Development of Platinum Complexes for Tumor Chemoimmunotherapy

Chemistry - A European Journal, Год журнала: 2024, Номер 30(10)

Опубликована: Янв. 3, 2024

Abstract Platinum complexes are potential antitumor drugs in chemotherapy. Their impact on tumor treatment could be greatly strengthened by combining with immunotherapy. Increasing evidences indicate that the activity of platinum is not limited to chemical killing effects, but also extends immunomodulatory actions. This review introduced general concept chemoimmunotherapy and summarized progress as chemoimmunotherapeutic agents recent years. developed into inducers immunogenic cell death, blockers immune checkpoint, regulators signaling pathway, modulators microenvironment, etc. The synergy between chemotherapeutic effects reinforces complexes, helps them circumvent drug resistance systemic toxicity. exploration for may create new opportunities revive discovery metal anticancer drugs.

Язык: Английский

---

Disruption of Zinc Homeostasis by a Novel Platinum(IV)‐Terthiophene Complex for Antitumor Immunity

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(8)

Опубликована: Дек. 22, 2022

Zinc homeostatic medicine is of great potential for cancer chemo-immunotherapy; however, there are few reports on antitumor compounds that can trigger Zn2+ -mediated immune responses. In this work, we developed a novel cyclometalated PtIV -terthiophene complex, Pt3, not only induces DNA damage and cellular metabolism dysregulation, but also disrupts zinc homeostasis as indicated by the abnormal transcriptional level regulatory proteins, excess accumulation in cytoplasm, down-regulation metallothioneins (MTs), which further caused redox imbalance. The simultaneous disruption response to Pt3 treatment activated gasdermin-D mediated pyroptosis accompanied cytoskeleton remodeling, thus releasing pro-inflammatory cytokines promote dendritic cell (DC) maturation T tumor-infiltration, eventually eliminating both primary distant tumors vivo. As far know, first metal complex regulate activate immunity.

Язык: Английский

---

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

Advanced Healthcare Materials, Год журнала: 2023, Номер 12(19)

Опубликована: Март 11, 2023

Abstract As the first line of host defense against pathogenic infections, innate immunity plays a key role in antitumor immunotherapy. The cyclic GMP‐AMP synthase (cGAS)‐stimulator interferon genes (STING) (cGAS‐STING) pathway has attracted much attention because secretion various proinflammatory cytokines and chemokines. Many STING agonists have been identified applied into preclinical or clinical trials for cancer However, fast excretion, low bioavailability, nonspecificity, adverse effects small molecule limit their therapeutic efficacy vivo application. Nanodelivery systems with appropriate size, charge, surface modification are capable addressing these dilemmas. In this review, mechanism cGAS‐STING is discussed agonists, focusing on nanoparticle‐mediated therapy combined cancers, summarized. Finally, future direction challenges nano‐STING expounded, emphasizing pivotal scientific problems technical bottlenecks hoping to provide general guidance its

Язык: Английский

---

Virus‐Like Particle‐Induced cGAS‐STING Activation and AIM2 Inflammasome‐Mediated Pyroptosis for Robust Cancer Immunotherapy

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(24)

Опубликована: Апрель 11, 2023

Abstract cGAS‐STING‐mediated DNA sensing is demonstrated to be critical for launching antitumor immunity. However, DNA‐based cGAS‐STING agonists are rarely reported owing low cell permeability, poor biostability and, especially, limited length of exogenous DNA. Here, we present a virus‐like particle which self‐assembled from long building blocks generated through rolling‐circle amplification (RCA) and covered with cationic liposomes. Based on densely packed structure, it could efficiently induce liquid phase condensation cGAS activate STING signaling produce inflammatory cytokines. Moreover, this also trigger the formation AIM2 inflammasome gasdermin D‐mediated pyroptosis, boosting Thus, study provides simple robust strategy cancer immunotherapy clinical application. This first report intrinsic immunogenicity RCA products, thus facilitating their biomedical applications.

Язык: Английский

---

Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer

National Science Review, Год журнала: 2023, Номер 11(1)

Опубликована: Дек. 18, 2023

ABSTRACT Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes (STING) agonists are promising cancer therapeutic regimens because they can amplify STING activation remodel the immunosuppressive tumor microenvironment. However, a single molecular entity comprising both has not yet been developed. Herein, we designed two PtIV-MSA-2 conjugates (I II) containing chemotherapeutic drug cisplatin innate immune-activating agonist MSA-2; these showed great potential as multispecific small-molecule drugs against pancreatic cancer. Mechanistic studies revealed conjugate I upregulated expression transcripts associated with immunity metabolism in cells, significantly differing from MSA-2. An analysis microenvironment demonstrated could enhance infiltration natural killer (NK) cells into tumors promote T NK dendritic tissues. These findings indicated I, which was created by incorporating Pt one molecule, is potent anticancer candidate, opening new avenues for small-molecule-based metalloimmunotherapy.

Язык: Английский

---

cGAS‐STING signaling in cell death: Mechanisms of action and implications in pathologies

European Journal of Immunology, Год журнала: 2023, Номер 53(9)

Опубликована: Июль 9, 2023

Cyclic GMP-AMP synthase (cGAS) monitors dsDNA in the cytosol response to pathogenic invasion or tissue injury, initiating cGAS-STING signaling cascades that regulate various cellular physiologies, including IFN /cytokine production, autophagy, protein synthesis, metabolism, senescence, and distinct types of cell death. is crucial for host defense homeostasis; however, its dysfunction frequently leads infectious, autoimmune, inflammatory, degenerative, cancerous diseases. Our knowledge regarding relationships between death rapidly evolving, highlighting their essential roles pathogenesis disease progression. Nevertheless, direct control by signaling, rather than IFN/NF-κB-mediated transcriptional regulation, remains relatively unexplored. This review examines mechanistic interplays apoptosis, necroptosis, pyroptosis, ferroptosis, autophagic/lysosomal We will also discuss pathological implications human diseases, particularly autoimmunity, cancer, organ injury scenarios. hope this summary stimulate discussion further exploration complex life-or-death responses damage mediated signaling.

Язык: Английский

---

Organic‐Platinum Hybrids for Covalent Binding of G‐Quadruplexes: Structural Basis and Application to Cancer Immunotherapy

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(36)

Опубликована: Июль 19, 2023

G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but G4-mediated immune response remains unclear. We designed a novel class G4-binding organic-platinum hybrids, L1 -cispt and -transpt, spatial matching for G4 binding DNA reactivity site locking. The solution structure -transpt-MYT1L demonstrated effectiveness covalent revealed binding-guided dynamic balance, accompanied by destruction A5-T17 base pairs to achieve platinum unit N7 G6 residue. Furthermore, -cispt- -transpt-mediated genomic dysfunction could activate retinoic acid-induced gene I (RIG-I) pathway induce immunogenic cell death (ICD). use -cispt/L1 -transpt-treated dying cells vaccines stimulated robust effectively inhibited tumor growth in vivo. Our findings highlight importance rational combination specific recognition locking G4-trageting drug design their potential immunotherapy.

Язык: Английский

---

Cell Death Pathway Regulation by Functional Nanomedicines for Robust Antitumor Immunity

Advanced Science, Год журнала: 2023, Номер 11(3)

Опубликована: Ноя. 20, 2023

Abstract Cancer immunotherapy has become a mainstream cancer treatment over traditional therapeutic modes. cells can undergo programmed cell death including ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis which are find to have intrinsic relationships with host antitumor immune response. However, direct use of inducers or regulators may bring about severe side effects that also be rapidly excreted degraded low efficacy. Nanomaterials able carry them for long circulation time, high tumor accumulation controlled release achieve satisfactory effect. Nowadays, large number studies focused on nanomedicines‐based strategies through modulating modalities potentiate immunity. Herein, types their function first summarized, state‐of‐the‐art research progresses in nanomedicines mediated pathways (e.g., cuproptosis) response provocation highlighted. Subsequently, the conclusion outlook potential focus discussed.

Язык: Английский

---

Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(18), С. 13072 - 13085

Опубликована: Сен. 13, 2023

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth metastasis, we not only optimized a series ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain Ru(III) complex (4b) remarkable cytotoxicity in vitro but also constructed 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The vivo results showed that 4b-DCT-Lip had stronger capacity inhibit metastasis than 4b-DCT addressed the co-delivery problems improved their ability. Furthermore, confirmed mechanism 4b-DCT/4b-DCT-Lip inhibiting tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 afford GSDME-N terminal then aggregated form nonselective pores on cell membrane tumor, thereby inducing pyroptosis pyroptosis-induced immune response.

Язык: Английский

---

Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(4), С. 1742 - 1758

Опубликована: Дек. 16, 2023

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to activation cellular oxidative stress and immune responses. While role in promoting inflammation hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which composed oxaliplatin (Oxa) acetaminophen (APAP), enhance anti-tumor amplify response. Our findings demonstrate that OAP2 induces nuclear damage, resulting production DNA. Additionally, downregulates expression Sam50, promote mtDNA secretion, double-stranded accumulation ultimately synergistically activating intracellular cGAS-STING pathway. The induced by overcomes limitations Oxa STING pathway simultaneously promotes gasdermin-D-mediated cell pyroptosis. also dendritic maturation enhances quantity efficacy cytotoxic T cells, thereby inhibiting cancer proliferation metastasis. Briefly, our study introduces first small-molecule inhibitor regulates for active immunotherapy research, may provide creative idea targeting organelle therapy.

Язык: Английский

---