Heparan sulfate glycomimetics via iterative assembly of "clickable" disaccharides.

Heparan sulfate (HS) glycosaminoglycans are widely expressed on the mammalian cell surfaces and extracellular matrices and play important roles in a variety of cell functions. Studies on the structure-activity relationships of HS have long been hampered by the challenges in obtaining chemically defined HS structures with unique sulfation patterns. Here, we report a new approach to HS glycomimetics based on iterative assembly of clickable disaccharide building blocks that mimic the disaccharide repeating units of native HS. Variably sulfated clickable disaccharides were facilely assembled into a library of mass spec-sequenceable HS-mimetic oligomers with defined sulfation patterns by solution-phase iterative syntheses. Microarray and surface plasmon resonance (SPR) binding assays corroborated molecular dynamics (MD) simulations and confirmed that these HS-mimetic oligomers bind protein fibroblast growth factor 2 (FGF2) in a sulfation-dependent manner consistent with that of the native HS. This work established a general approach to HS glycomimetics that can potentially serve as alternatives to native HS in both fundamental research and disease models.

Photocatalytic Depolymerization of Native Lignin toward Chemically Recyclable Polymer Networks.

As an inedible component of biomass, lignin features rich functional groups that are desired for chemical syntheses. How to effectively depolymerize lignin without compromising the more valuable cellulose and hemicellulose has been a significant challenge. Existing biomass processing procedures either induce extensive condensation in lignin that greatly hinders its chemical utilization or focus on fully depolymerizing lignin to produce monomers that are difficult to separate for subsequent chemical synthesis. Here, we report a new approach to selective partial depolymerization, which produces oligomers that can be readily converted to chemically recyclable polymer networks. The process takes advantage of the high selectivity of photocatalytic activation of the ß-O-4 bond in lignin by tetrabutylammonium decatungstate (TBADT). The availability of exogenous electron mediators or scavengers promotes cleavage or oxidation of this bond, respectively, enabling high degrees of control over the depolymerization and the density of a key functional group, C=O, in the products. The resulting oligomers can then be readily utilized for the synthesis of polymer networks through reactions between C=O and branched -NH2 as a dynamic covalent cross-linker. Importantly, the resulting polymer network can be recycled to enable a circular economy of materials directly derived from biomass.

Geared Toward Applications: A Perspective on Functional Sequence-Controlled Polymers.

Sequence-controlled polymers are an emerging class of synthetic polymers with a regulated sequence of monomers. In the past decade, tremendous progress has been made in the synthesis of polymers with the sophisticated sequence control approaching the level manifested in biopolymers. In contrast, the exploration of novel functions that can be achieved by controlling synthetic polymer sequences represents an emerging focus in polymer science. This Viewpoint will survey recent advances in the functional applications of sequence-controlled polymers and provide a perspective on the challenges and outlook for pursuing future applications of this fascinating class of macromolecules.

Electrochemically Triggered Chain Reactions for the Conversion of Furan Derivatives.

We report an electrochemical method for coupling biomass-derived C5/C6 compounds to value-added fuel precursors. Using only 2 % of equivalent charges, 2-methylfuran (2-MF) was oxidized to yield a cation radical, which readily reacted with 3-hexene-2,5-dione, a derivate of 2,5-dimethylfuran, to produce 3-(5-methylfuran-2-yl)hexane-2,5-dione. The product was converted to 4-ethylnonane (a component of biodiesel/jet fuel) in a single step in excellent yield. Importantly, the reaction was not sensitive to oxygen, and a trace amount of water was found to promote the reaction. Detailed mechanistic studies confirmed the proposed reaction pathways. Key to the mechanism is the radical generation that is enabled by electrochemistry. The radical is regenerated at the end of a reaction cycle to ensure chain propagation for an average of ca. 47 times, resulting in an apparent Faradaic efficiency of 4700 %.

A General Approach to O-Sulfation by a Sulfur(VI) Fluoride Exchange Reaction.

O-sulfation is an important chemical code widely existing in bioactive molecules, but the scalable and facile synthesis of complex bioactive molecules carrying O-sulfates remains challenging. Reported here is a general approach to O-sulfation by the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl fluorosulfates and silylated hydroxy groups. Efficient sulfate diester formation was achieved through systematic optimization of the electronic properties of aryl fluorosulfates. The versatility of this O-sulfation strategy was demonstrated in the scalable syntheses of a variety of complex molecules carrying sulfate diesters at various positions, including monosaccharides, disaccharides, an amino acid, and a steroid. Selective hydrolytic and hydrogenolytic removal of the aryl masking groups from sulfate diesters yielded the corresponding O-sulfate products in excellent yields. This strategy provides a powerful tool for the synthesis of O-sulfate bioactive compounds.

Layered Structure Causes Bulk NiFe Layered Double Hydroxide Unstable in Alkaline Oxygen Evolution Reaction.

NiFe-based layered double hydroxides (LDHs) are among the most efficient oxygen evolution reaction (OER) catalysts in alkaline medium, but their long-term OER stabilities are questionable. In this work, it is demonstrated that the layered structure makes bulk NiFe LDH intrinsically not stable in OER and the deactivation mechanism of NiFe LDH in OER is further revealed. Both operando electrochemical and structural characterizations show that the interlayer basal plane in bulk NiFe LDH contributes to the OER activity, and the slow diffusion of proton acceptors (e.g., OH- ) within the NiFe LDH interlayers during OER causes dissolution of NiFe LDH and therefore decrease in OER activity with time. To improve diffusion of proton acceptors, it is proposed to delaminate NiFe LDH into atomically thin nanosheets, which is able to effectively improve OER stability of NiFe LDH especially at industrial operating conditions such as elevated operating temperatures (e.g., at 80 °C) and large current densities (e.g., at 500 mA cm-2 ).

Sub-10 nm Theranostic Unimolecular Micelles with High Tumor-Specific Accumulation, Retention, and Inhibitory Effect.

Theranostic agents that integrate far-red/near-infrared fluorescence and anticancer drugs are useful for biomedical applications such as imaging-guided therapy of cancers. However, the clinical translation of previously reported theranostic agents is still limited by factors such as weak fluorescence of the imaging probe, premature and off-target release of fluorophores and drugs during blood circulation, the long-term retention in the reticuloendothelial system, and side effects of toxicity. Here, we report a new type of ultrasmall theranostic unimolecular micelles with an average diameter below 10 nm, and dual functionalities of bright fluorescence in the spectral window of 600-800 nm toward noninvasive in vivo bioimaging and covalently bound anticancer drugs for specific cancer treatment. Each unimolecular micelle is formed by an amphiphilic bottlebrush copolymer containing a fluorescent conjugated backbone of poly(fluorene-alt-(4,7-bis(hexylthien)-2,1,3-benzothiadiazole)), from which hydrophobic disulfide-linked camptothecin as an anticancer drug and hydrophilic oligo(ethylene glycol) are grafted. These ultrasmall unimolecular micelles exhibit remarkably high efficiency of accumulation and retention in tumor tissues with a tumor inhibitory rate of 50%, but little distribution in other healthy organs and tissues. Such a feature of enhanced tumor targeting and reduced toxic side effects against healthy cells and tissues is promising for future clinical translation of imaging-guided cancer therapy.

Facile Synthesis of Sequence-Regulated Synthetic Polymers Using Orthogonal SuFEx and CuAAC Click Reactions.

The orthogonal sulfur-fluoride exchange reaction (SuFEx) and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) are employed to synthesize sequence-regulated synthetic polymers. The high efficiency and broad tolerance of SuFEx and CuAAC to diverse chemical functionalities enable the one-pot synthesis of polydispersed sequence-controlled polymers by step-growth copolymerization in high yield and sequence complexity. Furthermore, iterative SuFEx and CuAAC coupling reactions on a solid support, without the need of protecting groups, afford monodispersed sequence-defined oligomers. The use of this orthogonal pair of click reactions provides new opportunities to facilely access sequence-regulated synthetic polymers with a high degree of structural diversity.

Contrast-enhanced photoacoustic imaging in the second near-infrared window using semiconducting polymer nanoparticles.

Photoacoustic imaging (PAI) is a fast growing deep-tissue imaging modality. However, light scattering and absorption in biological tissues limit imaging depth. Short near-infrared wavelengths (650 to 950 nm) are widely used for PAI. Using longer near-infrared wavelengths reduces scattering. We demonstrate deep-tissue contrast-enhanced in vivo photoacoustic imaging at a wavelength of 1064 nm. An ultranarrow bandgap semiconducting polymer poly (thienoisoindigo-alt-diketopyrrolopyrrole) (denoted as PIGD) is designed and demonstrated for imaging at 1064 nm. By embedding colloidal nanoparticles (NPs) of PIGD in chicken-breast tissue, an imaging depth of ∼5 cm is achieved. Intravenous injection of PIGD NPs in living rats showed brain vascular images with ∼2 times higher contrast compared with the brain vascular images without any contrast agent. Thus, PIGD NPs as an NIR-II contrast agent opens new opportunities for both preclinical and clinical imaging of deep tissues with enhanced contrast.

Improving the carrier stability and drug loading of unimolecular micelle-based nanotherapeutics for acid-activated drug delivery and enhanced antitumor therapy.

Nanomedicines based on unimolecular micelles (UMs) have shown unique advantages such as high micellar stability, programmed cargo delivery and enhanced therapeutic efficiency. Herein, we report an acid-activated amphiphilic prodrug based on a dextran (DEX) polymeric framework (DEX-PDOX-b-POEGMA, labelled DMO@DOX), which conjugates a diblock copolymer of a hydrophobic doxorubicin (DOX) prodrug block and a hydrophilic poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) block by atom transfer radical polymerization. The DMO@DOX prodrug can form nano-sized UMs in aqueous media attributed to its amphiphilic structure and achieve a very high drug loading rate of 80.4 wt%. In the presence of an acidic medium resembling a tumor microenvironment, the hydrazone bond embedded in the prodrug is broken, which releases the loaded drug of DOX. The DMO@DOX prodrug shows a notable and preferential inhibition effect on the growth of tumor cells in vitro compared to healthy cells, leading to advantageous biocompatibility and effective antitumor activity. For verification, the DMO@DOX prodrug was applied in the treatment of a mouse model bearing xenograft tumors and showed a remarkable therapeutic performance. This study demonstrates an effective design of UM-based nanoagents to improve the micellar stability of polymeric prodrug micelles with enhanced performance in cancer therapy.

Theranostic Colloidal Nanoparticles of Pyrrolopyrrole Cyanine Derivatives for Simultaneous Near-Infrared Fluorescence Cancer Imaging and Photothermal Therapy.

Theranostic agents incorporating diagnostic and therapeutic agents together play crucial roles in clinical cancer treatment. On the one hand, near-infrared (NIR) fluorescence imaging strategies are expected to provide high-resolution real-time structural and molecular information with deep penetration to biological tissues in vivo. On the other hand, photothermal therapy (PTT) offers a highly efficient treatment to cancer with negligible safety concerns. To combine the strengths of both NIR fluorescence imaging and PTT for simultaneous cancer imaging and therapy, we report a type of NIR fluorescent nanoparticles (NPs) composed of pyrrolopyrrole cyanines (PPCys) with a strong absorbance in the NIR optical window. These NPs as effective theranostic agents show strong NIR fluorescence and photothermal effect for simultaneous cancer imaging and therapy at both in vitro and in vivo levels. The in vivo imaging and therapy results in nude mice demonstrate the promising potential of these NIR NPs for preclinical and clinical cancer imaging and therapy applications.

Multifunctional polymeric micelles loaded with doxorubicin and poly(dithienyl-diketopyrrolopyrrole) for near-infrared light-controlled chemo-phototherapy of cancer cells.

Polymeric micelles loaded with multiple therapeutic modalities are important to overcome challenges such as drug resistance and improve the therapeutic efficacy. Here we report a new polymer micellar drug carrier that integrates chemotherapy and photothermal therapy in a single platform. Specifically, a narrow bandgap poly(dithienyl-diketopyrrolopyrrole) (PDPP) polymer was encapsulated together with a model anticancer drug doxorubicin (DOX) in the hydrophobic cores of polymeric micelles formed by Pluronic F127, an amphiphilic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer. The PDPP polymer served as an organic photothermal agent that absorbs near-infrared light (700-1000nm) and transforms into heat efficiently. The dual functional micelles co-loaded with PDPP and DOX in the hydrophobic compartment showed good colloidal stability after being stored at 4°C at least over two months, and remained visibly stable after 808-nm laser irradiation. The loaded DOX had negligible effect on the size and photothermal property of the micelles. The release of DOX from the micelles could be enhanced by the "breathing" effect of shrinking/swelling of the micelles induced by the temperature change, owing to the thermosensitive nature of the F127 polymers. Importantly, the ternary F127/PDPP/DOX micelles under 808-nm laser irradiation showed enhanced cytotoxicity against cancer cells such as HeLa cells, compared to F127 micelles containing single modality of either PDPP or DOX only.

Fluorescent Poly(glycerol-co-sebacate) Acrylate Nanoparticles for Stem Cell Labeling and Longitudinal Tracking.

The stable presence of fluorophores within the biocompatible and biodegradable elastomer poly(glycerol-co-sebacate) acrylate (PGSA) is critical for monitoring the transplantation, performance, and degradation of the polymers in vivo. However, current methods such as physically entrapping the fluorophores in the polymer matrix or providing a fluorescent coating suffer from rapid leakage of fluorophores. Covalent conjugation of fluorophores with the polymers and the subsequent core-cross-linking are proposed here to address this challenge. Taking rhodamine as the model dye and PGSA nanoparticles (NPs) as the model platform, we successfully showed that the synthesized rhodamine-conjugated PGSA (PGSAR) NPs only released less than 30% rhodamine at day 28, whereas complete release of dye occurred for rhodamine-encapsulated PGSA (PGSA-p-R) NPs at day 7 and 57.49% rhodamine was released out for the un-cross-linked PGSAR NPs at day 28. More excitingly, PGSAR NPs showed a strong quantum yield enhancement (26.24-fold) of the fluorophores, which was due to the hydrophobic environment within PGSAR NPs and the restricted rotation of (6-diethylamino-3H-xanthen-3-ylidene) diethyl group in rhodamine after the conjugation and core-cross-linking. The stable presence of dye in the NPs and enhanced fluorescence allowed a longitudinal tracking of stem cells both in vitro and in vivo for at least 28 days.

Near-Infrared Light-Responsive Semiconductor Polymer Composite Hydrogels: Spatial/Temporal-Controlled Release via a Photothermal "Sponge" Effect.

Near-infrared (NIR) light-responsive hydrogels are important for biomedical applications, such as remote-controlled release, but the NIR agents previously used were largely limited to heavy-metal inorganic materials such as gold nanoparticles. In this article, we report a new type of NIR photothermal-responsive hydrogel that can undergo structural changes in response to NIR light for biomedical applications in drug delivery and controlled release. The hydrogels synthesized by integrating a narrow-bandgap semiconductor polymer poly(diketopyrrolopyrrole-alt-3,4-ethylenedioxythiophene) with the polymerization of N-isopropylacrylamide show rapid and reversible mechanical shrinkage upon NIR light irradiation and can serve as carriers for anticancer drug loading and spatial/temporal control of drug release. These stimuli-responsive hydrogels, which can be prepared in different sizes and shapes, integrate photothermal properties and hydrogel characteristics and can provide on-demand, repeated, remote-controlled drug delivery for biomedical applications such as cancer treatment.

Unimolecular micelles of pH-responsive star-like copolymers for co-delivery of anticancer drugs and small-molecular photothermal agents: a new drug-carrier for combinational chemo/photothermal cancer therapy.

Development of stimuli-responsive drug carriers that can efficiently retain the encapsulated drug during blood circulation and selectively release the drug in disease targets under internal and/or external stimulation is important to minimize the side effects and improve the drug efficacy. Herein, we report a nanoscale polymeric carrier based on robust and pH-responsive unimolecular micelles that are able to carry multiple functional agents such as anticancer drugs and photothermal agents for improved treatment of cancer cells through combinational chemo/photothermal therapy. Specifically, we synthesized three pH-responsive amphiphilic star-like copolymers (denoted as CPDOs), which were facilely synthesized via one-step atom transfer radical polymerization (ATRP) with pH-responsive 2-(diisopropylamino) ethyl methacrylate and hydrophilic poly[(oligo ethylene glycol)methyl ether methacrylate] as co-monomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl)-ß-cyclodextrin] as the initiator. Then the anticancer drug doxorubicin (DOX) and a narrow-bandgap molecule benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene (denoted as BBT-2FT) as a near-infrared photothermal agent were co-encapsulated into the CPDO polymers, resulting in stable unimolecular micelles in aqueous media. The tertiary unimolecular micelles loaded with DOX and BBT-2FT showed controllable drug release kinetics and enhanced therapeutic effect against cancer cells under co-stimulation of pH change and 808 nm laser irradiation.

Robust Colloidal Nanoparticles of Pyrrolopyrrole Cyanine J-Aggregates with Bright Near-Infrared Fluorescence in Aqueous Media: From Spectral Tailoring to Bioimaging Applications.

Colloidal nanoparticles (NPs) containing near-infrared-fluorescent J-aggregates (JAGGs) of pyrrolopyrrole cyanines (PPcys) stabilized by amphiphilic block co-polymers were prepared in aqueous medium. JAGG formation can be tuned by means of the chemical structure of PPcys, the concentration of chromophores inside the polymeric NPs, and ultrasonication. The JAGG NPs exhibit a narrow emission band at 773 nm, a fluorescence quantum yield comparable to that of indocyanine green, and significantly enhanced photostability, which is ideal for long-term bioimaging.

Unimolecular Micelles of Amphiphilic Cyclodextrin-Core Star-Like Copolymers with Covalent pH-Responsive Linkage of Anticancer Prodrugs.

Multifunctional stable and stimuli-responsive drug delivery systems are important for efficient cancer treatment due to their advantages such as enhanced cancer-targeting efficiency, improved pharmacokinetics, minimized drug leaching, and reduced undesirable side effects. Here we report a robust and pH-responsive anticancer drug delivery system based on unimolecular micelles of star-like amphiphilic copolymers. The polymers (denoted as CPOFs) were facilely synthesized via one-step atom transfer radical polymerization of functionalizable benzoaldehyde and hydrophilic poly[(oligo ethylene glycol) methyl ether methacrylate] as comonomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl]-ß-cyclodextrin as the initiator. Doxorubicin (DOX) as an anticancer drug was covalently linked to the benzoaldehyde groups of CPOFs through pH-sensitive Schiff-base bonds. The DOX-conjugated polymers, denoted as CPOF-DOX, formed robust unimolecular micelles with an average diameter of 18 nm in aqueous media. More importantly, these unimolecular micelles showed higher drug loading capacity and more controllable drug release characteristics, compared to our previous unimolecular micelles of ß-cyclodextrin-poly(lactic acid)-b-poly[(oligo ethylene glycol) methyl ether methacrylates] that physically encapsulated DOX via hydrophobic interaction. Moreover, the CPOF-DOX unimolecular micelles could be internalized by human cervical cancer HeLa cells in a stepwise way and showed less cytotoxicity compared to carrier-free DOX. We foresee that CPOF-DOX would provide a promising robust and controllable anticancer drug delivery system for future animal study and clinical trials for cancer treatment.

Hydrophobic-Sheath Segregated Macromolecular Fluorophores: Colloidal Nanoparticles of Polycaprolactone-Grafted Conjugated Polymers with Bright Far-Red/Near-Infrared Emission for Biological Imaging.

This article describes molecular design, synthesis and characterization of colloidal nanoparticles containing polycaprolactone-grafted conjugated polymers that exhibit strong far red/near-infrared (FR/NIR) fluorescence for bioimaging. Specifically, we synthesized two kinds of conjugated polymer bottle brushes (PFTB(out)-g-PCL and PFTB(in)-g-PCL) with different positions of the hexyl groups on the thiophene rings. A synthetic amphiphilic block copolymer PCL-b-POEGMA was employed as surfactants to encapsulate PFTB-g-PCL polymers into colloidal nanoparticles (denoted as "nanoREDs") in aqueous media. The chain length of the PCL side chains in PFTB-g-PCL played a critical role in determining the fluorescence properties in both bulk solid states and the colloidal nanoparticles. Compared to semiconducting polymer dots (Pdots) composed of PFTB(out) without grafted PCL, nanoRED(out) showed at least four times higher fluorescence quantum yield (∼20%) and a broader emission band centered at 635 nm. We further demonstrated the application of this new class of nanoREDs for effective labeling of L929 cells and HeLa cancer cells with good biocompatibility. This strategy of hydrophobic-sheath segregated macromolecular fluorophores is expected to be applicable to a broad range of conjugated polymers with tunable optical properties for applications such as bioimaging.