Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 2, 2022

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos paired via reactions. Due its simplicity, high efficiency, and specificity, has demonstrated great application potential drug delivery. On the one hand, improve therapeutic agent delivery target sites, overcoming off-target distribution. other nanoparticles biomolecules linked membranes by reactions, providing approaches developing multi-functional systems (DDSs). In this review, we first describe principle of labeling cells or pathogenic microorganisms groups. We then highlight recent breakthroughs active targeting DDSs tumors, immune systems, bacteria chemistry, as well applications functional bio-inspired (biomimetic DDSs, cell-based bacteria-based phage-based DDSs) hydrogels. Finally, discuss difficulties prospective direction expect review will help us understand latest advances development using inspire innovative smart for disease treatment.

Language: Английский

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The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 7946 - 7946

Published: April 27, 2023

Clear cell renal carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining tubes kidney. The tumor immune microenvironment (TIME) ccRCC complex interplay various cells, cytokines, and signaling pathways. One critical features TIME presence infiltrating including T B natural killer dendritic myeloid-derived suppressor cells. Among these CD8+ are particularly important in controlling growth by recognizing killing However, also characterized an immunosuppressive environment hinders function Several mechanisms contribute to nature TIME. For instance, produce cytokines such as interleukin-10 (IL-10) transforming factor-beta (TGF-β), which suppress activation promote differentiation regulatory (Tregs). Tregs, turn, dampen activity effector growth. In addition, can express programmed death-ligand 1 (PD-L1), interacts with death protein (PD-1) receptor on inhibit their function. other checkpoint proteins, cytotoxic T-lymphocyte-associated 4 (CTLA-4) lymphocyte gene 3 (LAG-3), milieu Finally, hypoxic nutrient-poor stimulate production metabolites, adenosine kynurenine, further impair Understanding between system crucial for developing effective immunotherapies treat this disease.

Language: Английский

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Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(30), P. 16642 - 16649

Published: July 21, 2023

Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging precisely control PROTAC function in tumor regions vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis tumor-bearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate linked with NIR photosensitizer through singlet oxygen (1O2)-cleavable linker. The initially silenced but can be remotely switched on upon photoirradiation generate 1O2 photosensitizer. demonstrated that enabled tumor-specific bromodomain-containing 4 (BRD4) light-instructed manner. This combination photodynamic therapy (PDT) elicited effective suppression growth. work thus presents novel approach spatiotemporal over targeted PROTAC.

Language: Английский

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Microneedle Patch Delivery of PROTACs for Anti-Cancer Therapy

ACS Nano, Journal Year: 2023, Volume and Issue: 17(12), P. 11855 - 11868

Published: June 9, 2023

Proteolysis-targeting chimera (PROTAC) is an emerging technique for degrading disease-related proteins. However, the current PROTACs suffer from inadequate solubility and lack of organ targeting, which has hampered their druggability. Herein, we report direct sustained delivery using microneedle patches to diseased tissues. In this study, use estrogen receptor alpha (ERα)-degrading PROTAC, ERD308, treat ER-positive breast cancer. A pH-sensitive micelle, MPEG-poly(β-amino ester) (MPEG-PAE), used encapsulate ERD308 along with FDA-approved CDK4/6 inhibitor, Palbociclib (Pal), before loading into biodegradable patches. These enable prolonged drug release deep tumors, maintaining therapeutic levels at least 4 days, excellent retention rate over 87% in tumors. released can sufficiently degrade ERα MCF7 cells. Co-administration exhibits efficacy by 80% tumor reduction as well a good safety profile. Our work demonstrates feasibility proof-of-concept potential directly deliver

Language: Английский

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Glutathione‐Scavenging Nanoparticle‐Mediated PROTACs Delivery for Targeted Protein Degradation and Amplified Antitumor Effects

Advanced Science, Journal Year: 2023, Volume and Issue: 10(16)

Published: April 17, 2023

PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins interest by hijacking the ubiquitin-proteasome system. However, lack techniques to efficiently transport these degraders targeted cells and consequently potential toxicity PROTACs limit their clinical applications. Here, a strategy nanoengineered PROTACs, is, Nano-PROTACs, is reported, which improves bioavailability maximizes capacity therapeutically oncogenic for tumor therapy. The Nano-PROTACs developed encapsulating in glutathione (GSH)-responsive poly(disulfide amide) polymeric (PDSA) nanoparticles show ARV@PDSA Nano-PROTAC, BRD4 degrader ARV-771, protein degradation decreases downstream oncogene c-Myc expression. Benefiting from GSH-scavenging ability amply c-Myc-related ferroptosis cell cycle arrest, this shows superior anti-tumor efficacy with low dose administration good biocompatibility vivo. findings reveal treat broad range diseases dismantling associated pathogenic proteins.

Language: Английский

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New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 21, 2024

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.

Language: Английский

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PROTAC Prodrug‐Integrated Nanosensitizer for Potentiating Radiation Therapy of Cancer

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(23)

Published: Feb. 14, 2024

Abstract Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, crucial role bromodomain‐containing protein 4 (BRD4)‐RAD51 associated 1 (RAD51AP1) axis sensitizing RT HNSCC revealed. A versatile nanosensitizer (RPB7H) thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) hafnium dioxide (HfO 2 ) nanoparticles to downregulate BRD4‐RAD51AP1 pathway sensitize tumor RT. Upon intravenous administration, RPB7H selectively accumulate at tissue internalize into cells recognizing neuropilin‐1 overexpressed mass. HfO enhance effectiveness amplifying X‐ray deposition, intensifying DNA damage, boosting oxidative stress. Meanwhile, BPA771 can be activated RT‐induced H O secretion degrade BRD4 inactivate RAD51AP1, impeding damage repair. This nanosensitizer, combined with irradiation, effectively regresses growth mouse model. The findings introduce PROTAC prodrug‐based radiosensitization strategy targeting axis, may offer promising avenue augment more effective therapy.

Language: Английский

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Targeted protein degradation: advances in drug discovery and clinical practice

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

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Nano-PROTACs: state of the art and perspectives

Nanoscale, Journal Year: 2024, Volume and Issue: 16(9), P. 4378 - 4391

Published: Jan. 1, 2024

Schematic illustration of the combinational strategy nanotechnology and PROTACs (Nano-PROTACs): typical shortcomings traditional nanotechnology-based strategies for PROTAC drugs optimization.

Language: Английский

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Research Progress of Disulfide Bond Based Tumor Microenvironment Targeted Drug Delivery System

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 7547 - 7566

Published: July 1, 2024

Abstract: Cancer poses a significant threat to human life and health. Chemotherapy is currently one of the effective cancer treatments, but many chemotherapy drugs have cell toxicity, low solubility, poor stability, narrow therapeutic window, unfavorable pharmacokinetic properties. To solve above problems, target drug delivery tumor cells, reduce side effects drugs, an anti-tumor system based on microenvironment has become focus research in recent years. The construction reduction-sensitive nanomedicine disulfide bonds attracted much attention. Disulfide good reductive responsiveness can effectively high glutathione (GSH) levels environment, enabling precise delivery. further enhance targeting accelerate release, are often combined with pH-responsive nanocarriers highly expressed ligands cells construct systems. connect molecules polymer system, as well between different carrier molecules. This article summarized systems (DDS) that researchers constructed years bond microenvironment, cleavage-triggering conditions, various loading strategies, design. In this review, we also discuss controlled release mechanisms these DDS clinical applicability challenges faced translation. Keywords: bond, systems, GSH/ROS

Language: Английский

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