We have previously developed TNF prodrugs comprised of a N-terminal scFv targeting, a TNF effector and a C-terminal TNFR1-derived inhibitor module linked to TNF via a MMP-2 motif containing peptide, allowing activation by MMP-2-expressing tumor cells. To overcome the known heterogeneity of matrix metalloprotease expression, we developed TNF prodrugs that become processed by other tumor and/or stroma-associated proteases. These TNF prodrugs comprise either an uPA-selective or a dual uPA-MMP-2-specific linker which displayed efficient, target-dependent and cleavage sequence-specific activation by the corresponding tumor cell-expressed proteases. Selective pharmacologic inhibition of endogenous uPA and MMP-2 confirm independent prodrug processing by these two model proteases and indicate the functional superiority of a prodrug containing a multi-specific protease linker. Processing optimised TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11029883 | PMC |
| http://dx.doi.org/10.1007/s00262-006-0162-6 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Activating the cGAS-STING Pathway by Manganese-Based Nanoparticles Combined with Platinum-Based Nanoparticles for Enhanced Ovarian Cancer Immunotherapy.
ACS Nano
January 2025
Department of Gynecology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China.
Recent research has demonstrated that activating the cGAS-STING pathway can enhance interferon production and the activation of T cells. A manganese complex, called TPA-Mn, was developed in this context. The reactive oxygen species (ROS)-sensitive nanoparticles (NPMn) loaded with TPA-Mn are developed.
View Article and Find Full Text PDFDeep Red-Light-Mediated Nitric Oxide and Photodynamic Synergistic Antibacterial Therapy for the Treatment of Drug-Resistant Bacterial Infections.
Small
January 2025
Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning, Nanjing, 210009, China.
Infections caused by persistent, drug-resistant bacteria pose significant challenges in inflammation treatment, often leading to severe morbidity and mortality. Herein, the photosensitizer rhodamine derivatives are selected as the light-trapping dye and the electron-rich substituent N-nitrosoaminophen as the nitric oxide (NO)-releasing component to develop a multifunctional (deep) red-light activatable NO photocage/photodynamic prodrug for efficient treatment of wounds and diabetic foot infections. The prodrug, RhB-NO-2 integrates antimicrobial photodynamic therapy (aPDT), NO sterilization, and NO-mediated anti-inflammatory properties within a small organic molecule and is capable of releasing NO and generating Reactive oxygen species (ROS) when exposed to (deep) red laser (660 nm).
View Article and Find Full Text PDFDiscovery and synthesis of novel glyrrhizin-analogs containing furanoylpiperazine and the activity against myocardial injury in sepsis.
Bioorg Chem
December 2024
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
Article Synopsis
- - The study investigates how the HMGB1 protein contributes to heart damage during sepsis and shows that a natural compound called Glyrrhizin (GL) can inhibit HMGB1 by forming a complex with it, but its effectiveness is limited due to its metabolism to a less potent form (GA) in the body.
- - Researchers synthesized 24 analogs of GL to improve its effectiveness and pharmacokinetic properties, ultimately identifying compound 11, which acts as a prodrug that converts to a more active form (11a) in the body with lower toxicity.
- - The promising compound 11a not only reduced inflammation and oxidative stress in heart cells, improved heart function in septic mice, but also showed stronger binding to HM
Anti-Inflammatory Immunomodulatory Activity of Valacyclovir on the Activated Mammalian Macrophages.
Discov Med
August 2024
Department of Biomedical Engineering, Faculty of Engineering and Life Sciences, Biruni University, 34015 Istanbul, Turkiye.
Article Synopsis
- Aciclovir and valacyclovir are antiviral agents, with valacyclovir being a prodrug of aciclovir, known for their effects against various herpesviruses like HHV-6 and HSV.
- The study involved treating activated mammalian macrophages with different concentrations of valacyclovir to assess its impact on inflammation by measuring pro-inflammatory cytokines like TNF-α and IL-6.
- Results indicated that valacyclovir exhibits anti-inflammatory properties, suggesting its potential use in clinical settings beyond just antiviral effects, while further research is needed on its effects on other immune cells.
Restoring physiological parameters of the pancreas and kidney through treatment with a polymeric nano-formulation of C-peptide and lisofylline combination in diabetic nephropathy.
Nanoscale
August 2024
Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan, 333031, India.
Diabetic nephropathy (DN) is a progressive kidney disorder that develops as a complication of diabetes due to long-term exposure to elevated blood glucose levels (BGLs). In this case, an intervention of therapeutic moieties is needed to target the specific elements involved in diabetes to prevent/delay the deterioration of kidney function. Therefore, the present study focused on designing and evaluating a potent nano-formulation of a combination of C-peptide (CPep) and the anti-diabetic drug lisofylline (LSF) to prevent streptozotocin (STZ)-induced DN.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!