Toughening and Imparting Deconstructability to 3D-Printed Glassy Thermosets with "Transferinker" Additives.

Thermoset toughness and deconstructability are often opposing features; simultaneously improving both without sacrificing other mechanical properties (e.g., stiffness and tensile strength) is difficult, but, if achieved, could enhance the usage lifetime and end-of-life options for these materials. Here, a strategy that addresses this challenge in the context of photopolymer resins commonly used for 3D printing of glassy, acrylic thermosets is introduced. It is shown that incorporating bis-acrylate "transferinkers," which are cross-linkers capable of undergoing degenerative chain transfer and new strand growth, as additives (5-25 mol%) into homemade or commercially available photopolymer resins leads to photopolymer thermosets with substantially improved tensile toughness and triggered chemical deconstructability with minimal impacts on Young's moduli, tensile strengths, and glass transition temperatures. These properties result from a transferinker-driven topological transition in network structure from the densely cross-linked long, heterogeneous primary strands of traditional photopolymer networks to more uniform, star-like networks with few dangling ends; the latter structure more effectively bear stress yet is also more easily depercolated via solvolysis. Thus, transferinkers represent a simple and effective strategy for improving the mechanical properties of photopolymer thermosets and providing a mechanism for their triggered deconstructability.

Remolding and Deconstruction of Industrial Thermosets via Carboxylic Acid-Catalyzed Bifunctional Silyl Ether Exchange.

Convenient strategies for the deconstruction and reprocessing of thermosets could improve the circularity of these materials, but most approaches developed to date do not involve established, high-performance engineering materials. Here, we show that bifunctional silyl ether, i.e., R'O-SiR2-OR'', (BSE)-based comonomers generate covalent adaptable network analogues of the industrial thermoset polydicyclopentadiene (pDCPD) through a novel BSE exchange process facilitated by the low-cost food-safe catalyst octanoic acid. Experimental studies and density functional theory calculations suggest an exchange mechanism involving silyl ester intermediates with formation rates that strongly depend on the Si-R2 substituents. As a result, pDCPD thermosets manufactured with BSE comonomers display temperature- and time-dependent stress relaxation as a function of their substituents. Moreover, bulk remolding of pDCPD thermosets is enabled for the first time. Altogether, this work presents a new approach toward the installation of exchangeable bonds into commercial thermosets and establishes acid-catalyzed BSE exchange as a versatile addition to the toolbox of dynamic covalent chemistry.

Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma.

Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma.

Clip Chemistry: Diverse (Bio)(macro)molecular and Material Function through Breaking Covalent Bonds.

In the two decades since the introduction of the "click chemistry" concept, the toolbox of "click reactions" has continually expanded, enabling chemists, materials scientists, and biologists to rapidly and selectively build complexity for their applications of interest. Similarly, selective and efficient covalent bond breaking reactions have provided and will continue to provide transformative advances. Here, we review key examples and applications of efficient, selective covalent bond cleavage reactions, which we refer to herein as "clip reactions." The strategic application of clip reactions offers opportunities to tailor the compositions and structures of complex (bio)(macro)molecular systems with exquisite control. Working in concert, click chemistry and clip chemistry offer scientists and engineers powerful methods to address next-generation challenges across the chemical sciences.

Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities.

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.

Publisher Correction: Cleavable comonomers enable degradable, recyclable thermoset plastics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cleavable comonomers enable degradable, recyclable thermoset plastics.

Thermosets-polymeric materials that adopt a permanent shape upon curing-have a key role in the modern plastics and rubber industries, comprising about 20 per cent of polymeric materials manufactured today, with a worldwide annual production of about 65 million tons1,2. The high density of crosslinks that gives thermosets their useful properties (for example, chemical and thermal resistance and tensile strength) comes at the expense of degradability and recyclability. Here, using the industrial thermoset polydicyclopentadiene as a model system, we show that when a small number of cleavable bonds are selectively installed within the strands of thermosets using a comonomer additive in otherwise traditional curing workflows, the resulting materials can display the same mechanical properties as the native material, but they can undergo triggered, mild degradation to yield soluble, recyclable products of controlled size and functionality. By contrast, installation of cleavable crosslinks, even at much higher loadings, does not produce degradable materials. These findings reveal that optimization of the cleavable bond location can be used as a design principle to achieve controlled thermoset degradation. Moreover, we introduce a class of recyclable thermosets poised for rapid deployment.

Phenolic Building Blocks for the Assembly of Functional Materials.

Phenolic materials have long been known for their use in inks, wood coatings, and leather tanning. However, there has recently been a renewed interest in engineering advanced materials from phenolic building blocks. The intrinsic properties of phenolic compounds, such as metal chelation, hydrogen bonding, pH responsiveness, redox potentials, radical scavenging, polymerization, and light absorbance, have made them a distinct class of structural motifs for the synthesis of functional materials. Materials prepared from phenolic compounds often retain many of these useful properties with synergistic effects in applications ranging from catalysis to biomedicine. This Review provides an overview of the diverse functional materials that can be prepared from natural and synthetic phenolic building blocks, as well as their applications.

Monomer design strategies to create natural product-based polymer materials.

Covering: 2010-Aug. 2016In an effort towards enhancing function and sustainability, natural products have become of interest in the field of polymer chemistry. This review details the blending of chemistries developed through synthetic organic chemistry and polymer chemistry. Through synthetic organic chemical transformations, such as functional group interconversion, a protection/deprotection series, or installation of a functional group, various designs towards novel, synthetic, bio-based polymer systems are described. This review covers several classifications of natural products - oils and fatty acids, terpenes, lignin, and sugar derivatives - focusing on exploring monomers prepared by one or more synthetic steps.

Synthesis, Characterization, and Cross-Linking Strategy of a Quercetin-Based Epoxidized Monomer as a Naturally-Derived Replacement for BPA in Epoxy Resins.

The natural polyphenolic compound quercetin was functionalized and cross-linked to afford a robust epoxy network. Quercetin was selectively methylated and functionalized with glycidyl ether moieties using a microwave-assisted reaction on a gram scale to afford the desired monomer (Q). This quercetin-derived monomer was treated with nadic methyl anhydride (NMA) to obtain a cross-linked network (Q-NMA). The thermal and mechanical properties of this naturally derived network were compared to those of a conventional diglycidyl ether bisphenol A-derived counterpart (DGEBA-NMA). Q-NMA had similar thermal properties [i.e., glass transition (Tg ) and decomposition (Td ) temperatures] and comparable mechanical properties (i.e., Young's Modulus, storage modulus) to that of DGEBA-NMA. However, it had a lower tensile strength and higher flexural modulus at elevated temperatures. The application of naturally derived, sustainable compounds for the replacement of commercially available petrochemical-based epoxies is of great interest to reduce the environmental impact of these materials. Q-NMA is an attractive candidate for the replacement of bisphenol A-based epoxies in various specialty engineering applications.