Nuclear-Targeting Lipid Pt^IV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 146(1), P. 1185 - 1195

Published: Dec. 27, 2023

Patients treated with Pt-based anticancer drugs (Pt

Language: Английский

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Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(3), P. 2031 - 2048

Published: Jan. 17, 2024

Metastasis is the major obstacle to survival of cancer patients. Herein, a series new desloratadine platinum(IV) conjugates with promising antiproliferative and antimetastatic activities were developed evaluated. The candidate complex caused significant DNA damage stimulated mitochondrial apoptosis through Bcl-2/Bax/caspase3 pathway. Then, it suppressed epithelial–mesenchymal transition (EMT) process in tumors effectively NMT-1/HPCAL1 β-catenin signaling. Subsequently, angiogenesis was inhibited downregulation key proteins HIF-1α, VEGFA, MMP-9, CD34. Moreover, antitumor immunity aroused by synergism EMT reversion decrease histamine level; then, macrophage polarization from M2- M1-type increase CD4+ CD8+ T cells triggered simultaneously tumors.

Language: Английский

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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, Journal Year: 2023, Volume and Issue: 66(18), P. 13072 - 13085

Published: Sept. 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.

Language: Английский

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Alendronate Pt^IV Prodrug Amphiphile for Enhanced Chemotherapy Targeting and Bone Destruction Inhibition in Osteosarcoma

Advanced Healthcare Materials, Journal Year: 2023, Volume and Issue: 13(7)

Published: Nov. 22, 2023

Abstract Chemotherapy remains the primary treatment method for osteosarcoma after surgery. However, lack of selectivity chemotherapy leads to unpredictable therapeutic effects, undesirable side and drug resistance. A platinum(IV) (Pt IV ) prodrug amphiphile (ALN‐Pt ‐Lipo) covalently bound alendronate (ALN) a lipid tail is designed overcome these limitations. ALN‐Pt ‐Lipo can self‐assemble into Pt nanoparticles (APt targeting bone destruction inhibition. It demonstrated that APt achieved an eightfold increase in eradication cells compared cisplatin threefold selective inhibition over breast cancer via vitro. After intravenous injection, effectively accumulates at site vivo, resulting significantly suppressed growth, alleviation destruction. Therefore, delivers promising solution enhanced osteosarcoma.

Language: Английский

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Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties

Molecules, Journal Year: 2024, Volume and Issue: 29(4), P. 746 - 746

Published: Feb. 6, 2024

Platinum-based drugs are widely used in chemotherapy for various types of cancer and considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention been extensively researched among these drugs. Traditionally, Pt(IV) reduced to divalent (Pt(II)) after entering cells, causing DNA lesions exhibiting their anti-tumor effect. However, the available evidence indicates that some derivatives may differ from traditional mechanism exert effect through overall structure. This review primarily focuses on existing literature regarding targeted Pt(II) compounds, with a specific emphasis vivo mode action properties reduction release multifunctional compounds. provides comprehensive summary design synthesis strategies employed selectively target enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines summarizes rational design, action, reductive capacity novel such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, drug delivery systems. Finally, this aims provide theoretical support development new

Language: Английский

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Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6218 - 6237

Published: April 4, 2024

Although cisplatin has been widely used for clinical purposes, its application is limited due to obvious side effects. To mitigate the defects of cisplatin, here, six "multitarget prodrugs" were synthesized by linking and NF-κB inhibitors. Notably, complex 9 demonstrated a 63-fold enhancement in activity against A549/CDDP cells with lower toxicity toward normal LO2 compared cisplatin. Additionally, could effectively cause DNA damage, induce mitochondrial dysfunction, generate reactive oxygen species, cell apoptosis through pathway ER stress. Remarkably, inhibited NF-κB/MAPK signaling disrupted PI3K/AKT transduction. Importantly, showed superior vivo antitumor efficiency or combination cisplatin/4, without systemic A549 xenograft models. Our results that dual-acting mechanism endowed complexes high low toxicity, which may represent an efficient strategy cancer therapy.

Language: Английский

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Exploiting Nanotechnology for Drug Delivery: Advancing the Anti-Cancer Effects of Autophagy-Modulating Compounds in Traditional Chinese Medicine

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 2507 - 2528

Published: March 1, 2024

Background: Cancer continues to be a prominent issue in the field of medicine, as demonstrated by recent studies emphasizing significant role autophagy development cancer. Traditional Chinese Medicine (TCM) provides variety anti-tumor agents capable regulating autophagy. However, clinical application autophagy-modulating compounds derived from TCM is impeded their restricted water solubility and bioavailability. To overcome this challenge, utilization nanotechnology has been suggested potential solution. Nonetheless, current body literature on nanoparticles delivering TCM-derived for cancer treatment limited, lacking comprehensive summaries detailed descriptions. Methods: Up November 2023, research study was conducted gather relevant data using databases, including PubMed, ScienceDirect, Springer Link, Web Science, CNKI. The keywords utilized investigation included "autophagy", "nanoparticles", "traditional medicine" "anticancer". Results: This review analysis overcoming delivery challenges enhancing anti-cancer properties TCM. evaluation based synthesis different classes TCM, mechanisms action treatment, benefits reported various scholarly sources. findings indicate that shows availability thereby opening up plethora therapeutic avenues. Conclusion: Nanotechnology enhance efficacy traditional through regulation Keywords: autophagy, nano-delivery, anti-cancer, medicine

Language: Английский

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PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 63, P. 219 - 230

Published: Nov. 1, 2023

Natural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify targets NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple or pathways, which also poses great difficulties for target identification

Language: Английский

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Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 8020 - 8042

Published: May 10, 2024

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking agents glycyrrhetinic acid (GA) were designed synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin than simultaneously displayed good liver-targeting ability. Moreover, can significantly cause DNA damage mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, eventually induce apoptosis. Additionally, effectively inhibit cell migration invasion trigger autophagy ferroptosis HepG-2 cells. More importantly, demonstrated stronger tumor inhibition ability or the combo of cisplatin/GA with almost no systemic toxicity A549 xenograft models. Collectively, could be developed as a potential anti-HCC agent treatment.

Language: Английский

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NIR Light and GSH Dual-Responsive Upconversion Nanoparticles Loaded with Multifunctional Platinum(IV) Prodrug and RGD Peptide for Precise Cancer Therapy

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(31), P. 40753 - 40766

Published: July 24, 2024

Platinum(II) drugs as a first-line anticancer reagent are limited by side effects and drug resistance. Stimuli-responsive nanosystems hold promise for precise spatiotemporal manipulation of delivery, with the aim to promote bioavailability minimize effects. Herein, multitargeting octahedral platinum(IV) prodrug octadecyl aliphatic chain histone deacetylase inhibitor (phenylbutyric acid, PHB) at axial positions improve therapeutic effect cisplatin was loaded on upconversion nanoparticles (UCNPs) through hydrophobic interaction. Followed attachment DSPE-PEG2000 arginine-glycine-aspartic (RGD) peptide endowed nanovehicles high biocompatibility tumor specificity. The fabricated (UCNP/Pt(IV)-RGD) can be triggered luminescence (UCL) irradiation glutathione (GSH) reduction controllably release Pt(II) species PHB, inducing profound cytotoxicity. Both in vitro vivo experiments demonstrated that UCNP/Pt(IV)-RGD exhibited remarkable antitumor efficiency, tumor-targeting specificity, real-time UCL imaging capacity, presenting an intelligent prodrug-loaded nanovehicle UCL-guided dual-stimuli-responsive combination therapy.

Language: Английский

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