An official website of the United States government
Abstract Aggressive cancers, characterized by high metastatic potential and resistance to conventional therapies, present a significant challenge in oncology. Current treatments often fail to effectively target metastasis, recurrence, and the immunosuppressive tumor microenvironment, while causing significant off‐target toxicity. Here, superparamagnetic copper iron oxide nanoparticles (SCIONs) as a multifunctional platform that integrates magnetic hyperthermia therapy, immune modulation, and targeted chemotherapeutic delivery, aiming to provide a more comprehensive cancer treatment is presented. Specifically, SCIONs generate localized hyperthermia under an alternating magnetic field while delivering a copper‐based anticancer agent, resulting in a synergistic anticancer effect. The hyperthermia induced by SCIONs caused ER stress and ROS production, leading to significant tumor cell death, while the copper complex further enhanced oxidative stress, ferroptosis, and apoptosis. Beyond direct cytotoxicity, SCIONs disrupted the tumor microenvironment by inhibiting cancer‐associated fibroblasts, downregulating epithelial‐mesenchymal transition markers, and reducing cell migration and invasion, thereby limiting metastasis. Additionally, SCION‐based therapy reprogrammed the immune microenvironment by inducing immunogenic cell death and enhancing dendritic cell activation, resulting in increased CD8+ T cell infiltration and amplified antitumor immunity. This integrated approach targets primary and metastatic tumors while mitigating immunosuppression, offering a promising next‐generation therapy for combating cancer with enhanced efficacy and reduced side effects.
more »
« less
Copper Nanodrugs by Atom Transfer Radical Polymerization
Abstract In this study, some copper catalysts used for atom transfer radical polymerization (ATRP) were explored as efficient anti‐tumor agents. The aqueous solution of copper‐containing nanoparticles with uniform spheric morphology was in situ prepared through a copper‐catalyzed activator generated by electron transfer (AGET) ATRP in water. Nanoparticles were then directly injected into tumor‐bearing mice for antitumor chemotherapy. The copper nanodrugs had prolonged blood circulation time and enhanced accumulation at tumor sites, thus showing potent antitumor activity. This work provides a novel strategy for precise and large‐scale preparation of copper nanodrugs with high antitumor activity.
more »
« less
- Award ID(s):
- 2202747
- PAR ID:
- 10577595
- Publisher / Repository:
- Wiley VCH
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 63
- Issue:
- 20
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Atom Transfer Radical Polymerization: Billion Times More Active Catalysts and New Initiation SystemsAbstract Approaching 25 years since its invention, atom transfer radical polymerization (ATRP) is established as a powerful technique to prepare precisely defined polymeric materials. This perspective focuses on the relation between structure and activity of ATRP catalysts, and the consequent choice of the initiating system, which are paramount aspects to well‐controlled polymerizations. The ATRP mechanism is discussed, including the effect of kinetic and thermodynamic parameters and side reactions affecting the catalyst. The coordination chemistry and activity of copper complexes used in ATRP are reviewed in chronological order, while emphasizing the structure–activity correlation. ATRP‐initiating systems are described, from normal ATRP to low ppm Cu systems. Most recent advancements regarding dispersed media and oxygen‐tolerant techniques are presented, as well as future opportunities that arise from progressively more active catalysts and deeper mechanistic understanding.more » « less
-
Abstract Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.more » « less
-
The 3d transition metal (Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II)) complexes, supported by anions of sterically demanding β-diketones, 1,3-dimesitylpropane-1,3-dione (HLMes) and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HLCF3), were synthesized and evaluated for their antitumor activity. To assess the biological effects of substituents on phenyl moieties, we also synthesized and investigated the analogous metal(II) complexes of the anion of the less bulky 1,3-diphenylpropane-1,3-dione (HLPh) ligand. The compounds [Cu(LCF3)2], [Cu(LMes)2] and ([Zn(LMes)2]) were characterized by X-ray crystallography. The [Cu(LCF3)2] crystallizes with an apical molecule of solvent (THF) and features a rare square pyramidal geometry at the Cu(II) center. The copper(II) and zinc(II) complexes of diketonate ligands, derived from the deprotonated 1,3-dimesitylpropane-1,3-dione (HLMes), adopt a square planar or a tetrahedral geometry at the metal, respectively. We evaluated the antitumor properties of the newly synthesized (Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II)) complexes against a series of human tumor cell lines derived from different solid tumors. Except for iron derivatives, cellular studies revealed noteworthy antitumor properties, even towards cancer cells endowed with poor sensitivity to the reference drug cisplatin.more » « less
-
Abstract Abnormal cancer metabolism causes hypoxic and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal–organic layer (MOL) with anchored 3‐bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production. This metabolic reprogramming enhanced reactive oxygen species generation during PDT and reshaped the immunosuppressive TME to enhance antitumor immunity. BrP@MOL‐mediated PDT inhibited tumor growth by >90 % with 40 % of mice being tumor‐free, rejected tumor re‐challenge, and prevented lung metastasis. Further combination with immune checkpoint blockade potently regressed the tumors with >98 % tumor inhibition and 80 % of mice being tumor‐free.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1002/anie.202402747
