In Vivo Self‐Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy DOI
Shaowen Xie, Jingjie Zhu, Yihan Peng

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Abstract Proteolysis targeting chimeras (PROTACs) hold immense promise for targeted protein degradation; however, challenges such as off‐target effects, poor drug‐likeness properties, and the “hook effect” remain. This study introduces Nano‐Click‐formed PROTACs (Nano‐CLIPTACs) precise tumor degradation in vivo. Traditional with high molecular weight were first divided into two smaller druglike precursors capable of self‐assembling to form functional through a bioorthogonal reaction. Then, optimal CLIPTACs ( W4 Z2 ) encapsulated individually cyclic RGDfC‐peptide‐modified liposomes prepare Nano‐CLIPTACs, enabling tumor‐targeted delivery subsequent situ self‐assembly WZ42 within cells. The abilities Nano‐CLIPTACs vitro vivo further verified using key oncology target, anaplastic lymphoma kinase (ALK), validating safety, efficacy “anti‐hook this strategy. Overall, represent critical step towards clinical translation technology anti‐cancer therapies.

Language: Английский

PROTAC technology: From drug development to probe technology for target deconvolution DOI

Si Yan,

Guangshuai Zhang,

Wei Luo

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 276, P. 116725 - 116725

Published: July 30, 2024

Language: Английский

Citations

21
Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy DOI
Shipeng He, Yuxin Fang,

Yaojin Zhu

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(25)

Published: April 19, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer‐PROTAC conjugation approach is developed to enhance tumor targeting antitumor potency. Specifically, smart prodrug designed by conjugating “drugtamer” nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using microenvironment responsible linker. The consists fluorouridine nucleotide DNA‐like oligomer. Compared NAMPT combination + fluorouracil, AS‐2F‐NP demonstrates superior targeting, efficient cellular uptake, improved in vivo potency reduced side effects. This study provides precise delivery synergistic agents.

Language: Английский

Citations

17
Nanomaterials Enhanced Sonodynamic Therapy for Multiple Tumor Treatment DOI Creative Commons
Mengyao Yang, Xin Wang,

Mengke Peng

et al.

Nano-Micro Letters, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 24, 2025

Abstract Sonodynamic therapy (SDT) as an emerging modality for malignant tumors mainly involves in sonosensitizers and low-intensity ultrasound (US), which can safely penetrate the tissue without significant attenuation. SDT not only has advantages including high precision, non-invasiveness, minimal side effects, but also overcomes limitation of low penetration light to deep tumors. The cytotoxic reactive oxygen species be produced by utilization combined with US kill tumor cells. However, underlying mechanism been elucidated, its unsatisfactory efficiency retards further clinical application. Herein, we shed on main mechanisms types sonosensitizers, organic inorganic sonosensitizers. Due development nanotechnology, many novel nanoplatforms are utilized this arisen field solve barriers enable continuous innovation. This review highlights potential nanosonosensitizers focus enhanced based monotherapy or synergistic that difficult reach traditional treatment, especially orthotopic cancers.

Language: Английский

Citations

2
Cleavage of Homonuclear Chalcogen‐Chalcogen Bonds in a Hybrid Platform in Response to X‐Ray Radiation Potentiates Tumor Radiochemotherapy DOI Open Access

Yuanyuan You,

Yanzhou Chang,

Shuya Pan

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 64(1)

Published: Aug. 23, 2024

Chalcogens are used as sensitive redox-responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than internal environmental stimuli, enable site-directed and real-time drug degradation target lesions. This approach helps to bypass chemoresistance global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated hybrid monodisperse organosilica nanoprodrug based on homonuclear single (disulfide (S-S, approximately 240 kJ/mol), diselenium (Se-Se, 172 tellurium (Te-Te, 126 kJ/mol)), including ditelluride-bond-bridged MONs (DTeMSNs), diselenide-bond-bridged (DSeMSNs) disulfide-bond-bridged (DSMSNs). The results demonstrated that differences electronegativities atomic radii influenced their oxidation sensitivities reactivities. Tellurium, with the lowest electronegativity, showed highest sensitivity, followed selenium sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure X-rays, resulting TeO

Language: Английский

Citations

7
Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions DOI Creative Commons
Rajamanikkam Kamaraj, Subhrojyoti Ghosh,

Souvadra Das

et al.

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: 35(8), P. 1089 - 1115

Published: July 11, 2024

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated and autophagy-mediated degradation. This approach has shown great promise in preclinical studies now being translated treat numerous diseases, neurodegenerative infectious cancer. review discusses latest advances its potential new chemical modality immunotherapy, with special focus on innovative applications cutting-edge research PROTACs (Proteolysis TArgeting Chimeras) their efficient translation from scientific discovery technological achievements. Our also addresses significant obstacles prospects this domain, while offering insights into future immunotherapeutic applications.

Language: Английский

Citations

4
Cleavage of Homonuclear Chalcogen‐Chalcogen Bonds in a Hybrid Platform in Response to X‐Ray Radiation Potentiates Tumor Radiochemotherapy DOI Open Access

Yuanyuan You,

Yanzhou Chang,

Shuya Pan

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 137(1)

Published: Aug. 23, 2024

Abstract Chalcogens are used as sensitive redox‐responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than internal environmental stimuli, enable site‐directed and real‐time drug degradation target lesions. This approach helps to bypass chemoresistance global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated hybrid monodisperse organosilica nanoprodrug based on homonuclear single (disulfide (S−S, approximately 240 kJ/mol), diselenium (Se−Se, 172 tellurium (Te−Te, 126 kJ/mol)), including ditelluride‐bond‐bridged MONs (DTeMSNs), diselenide‐bond‐bridged (DSeMSNs) disulfide‐bond‐bridged (DSMSNs). The results demonstrated that differences electronegativities atomic radii influenced their oxidation sensitivities reactivities. Tellurium, with the lowest electronegativity, showed highest sensitivity, followed selenium sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure X‐rays, resulting TeO 3 2− . Furthermore, chalcogen‐hybridized was loaded manganese ions (Mn 2+ ) enhance release of Mn during radiotherapy, thereby activating stimulator interferon genes (STING) pathway enhancing immune response inhibit growth. investigation deepens our understanding chalcogens characteristics radiotherapy enriches design principles for nanomedicine prodrugs.

Language: Английский

Citations

4
Powering up targeted protein degradation through active and passive tumour-targeting strategies: Current and future scopes DOI
Janarthanan Venkatesan, Dhanashree Murugan,

Kalaiarasu Lakshminarayanan

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 263, P. 108725 - 108725

Published: Sept. 24, 2024

Language: Английский

Citations

4
Strategies for Precise Modulation of Protein Degradation DOI
Shipeng He, Guoqiang Dong, Chunquan Sheng

et al.

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

ConspectusTargeted protein degradation (TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have revolutionized therapeutic strategies facilitating the selective of pathogenic proteins instead simply inhibiting their functions. This degradation-based strategy offers significant advantages over traditional small-molecule inhibitors, which often block activity without eliminating target. PROTACs function leveraging ubiquitin-proteasome system to selectively degrade target proteins, thus enabling modulation a broader range disease-causing including those that were previously considered undruggable. As result, PROTAC-based therapies gained considerable attention in drug discovery, especially oncology, immunology, and neurodegenerative diseases. However, clinical translation conventional remains challenging due issues such as limited specificity, poor solubility, inadequate cellular permeability, unfavorable pharmacokinetic profiles, absence spatiotemporal resolution.To address these hurdles, various innovative been developed enhance precision degradation. These approaches focus on improving targeted delivery, membrane control with goal overcoming inherent limitations PROTAC designs. For instance, aptamer-conjugated shown great promise tumor selectivity reducing off-target effects through tumor-specific receptor recognition subsequent internalization. Moreover, development drugtamer-PROTAC conjugates enables more precise codelivery agents, optimizing synergistic both modalities while minimizing systemic toxicity. Additionally, RGD peptide-based conjugation capitalize use tumor-homing peptides uptake, improve penetration, increase specificity cells, further toxicities healthy tissues.Another critical advancement is photocontrolled PROTACs, allow for temporal regulation vivo. By light-responsive molecules, systems provide ability trigger at specific time points, offering unparalleled interventions. Furthermore, theranostic combine diagnostic functions, facilitate real-time monitoring events living cells animal models, simultaneous assessment efficacy biomarker visualization.This Account reviews recent advancements design smart highlighting control. innovations promising solutions paving way progress discovery evolution medicine. While discussed present opportunities, we also explore challenges, limitations, future directions translation, insights into potential degrader-based setting.

Language: Английский

Citations

0
Prussian blue nanoparticle-based pH-responsive self-assembly for enhanced photothermal and chemotherapy of tumors DOI
Linrong Shi, Mingzhi Zhu, Ruimin Long

et al.

Journal of Photochemistry and Photobiology B Biology, Journal Year: 2024, Volume and Issue: 256, P. 112938 - 112938

Published: May 10, 2024

Language: Английский

Citations

2
MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation DOI
Jiayin Zhan, Xiang Li, Zhe Feng

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 9, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miR NA‐ i nitiated ssembled pre‐PRO TAC (miRiaTAC) platform that enables the activation termination target degradation in cell type‐specific manner. Using miRNA‐21 as model, engineered DNA hairpins labeled with JQ‐1 pomalidomide facilitated modular assembly DNA‐encoded pre‐PROTACs through hybridization chain reaction. This configuration promoted selective polyubiquitination BRD4 upon miR‐21 initiation, highlighting significant minimal systemic toxicity. Furthermore, incorporates photolabile groups, enabling precise optical control during assembly/disassembly, mitigating risk excessive Additionally, by introducing secondary ligand targeting CDK6, these were used scaffold for programmable active miRiaTACs containing two different warheads exact stoichiometry, orthogonal multitarget The integration near‐infrared light‐mediated photodynamic therapy an upconversion nanosystem further enhanced efficacy potent vivo anticancer activity. We anticipate miRiaTAC represents intersection between dynamic nanotechnology PROTAC, potentially expanding versatility PROTAC toolkit cancer therapy.

Language: Английский

Citations

2