Deliver on a Promise: Hydrogen-Bonded Polymer Nanomedicine with a Precise Ratio of Chemodrug and Photosensitizer for Intelligent Cancer Therapy.

The outcomes of combined cancer therapy are largely related to loading content and contribution of each therapeutic agent; however, fine-tuning the ratio of two coloaded components toward precise cancer therapy is a great challenge and still remains in its infancy. We herein develop a supramolecular polymer scaffold to optimize the coloading ratio of chemotherapeutic agent and photosensitizer through hydrogen-bonding (H-bonding) interaction, for maximizing the efficacy of intelligent cancer chemo/photodynamic therapies (CT/PDT). To do so, we first synthesize a thymine (THY)-functionalized tetraphenylporphyrin photosensitizer (i.e., TTPP), featuring the same molecular configuration of H-bonding array with chemotherapeutic carmofur (e.g., 1-hexylcarbamoyl-5-fluorouracil, HCFU). Meanwhile, a six-arm star-shaped amphiphilic polymer vehicle P(DAPA-co-DPMA-co-OEGMA)6 (poly(diaminopyridine acrylamide-co-2-(diisopropylamino)ethyl methacrylate-co-oligo(ethylene glycol) monomethyl ether methacrylate)6) is prepared, bearing hydrophilic and biocompatible POEGMA segment, along with hydrophobic PDAPA and PDPMA segments, characterizing the randomly dispersed dual functionalities, i.e., heterocomplementary H-bonding DAP motifs and pH-responsive protonation DPMA content. Thanks to the identical DAP/HCFU and DAP/TTPP H-bonding association capability, the incorporation of both HCFU and TTPP to six-arm star-shaped P(DAPA-co-DPMA-co-OEGMA)6 vehicle, with an optimized coloading ratio, can be straightforwardly realized by adjusting the feeding concentrations, thus yielding the hydrogen-bonded supramolecular nanoparticles (i.e., HCFU-TTPP-SPNs), demonstrating the codelivery of two components with the promise to optimize the combined CT/PDT efficacy.

Polyphenol-sodium alginate supramolecular injectable hydrogel with antibacterial and anti-inflammatory capabilities for infected wound healing.

Injectable hydrogel has attracted appealing attention for skin wound treatment. Although multifunctional injectable hydrogels can be prepared by introducing bioactive ingredients with antibacterial and anti-inflammatory capabilities, their preparation remains complicated. Herein, a polyphenol-based supramolecular injectable hydrogel (PBSIH) based on polyphenol gallic acid and biological macromolecule sodium alginate is developed as a wound dressing to accelerate wound healing. We show that such PBSIH can be rapidly formed within 15 s by mixing the sodium alginate and gallic acid solutions based on the hydrogen bonding and hydrophobic interactions. The PBSIH shows excellent cytocompatibility, antibacterial, and antioxidant properties, which enhance infected wound healing by inhibiting bacterial infection and alleviating inflammation after treatment of 11 days. Moreover, we show that the preparative strategies of injectable supramolecular hydrogels can be extended to other polyphenols, including protocatechuic and tannic acids. This study provides a facile yet highly effective method to design injectable polyphenol- sodium alginate hydrogel for wound dressing based on naturally bioactive ingredients.

Hydrogen-Bonded Polymer Nanomedicine with AIE Characteristic for Intelligent Cancer Therapy.

One of the major goals of biomedical science is to pioneer advanced strategies toward precise and smart medicine. Hydrogen-bonding (H-bonding) assembly incorporated with an aggregation-induced emission (AIE) capability can serve as a powerful tool for developing supramolecular nanomedicine with clear tumor imaging and smart therapeutic performance. We here report a H-bonded polymeric nanoformulation with an AIE characteristic toward smart antitumor therapy. To do so, we first design a structurally novel tetraphenylethylene (TPE)-based H-bonding theranostic prodrug, TPE-(FUA)4, characterized by four chemotherapeutic fluorouracil-1-acetic acid (FUA) moieties arched to the TPE core. A six-arm star-shaped amphiphilic polymer vehicle, P(DAP-co-OEGEA)6, is prepared, bearing hydrophilic and biocompatible POEGEA (poly(oligo (ethylene glycol) ethyl acrylate) segments, along with a hydrophobic and H-bonding PDAP (poly(diaminopyridine acrylamide)) segment. Thanks to the establishment of the DAP/FUA H-bonding association, incorporating the TPE-(FUA)4 prodrug to the P(DAP-co-OEGEA)6 vehicle can yield H-bond cross-linked nanoparticles with interpenetrating networks. For the first time, AIE luminogens are interwoven into a six-arm star-shaped polymer via an intrinsic H-bonding array of the chemotherapeutic agent FUA, thus imposing an effective restriction of TPE molecular rotations. Concomitantly, encapsulated photothermal agent (IR780) via a hydrophobic interaction facilitates the formation of nanoassemblies, TPE-(FUA)4/IR780@P(DAP-co-OEGEA)6, featuring synergistic cancer chemo/photothermal therapy (CT/PTT). Our study can contribute a practical solution to fulfill biomedical requirements with a conductive advance in precision nanomedicine.

Large-Area Arrays of Polymer-Tethered Gold Nanorods with Controllable Orientation and Their Application in Nano-Floating-Gate Memory Devices.

In this work, it is reported that large-area (centimeter-scale) arrays of non-close-packed polystyrene-tethered gold nanorod (AuNR@PS) can be prepared through a liquid-liquid interfacial assembly method. Most importantly, the orientation of AuNRs in the arrays can be controlled by changing the intensity and direction of electric field applied in the solvent annealing process. The interparticle distance of AuNR can be tuned by varying the length of polymer ligands. Moreover, the AuNR@PS with short PS ligand are favorited to form orientated arrays with the assistance of electric field, while long PS ligands make the orientation of AuNRs difficult. The orientated AuNR@PS arrays are employed as the nano-floating gate of field-effect transistor memory device. Tunable charge trapping and retention characteristics in the device can be realized by electrical pulse with visible light illumination. The memory device with orientated AuNR@PS array required less illumination time (1 s) at the same onset voltage in programming operation, compared to the control device with disordered AuNR@PS array (illumination time: 3 s). Moreover, the orientated AuNR@PS array-based memory device can maintain the stored data for more than 9000 s, and exhibits stable endurance characteristic without significant degradation in 50 programming/reading/erasing/reading cycles.

Monolayer LDH Nanosheets with Ultrahigh ICG Loading for Phototherapy and Ca2+-Induced Mitochondrial Membrane Potential Damage to Co-Enhance Cancer Immunotherapy.

Tumor recurrence and metastasis are the main causes of cancer mortality; traditional chemotherapeutic drugs have severe toxicity and side effects in cancer treatment. To overcome these issues, here, we present a pH-responsive, self-destructive intelligent nanoplatform for magnetic resonance/fluorescence dual-mode image-guided mitochondrial membrane potential damage (MMPD)/photodynamic (PDT)/photothermal (PTT)/immunotherapy for breast cancer treatment with external near infrared (NIR) light irradiation. To do so, we construct multifunctional monolayer-layered double hydroxide (LDH) nanosheets (MICaP), co-loading indocyanine green (ICG) with ultrahigh loading content realized via electrostatic interactions, and calcium phosphate (Ca3(PO4)2) coating via biomineralization. Such a combined therapy design is featured by the outstanding biocompatibility and provokes immunogenic cell death (ICD) of tumors toward cancer immunotherapy. The active transport of excess Ca2+ released from pH-sensitive Ca3(PO4)2 can induce MMPD of tumor cells to minimize oxygen consumption in the tumor microenvironment (TME). The presence of ICG not only generates singlet oxygen (1O2) to induce apoptosis by photodynamic therapy (PDT) but also initiates tumor cell necrosis by photothermal therapy (PTT) under near-infrared (NIR) light radiation. Eventually, the immune response generated by MMPD/PDT/PTT greatly promotes a cytotoxic T lymphocyte (CTL) response that can limit tumor growth and metastasis. Both in vitro and in vivo studies indeed illustrate outstanding antitumor efficiency and outcomes. We anticipate that such precisely designed nanoformulations can contribute in a useful and advantageous way that is conducive to explore novel nanomedicines with notable values in antitumor therapy.

Starvation-assisted and photothermal-thriving combined chemo/chemodynamic cancer therapy with PT/MR bimodal imaging.

Chemodynamic therapy (CDT) reflects a novel reactive oxygen species (ROS)-related cancer therapeutic approach. However, CDT monotherapy is often limited by weak efficacy and insufficient endogenous H2O2. Herein, a multifunctional combined bioreactor (MnFe-LDH/MTX@GOx@Ta, MMGT) relying on MnFe-layered double hydroxide (MnFe-LDH) loaded with methotrexate (MTX) and coated with glucose oxidase (GOx)/tannin acid (Ta) is established for applications in H2O2 self-supply and photothermal enhanced chemo/chemodynamic combined therapy along with photothermal (PT) /magnetic resonance (MR) dual-modality imaging ability for cancer treatment. Once internalized into tumor cells, MMGT achieves starvation therapy by catalyzing the oxidation of glucose with GOx, accompanied by the regeneration of H2O2, enabling a Fenton-like reaction to accomplish GOx catalytic amplified CDT. Moreover, MMGT manifests significant tumor-killing ability through improved CDT performance with outstanding photothermal conversion efficiency (η = 52.2%) under 808 nm laser irradiation. In addition, the release of Mn2+ from MnFe-LDH in a solid tumor can significantly enhance T1-contrast MR imaging signals. Combined with MnFe-LDH-induced PT imaging under 808 nm laser irradiation, a dual-modality imaging directed theranostic nanoplatform has been developed. The present study provides a new strategy to design H2O2 self-supply and ROS evolving NIR light-absorption theranostic nanoagent for highly efficient and combined chemo/chemodynamic cancer treatment.

Assembled Morphology of Copper-Thiourea Coordination-Mediated Metallo-Supramolecular Polymers.

Metallo-supramolecular polymers represent a powerful platform to construct self-assembled morphologies. Copper-thiourea (Cu-TU) coordination interactions, though have been extensively studied in small molecular system, the role of TU motifs in synthetic polymers using metal-ligand coordination to afford supramolecular aggregation and their morphology are often overlooked. Herein, an amphiphilic random copolymer, poly(oligo(ethylene glycol) ethyl acrylate-r-acylthiourea) (P(OEGEA-r-ATU)), bearing pendant TU motifs behaving as the ligand to coordinate Cu, a design characterized by core-coordinated metallo-supramolecular polymer is rationally synthesized. Indeed, rod-like nano-objects are successfully generated via the self-assembly and coordination interaction between P(OEGEA-r-ATU) and Cu. The spatial distribution of TU moieties in polymer chain, along with their Cu chelating capability, featuring the interchain coordination interaction, is tightly related to metallo-supramolecular polymer organization. The specific Cu-TU coordination interactions enable the prompted robustness and stability of soft P(OEGEA-r-ATU), induce the polymer chain configuration, which eventually furnish efficient fabrication of rod-like nano-objects via straightforward nanoprecipitation procedure. These structural motifs of copper-coordinated, rod-like nano-objects from such metallo-supramolecular polymers endow the potential therapeutic properties, such as anti-inflammatory and antitumor effects.

Electric, magnetic, and shear field-directed assembly of inorganic nanoparticles.

Ordered assemblies of inorganic nanoparticles (NPs) have shown tremendous potential for wide applications due to their unique collective properties, which differ from those of individual NPs. Various assembly methods, such as external field-directed assembly, interfacial assembly, template assembly, biomolecular recognition-mediated assembly, confined assembly, and others, have been employed to generate ordered inorganic NP assemblies with hierarchical structures. Among them, the external field-directed assembly method is particularly fascinating, as it can remotely assemble NPs into well-ordered superstructures. Moreover, external fields (e.g., electric, magnetic, and shear fields) can introduce a local and/or global field intensity gradient, resulting in an additional force on NPs to drive their rotation and/or translation. Therefore, the external field-directed assembly of NPs becomes a robust method to fabricate well-defined functional materials with the desired optical, electronic, and magnetic properties, which have various applications in catalysis, sensing, disease diagnosis, energy conversion/storage, photonics, nano-floating-gate memory, and others. In this review, the effects of an electric field, magnetic field, and shear field on the organization of inorganic NPs are highlighted. The methods for controlling the well-ordered organization of inorganic NPs at different scales and their advantages are reviewed. Finally, future challenges and perspectives in this field are discussed.

Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy.

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-co-thiourea] [P(OEGEA-co-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-co-(ATU-g-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H2O2 to create •OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and in vitro as well as in vivo studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.

Hydrogen Bond-Mediated Supramolecular Polymeric Nanomedicine with pH/Light-Responsive Methotrexate Release and Synergistic Chemo-/Photothermal Therapy.

Complete cancer cure and healing are still difficult, owing to its complexity and heterogeneity. Integration of supramolecular forces, for example, hydrogen bonds (H-bonds), to anti-cancer nanomedicine affords new scaffolds for biomedical material decoration, featuring the advantages of dynamic property and easier processability. Here, we target the construction of H-bond-mediated supramolecular polymer micelles, loaded with a chemotherapeutic drug along with a photothermal agent for synergistic chemo-/photothermal therapies (CT/PTT). To do so, we design and synthesize an amphiphilic ABA-type triblock copolymer, bearing H-bonding moiety (barbiturate, Ba) within the middle hydrophobic B block. The presence of pendant Ba moieties within the hydrophobic core promotes the loading capability of methotrexate (MTX) and transportation stability, benefitting from the formation of specific Ba/MTX H-bonding interactions. IR780, a photothermal agent, concomitantly encapsulated via hydrophobic interactions, facilitates the development of a synergistic CT/PTT modalities, where MTX can be released on demand owing to the dissociation of Ba/MTX H-bonding interactions induced by elevated temperature. Such H-bonding nanomedicine possesses enhanced drug loading capacity and transport performance and can also trigger stimuli-responsive drug release in the tumor zone. We believe that H-bonded nanomedicines provide a fine toolbox that is conducive to attaining biomedical requirements with remarkable values in theranostics that are highly promising in clinical applications.

Hydrogen-Bonds-Mediated Nanomedicine: Design, Synthesis, and Applications.

Among the various challenges in medicine, diagnosis, complete cure, and healing of cancers remain difficult given the heterogeneity and complexity of such a disease. Differing from conventional platforms with often unsatisfactory theranostic capabilities, the contribution of supramolecular interactions, such as hydrogen-bonds (H-bonds), to cancer nanotheranostics opens new perspectives for the design of biomedical materials, exhibiting remarkable properties and easier processability. Thanks to their dynamic characteristics, a feature generally observed for noncovalent interactions, H-bonding (macro)molecules can be used as supramolecular motifs for yielding drug- and diagnostic carriers that possess attractive features, arising from the combination of assembled nanoplatforms and the responsiveness of H-bonds. Thus, H-bonded nanomedicine provides a rich toolbox that is useful to fulfill biomedical needs with unique advantages in early-stage diagnosis and therapy, demonstrating the promising potential in clinical translations and applications. Here the design and synthetic routes toward H-bonded nanomedicines, focus on the growing understanding of the structure-function relationship for efficient cancer treatment are summarized. A guidance for designing new H-bonded intelligent theranostic agents is proposed, to inspire more successful explorations of cancer nanotheranostics and finally to promote potential clinical translations.

Hydrogen-Bonded Supramolecular Polymer Adhesives: Straightforward Synthesis and Strong Substrate Interaction.

High-performance adhesives are of great interest in view of industrial demand. We herein identify a straightforward synthetic strategy towards universal hydrogen-bonded (H-bonded) polymeric adhesives, using a side-chain barbiturate (Ba) and Hamilton wedge (HW) functionalized copolymer. Starting from a rubbery copolymer containing thiolactone derivatives, Ba and HW moieties are tethered as pendant groups via an efficient one-pot two-step amine-thiol-bromo conjugation. Hetero-complementary Ba/HW interactions thus yield H-bonded supramolecular polymeric networks. In addition to an enhanced polymeric network integrity induced by specific Ba/HW association, the presence of individual Ba or HW moieties enables strong binding to a range of substrates, outstanding compared to commercial glues and reported adhesives.

MnO2 coated nanotheranostic LDH for synergistic cascade chemo/chemodynamic cancer therapy under the guidance of MRI-targeted diagnosis.

Integrating magnetic resonance imaging (MRI)-targeted diagnosis with synergistic cascade treatments, such as chemo/chemodynamic therapy (CT/CDT), is highly desired for promoting the antitumor performance; however, the rational design of such "all-in-one" nanomedicine is still in its infancy. In this report, using MnO2 coated layered dihydroxide (LDH) as a carrier to load chemotherapy molecule 5-flurouracil (5-FU), a novel tumor microenvironment (TME) regulating nanodrug is formed: LDH/5-FU@MnO2. Combined guidance of CT/CDT and MRI is used to realize synergistic diagnosis and enhanced anti-tumor efficacy. MnO2 is converted into Mn2+ in the presence of reducing agent GSH, the in situ generated Mn2+, not only serves as the chemical fuel for the Fenton reaction, combining H2O2 depletion and ˙OH generation, but can also be used as a nuclear magnetic contrast agent for MRI. Moreover, the tumor acidic environment is able to trigger 5-FU release for initiating chemotherapy in the tumor zone. This "all-in-one" LDH/5-FU@MnO2 nanomedicine integrating multiple treatment modalities and magnetic resonance imaging properties, causes persistent modulation of the TME and exhibits effective antitumor theranostic performance. Such a sophisticated nanomedicine design not only achieves improved CT/CDT antitumor efficiency, but also realizes the activatable magnetic resonance imaging. This strategy combines the merits of each treatment, significantly enhancing the anticancer efficacy, and is anticipated to display promising potentials in the clinical translation plans.

Structure Regulation of Block Copolymer Assemblies in Emulsion Droplets by Adding a Selective Solvent.

Generally, nanostructured polymer particles are prepared by 3D confined self-assembly (3D-CSA) of block copolymers (BCPs), while micelles are obtained through self-assembly of BCPs in dilute solutions. Herein, a facile yet robust strategy is developed to regulate the assembled structures of BCP, poly(styrene-block-4-vinylpyridine) (PS-b-P4VP), from nanostructured particles to micelles. The assemblies are prepared by an emulsion-solvent diffusion-induced self-assembly route, which is conducted by dialysis. A key feature of this strategy is that a P4VP-selective solvent (e.g., ethanol) is added to the dialysate to tune the interfacial behavior of the droplets and assembled structures of PS-b-P4VP. The authors' results reveal that in the presence of slight ethanol, the surface and internal structural transitions of nanostructured particles are caused by changes in the interfacial selectivity and packing parameter. Interestingly, interfacial instability, which results in the formation of micelles, is observed when the dialysate contains 50 vol% ethanol or more. The reason can be ascribed to the decreased interface tension, which is induced by the increase in ethanol and enhanced solubility of P4VP. This facile strategy provides a new opportunity to bridge the gap between traditional 3D-CSA and solution self-assembly of BCPs, offering a promising route to engineer morphologies and nanostructures of polymeric assemblies.

Halogen-Bond Mediated 3D Confined Assembly of AB Diblock Copolymer and C Homopolymer Blends.

Halogen-bond driven assembly, a world parallel to hydrogen-bond, has emerged as an attractive tool for constructing (macro)molecular arrangement. However, knowledge about halogen-bond mediated confined-assembly in emulsion droplets is limited so far. An I…. N bond mediated confined-assembly pathway to enable order-order phase transitions is reported here. Compared to hydrogen bonds, the distinct features of halogen bonds (e.g., higher directionality, hydrophobicity, favored in polar solvents), offers opportunities to achieve novel nanostructures and materials. Polystyrene-b-poly(4-vinyl pyridine) (PS-b-P4VP) AB diblock copolymer is chosen as halogen acceptor, while an iodotetrafluorophenoxy substituted C-type homopolymer, (poly(3-(2,3,5,6-tetrafluoro-4-iodophenoxy)propyl acrylate), PTFIPA) is designed as halogen donor, synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Formation of halogen bonding donor-acceptor pairs between the PTFIPA homopolymer and the P4VP segments presented in PS-b-P4VP, increase the volume of P4VP domains, in turn inducing an order-to-order morphology transition sequence: changing from spherical → cylindrical → lamellar → inverse cylindrical, by tuning the PTFIPA content and choice of surfactant. Subsequent selective swelling/deswelling of the P4VP domains give rise to further internal morphology transitions, creating tailored mesoporous microparticles, disassembled nanodiscs, and superaggregates. It is believed that these results will stimulate further examinations of halogen bonding interactions in emulsion droplets and many areas of application.

Tunable Photonic Microspheres of Comb-Like Supramolecules.

Photonic crystals (PCs) are ideal candidates for reflective color pigments with high color purity and brightness due to tunable optical stop band. Herein, the generation of PC microspheres through 3D confined supramolecular assembly of block copolymers (polystyrene-block-poly(2-vinylpyridine), PS-b-P2VP) and small molecules (3-n-pentadecylphenol, PDP) in emulsion droplets is demonstrated. The intrinsic structural colors of the PC microspheres are effectively regulated by tuning hydrogen-bonding interaction between P2VP blocks and PDP, where reflected color can be readily tuned across the whole visible spectrum range. Also, the effects of both PDP and homopolymer (hPS) on periodic structure and optical properties of the microspheres are investigated. Moreover, the spectral results of finite element method (FEM) simulation agree well with the variation of structural colors by tuning the periodicity in PC microspheres. The supramolecular microspheres with tunable intrinsic structural color can be potentially useful in the various practical applications including display, anti-counterfeit printing and painting.

Segmental Janus nanoparticles of polymer composites.

We demonstrate a facile yet robust "plasma etching and grafting" strategy to prepare Janus nanoparticles (NPs) coated with binary polymer brushes on two different sides. The ratio of the two types of polymer ligands can be tailored by tuning the plasma etching power.

Opposing Phase-Segregation and Hydrogen-Bonding Forces in Supramolecular Polymers.

Phase segregation between different macromolecules and specific weak interactions are the basis of molecular organization in many biological systems, which are held together by attractive hydrogen bonds (H-bonds) and dissociated by phase segregation. We report significant changes in the association behavior of covalent H-bonds by the phase of attached polymer chains. Depending on the aggregation state, we observed either intact H-bonds despite segregation of the phases, or macrophase separation with a larger amount of H-bonding dissociation.

Supramolecular semifluorinated dendrons glued by weak hydrogen-bonds.

H-Bonded semifluorinated dendritic polymer networks are generated by association of macromolecules, driven by the weak diaminopyridine (DAP) and thymine (THY) couple. Solvent-dependent morphologies are observed: a continuous film structure when drop-cast from tetrahydrofuran (THF) solution or uniform nanoparticles with a diameter of ∼50 nm in toluene.