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Preclinical studies have shown that immunostimulatory cytokines elicit antitumor immune responses but their clinical use is limited by severe immune-related adverse events upon systemic administration. Here, we report a facile and versatile strategy for noncovalently anchoring potent Fc-fused cytokine molecules to the surface of size-discrete particles decorated with Fc-binding peptide for local administration. Following intratumoral injection, particle-anchored Fc cytokines exhibit size-dependent intratumoral retention. The 1-micrometer particle prolongs intratumoral retention of Fc cytokine for over a week and has minimal systemic exposure, thereby eliciting antitumor immunity while eliminating systemic toxicity caused by circulating cytokines. In addition, the combination of these particle-anchored cytokines with immune checkpoint blockade antibodies safely promotes tumor regression in various syngeneic tumor models and genetically engineered murine tumor models and elicits systemic antitumor immunity against tumor rechallenge. Our formulation strategy renders a safe and tumor-agnostic approach that uncouples cytokines' immunostimulatory properties from their systemic toxicities for potential clinical application.
Assuntos
Citocinas , Neoplasias , Camundongos , Animais , Imunoterapia , Neoplasias/tratamento farmacológico , Anticorpos , Linhagem Celular TumoralRESUMO
Precisely controlling macromolecular stereochemistry and sequences is a powerful strategy for manipulating polymer properties. Controlled synthetic routes to prepare degradable polyester, polycarbonate, and polyether are of recent interest due to the need for sustainable materials as alternatives to petrochemical-based polyolefins. Enantioselective ring-opening polymerization and ring-opening copolymerization of racemic monomers offer access to stereoregular polymers, specifically enantiopure polymers that form stereocomplexes with improved physicochemical and mechanical properties. Here, we highlight the state-of-the-art of this polymerization chemistry that can produce microstructure-defined polymers. In particular, the structures and performances of various homogeneous enantioselective catalysts are presented. Trends and future challenges of such chemistry are discussed.
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Stereoselective ring-opening polymerization catalysts are used to produce degradable stereoregular poly(lactic acids) with thermal and mechanical properties that are superior to those of atactic polymers. However, the process of discovering highly stereoselective catalysts is still largely empirical. We aim to develop an integrated computational and experimental framework for efficient, predictive catalyst selection and optimization. As a proof of principle, we have developed a Bayesian optimization workflow on a subset of literature results for stereoselective lactide ring-opening polymerization, and using the algorithm, we identify multiple new Al complexes that catalyze either isoselective or heteroselective polymerization. In addition, feature attribution analysis uncovers mechanistically meaningful ligand descriptors, such as percent buried volume (%Vbur) and the highest occupied molecular orbital energy (EHOMO), that can access quantitative and predictive models for catalyst development.
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Transforming renewable resources into functional and degradable polymers is driven by the ever-increasing demand to replace unsustainable polyolefins. However, the utility of many degradable homopolymers remains limited due to their inferior properties compared to commodity polyolefins. Therefore, the synthesis of sequence-defined copolymers from one-pot monomer mixtures is not only conceptually appealing in chemistry, but also economically attractive by maximizing materials usage and improving polymers' performances. Among many polymerization strategies, ring-opening (co)polymerization of cyclic monomers enables efficient access to degradable polymers with high control on molecular weights and molecular weight distributions. Herein, we highlight recent advances in achieving one-pot, sequence-controlled polymerizations of cyclic monomer mixtures using a single catalytic system that combines multiple catalytic cycles. The scopes of cyclic monomers, catalysts, and polymerization mechanisms are presented for this type of sequence-controlled ring-opening copolymerization.
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A polymer actuator typically responds to only one or two types of stimuli, where sensing and actuation are simultaneously exerted by the same responsive polymer. In cells, sensing and actuation are exerted separately by different biomolecules, which are integrated into nanoscale assemblies to construct the signaling network, making cells a multistimuli responsive and multimodal system. Inspired by the structure-function relationship of the signaling network in cells, we have developed a strategy to select and assemble proper functional polymers into assemblies, where sensing and actuation are exerted by different polymers, and the assemblies can present novel functions beyond that of each polymer component. Three polymers [polyaniline, PANi; poly(N-isopropylacrylamide), PNIPAm; and polydimethylsiloxane, PDMS] are integrated as nodes into a simple energy transduction network, which can be regulated by three molecular factors (pH, kosmotropic anions, and polyethylene glycol). PANi converts the light or electric stimulus into heat, which triggers the actuation of PNIPAm and PDMS. Relying on this energy transduction network, the polymer assembly can respond to six types of stimuli (light, electricity, temperature, water, ions, and organic solvents) and perform different actuation modes, serving as a powerful actuator. Programmable complex deformation upon multiple simultaneous or sequential stimuli has also been achieved by this actuator. An adaptive gripper to catch thin objects and a self-regulating switch to maintain environmental humidity illustrate the wide potential of this actuator for next-generation smart materials and soft robots.
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Multi-stimuli responsive fluorescence probe could pave the way for monitoring more complex environmental changes. Here we prepared multifunctional nanoparticle Fe3O4@SiO2@P(DMAEMA-co-TPEE), which displayed yolk-shell morphology with well-defined polymer brush. With superparamagnetic Fe3O4 component and pH/temperature dual sensitive PDMAEMA polymer brush, the as prepared nanoparticles (YS-NPs) exhibited as multi-stimuli responsive fluorescence probe for real-time visual monitoring of environmental changes such as magnetic field, temperature and pH. Such YS-NPs could also be applied as a sensitive detector for CO2 in aqueous solution. Notably, the solution of YS-NPs showed high colloidal stability during the environmental changes, and surface aggregation-induced emission (S-AIE) was proposed for the aggregation of TPE residue on the surface of YS-NPs.