b) of of only POSS-embedded core and the corresponding radius of of C4-POSS4-PEG28 molecule Download figure Download PowerPoint with hydrophobic interaction and self-adaptive capacity The precisely defined molecular structures, readily on POSS, and hydrophilic segments provided ideal scenarios in establishing a library of shape amphiphiles with virtually unlimited possibilities for structural In general, a Hc better for the amphiphiles in aqueous However, after installation of various lengths of PEG chains (Mn,PEG = 350, and onto cores, three amphiphilic polymers assembled into and in aqueous solution (Figure their Hc were Supporting Information Table These were mainly to a specific hydrophobic interaction originating from the rigidity–flexibility of POSS-embedded cores. building blocks that and with each other in the process of these rigid cores were to curl or to the energy of So the of hydrophilic and hydrophobic segments was in water, the multiarchitectural rigid cores to a distance from adjacent POSS molecules, in the of their hydrophobic spatial In addition, a number of internally ductile organic linkages and chains these POSS-embedded cores with and self-adaptive ability to facilitate the hydrophobic and to some the a of hydrophobic/hydrophilic balance was to in a of that was with which demonstrated the important coordination of rigid–flexible building blocks on self-assembly behaviors. we prepared (Mn,PEG = 160, 350, 550, and 750) polymers without ductile chains the cores, which only into micelles with varied sizes originating from their Hc ( Supporting Information Figure the important roles of interior flexible linkages on the self-assembly behaviors. This self-assembly of hydrophobic effects was also applied to C4-POSS4-PEG28 polymers, and in aqueous solutions ( Supporting Information Figure In to the self-assemblies from polymers, these distinctive of explicit geometric on the solution that was with the previous of external hydrophilic PEG length on the geometry of POSS-embedded cores by MD simulations (Figure the coordination of hydrophobic interaction and self-adaptive capacity from the explicit geometry and combination of stiffness and of POSS-embedded cores, and more possibilities for Cx-POSSm-PEGn polymers to into a series of Figure | by the polymers with (a) (b) electron microscopy (c) force microscopy and (d) of the self-assemblies by the Cx-POSSm-PEGn polymers with various of 350, and at the concentration of 1 in aqueous solutions. is the TEM The represents inner starting represents the POSS, and chain represents the Download figure Download PowerPoint DPD simulation The of experimental techniques a understanding of the the self-assembly To this we performed DPD simulations to better understand these self-assembly To of the features of POSS-embedded cores with various different CG models of Cx-G1 POSS dendrimers were constructed according to their architectures ( Supporting Information Figure and Table We the self-assembly of amphiphilic polymers (Mn,PEG = 350, and as example with different hydrophobic/hydrophilic by the PEG length from one to CG shown in Figure Supporting Information and were obtained in DPD simulations with the and structures were with the electron (Figure the micelles from the (Mn,PEG = were not well with the corresponding the of geometry and rigidity–flexibility of dendritic cores on the self-assembly which be the subject of the of and accurate simulation for the self-assembly this work provides a and understanding of dendrimers for study of diverse self-assemblies and tailor-made materials with and Figure 5 | of of various by DPD to the each process of (a) (b) and (c) structures by the molecules with various PEG lengths (Mn,PEG = 350, and The were their The water beads were for Download figure Download PowerPoint for hierarchical evolution we fixed the same PEG (Mn,PEG = onto these four Cx-G1 cores, various kinds of well-defined the and multicompartment micelles obtained under conditions, as shown in Figures According to previous were from with various or in selective through a hierarchical self-assembly and was simple and efficient method for preparation of because of the rigorous of phase the capacity of rigid POSS-embedded blocks for Cx-POSSm-PEGn polymers to form various the process, PEG chains were to form a of while and random POSS-embedded blocks were two blocks to to the of cores, to the

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