Cancer Cell Membrane-Coated Nanoparticle Co-loaded with Photosensitizer and Toll-like Receptor 7 Agonist for the Enhancement of Combined Tumor Immunotherapy

ACS Nano, Journal Year: 2023, Volume and Issue: 17(17), P. 16620 - 16632

Published: Aug. 22, 2023

Tumor immunotherapy has shown considerable therapeutic potential in the past few years, but clinical response rate of is less than 20%. Encountering high heterogeneity tumors, it will be a general trend to apply combined therapy for cancer treatment. Photodynamic (PDT) transiently kills tumor cells by producing reactive oxygen species (ROS), while residual are prone metastasis, leading recurrence. In combination with immunotherapy, hoped awaken host immune system and eradicate cells. Herein, cell membrane-coated nanoparticles as platform combine PDT, TLR7 agonist, antigen enhancement efficacy designed. The final biomimetic (CCMV/LTNPs) can specifically kill through strong antitumor responses elicited eliminate residue under help adjuvant from membrane. summary, photoimmunotherapy strategy designed that synergistically enhances effects killing PDT activating co-delivery antigen, which may offer promising future.

Language: Английский

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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(2), P. 533 - 578

Published: Sept. 12, 2023

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over past few decades, significant progress has been made development targeted epigenetic modulators (e.g., inhibitors). However, inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack subtype selectivity, drug resistance. As result, design new degraders) such as PROTACs, molecular glue, hydrophobic tagging (HyT) degraders garnered attention from both academia pharmaceutical industry, numerous discovered decade. In this review, we aim to provide an in-depth illustration degrading strategies (2017–2023) targeting proteins for cancer therapy, focusing on rational design, pharmacodynamics, pharmacokinetics, status, crystal structure information these degraders. Importantly, also deep insights into potential challenges corresponding remedies approach development. Overall, hope review will offer better mechanistic understanding serve useful guide emerging epigenetic-targeting

Language: Английский

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Small-molecule agents for cancer immunotherapy

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(3), P. 905 - 952

Published: Dec. 16, 2023

Cancer immunotherapy, exemplified by the remarkable clinical benefits of immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression overall survival benefit in many types cancer. With advances our knowledge about microenvironment, progress has been made development small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, checkpoints, oncogenic signaling, metabolic cytokine/chemokine immune-related kinases have extensively investigated. Monotherapy immunotherapeutic their combinations with other antitumor modalities are under active investigations to overcome tolerance circumvent inhibitor resistance. Here, we review latest agents immunotherapy defined pathways highlighting recent investigations.

Language: Английский

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Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

Cancers, Journal Year: 2023, Volume and Issue: 15(7), P. 2186 - 2186

Published: April 6, 2023

Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 Chikungunya virus, which exploits large extracellular loop EC2 cell entry. also an anticancer target implicated cancer proliferation mobility, tumor metastasis. signaling contributes to development solid tumors (notably colorectal, liver gastric cancers) has been aggressivity B-cell lymphomas. A variety partners can interact with CD81, either regulate attachment uptake viruses (HCV E2, claudin-1, IFIM1) or contribute growth dissemination (CD19, CD44, EWI-2). CD81-protein be modulated molecules targeting domain investigated as antiviral and/or agents. Several monoclonal antibodies anti-CD81 have developed, notably mAb 5A6 active against invasion metastasis triple-negative breast cells. CD81-EC2 targeted natural products (trachelogenin harzianoic acids A-B) synthetic compounds (such benzothiazole-quinoline derivatives). They are weak binders but offer templates design new open loop. There no compound clinical at present, this structurally well-characterized tetraspanin warrants more substantial considerations drug target.

Language: Английский

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Macrophages and microglia in inflammation and neuroinflammation underlying different pain states

Medical Review, Journal Year: 2023, Volume and Issue: 3(5), P. 381 - 407

Published: Oct. 1, 2023

Pain is a main symptom in inflammation, and inflammation induces pain via inflammatory mediators acting on nociceptive neurons. Macrophages microglia are distinct cell types, representing immune cells glial cells, respectively, but they share similar roles regulation. key regulators of pain. Macrophage polarization plays different inducing resolving Notably, macrophage phagocytosis can be induced by specialized pro-resolution (SPMs). SPMs also potently inhibit neuropathic immunomodulation neuromodulation. In this review, we discuss signaling involved induction resolution, as well maintaining physiological Microglia macrophage-like the central nervous system (CNS) drive neuroinflammation pathological various neurological disorders. Microglia-produced cytokines regulate excitatory inhibitory synaptic transmission neuromodulators. We highlight sex differences microglial Thus, targeting locations pharmacological approaches, including immunotherapies, non-pharmacological approaches will help to control chronic

Language: Английский

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

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(4), P. 1742 - 1758

Published: Dec. 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.

Language: Английский

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Metal–Phenolic‐Mediated Assembly of Functional Small Molecules into Nanoparticles: Assembly and Bioapplications

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(12)

Published: Jan. 29, 2024

Abstract Small molecules, including therapeutic drugs and tracer play a vital role in biological processing, disease treatment diagnosis, have inspired various nanobiotechnology approaches to realize their function, particularly drug delivery. Desirable features of delivery system for functional small molecules (FSMs) include high biocompatibility, loading capacity, simple manufacturing processes, without the need chemical modification FSM itself. Herein, we report versatile approach, based on metal–phenolic‐mediated assembly, assembling FSMs into nanoparticles (i.e., FSM‐MPN NPs) under aqueous ambient conditions. We demonstrate anticancer drugs, latency reversal agents, fluorophores at up ~80 % that is mostly facilitated by π hydrophobic interactions between nanoparticle components. Secondary engineering involving coating with polyphenol–antibody thin film or sequential co‐loading multiple enables cancer cell targeting combination delivery, respectively. Incorporating NPs visualization biodistribution different time points, revealing most these are retained kidney heart 24 h post intravenous administration. This work provides viable pathway rational design molecule platforms diverse applications.

Language: Английский

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The role of circular RNAs in regulating resistance to cancer immunotherapy: mechanisms and implications

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(5)

Published: May 2, 2024

Abstract Cancer immunotherapy has rapidly transformed cancer treatment, yet resistance remains a significant hurdle, limiting its efficacy in many patients. Circular RNAs (circRNAs), novel class of non-coding RNAs, have emerged as pivotal regulators gene expression and cellular processes. Increasing evidence indicates their involvement modulating to immunotherapy. Notably, certain circRNAs function miRNA sponges or interact with proteins, influencing the immune-related genes, including crucial immune checkpoint molecules. This, turn, shapes tumor microenvironment significantly impacts response In this comprehensive review, we explore evolving role orchestrating immunotherapy, specific focus on mechanisms expression. Additionally, underscore potential promising therapeutic targets augment effectiveness Understanding could contribute development new strategies overcome improve patient outcomes.

Language: Английский

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Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6027 - 6043

Published: April 10, 2024

Targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has evolved into one of most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved treating a variety tumors, while development small-molecule PD-1/PD-L1 inhibitors lagged far behind, with only few entering clinical trials. In addition to and inhibitors, reducing expression levels PD-L1 attracted extensive research interest as another strategy target pathway. Herein, we analyze structures mechanisms molecules that reduce classify them degraders downregulators according whether they directly bind PD-L1. Moreover, discuss potential prospects developing PD-L1-targeting based on these molecules. It is hoped this perspective will provide profound insights discovery potent antitumor immunity drugs.

Language: Английский

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Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress

Expert Opinion on Therapeutic Targets, Journal Year: 2024, Volume and Issue: 28(4), P. 237 - 250

Published: April 2, 2024

Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T B dendritic and other immune cells. Loss of HPK1 activity results exacerbated cytokine secretion, enhanced cell signaling, improved viral clearance, thus increased restraint tumor growth. These findings highlight promising target for immuno-oncology treatments, culminating the advancement candidate compounds targeting to clinical trials by several biotech enterprises.

Language: Английский

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