ArticleJournal of controlled release : official journal of the Controlled Release Society2017
Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma.
Article in Journal of controlled release : official journal of the Controlled Release Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
39 citing papers in PubMed, 81 citations in OpenAlex.
- A Microdosing Study withJournal of nuclear medicine : official publication, Society of Nuclear Medicine · 2021Trial
- Real-world pharmacovigilance signals of antibody-drug conjugates: reporting patterns by payload, linker, target, and sex in FAERS.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Multivalent Antibody-Recruiting Molecules for Targeted Immune-Killing of Carbonic Anhydrase IX-Expressing Cancer Cells.Angewandte Chemie (International ed. in English) · 2026Article
- From DNA-Encoded Chemistry to Tumor-Targeted Small Molecule Therapeutics.Pharmaceuticals (Basel, Switzerland) · 2026Review
- A Dual-Mechanism Targeted Cross-Convergence Prodrug Activation Strategy Enabled by Biological Stimulus Amplification toward Precision Cancer Therapy.Biomaterials research · 2026Article
- A comprehensive review on the role of acetamido as a linker for the design and discovery of anticancer agents.Medical oncology (Northwood, London, England) · 2025Review
- Tracking the Fate of Therapeutic Proteins Using Ratiometric Imaging of Responsive Shortwave Infrared Probes.Journal of the American Chemical Society · 2025Article
- Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Targeted drug conjugates in cancer therapy: Challenges and opportunities.Pharmaceutical science advances · 2024Review
- Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment.Acta pharmaceutica Sinica. B · 2024Review
- Antibody-Drug Conjugates: The Dynamic Evolution from Conventional to Next-Generation Constructs.Cancers · 2024Review
- A DNA-encoded chemical library based on chiral 4-amino-proline enables stereospecific isozyme-selective protein recognition.Nature chemistry · 2023Article
- Optimizing the enzymatic release of MMAE fromFrontiers in pharmacology · 2023Article
- A low molecular weight multifunctional theranostic molecule for the treatment of prostate cancer.Theranostics · 2022Article
- Bioorthogonal Self-Immolative Linker Based on Grob Fragmentation.Organic letters · 2021Article
- The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers.Acta pharmaceutica Sinica. B · 2021Review
- Immunotherapy with Immunocytokines and PD-1 Blockade Enhances the Anticancer Activity of Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX.Molecular cancer therapeutics · 2021Article
- Sortase-Mediated Site-Specific Modification of Interleukin-2 for the Generation of a Tumor-Targeting Acetazolamide-Cytokine Conjugate.ACS omega · 2020Article
- Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New HInternational journal of molecular sciences · 2020Review
- Carbonic Anhydrase-IX Guided Albumin Nanoparticles for Hypoxia-mediated Triple-Negative Breast Cancer Cell Killing and Imaging of Patient-derived Tumor.Molecules (Basel, Switzerland) · 2020Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Small molecule-drug conjugates (SMDCs) are increasingly being considered as an alternative to antibody-drug conjugates (ADCs) for the selective delivery of anticancer agents to the tumor site, sparing normal tissues. Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme, which is over-expressed in the majority of renal cell carcinomas and which can be efficiently targeted in vivo, using charged derivatives of acetazolamide, a small heteroaromatic sulfonamide. Here, we show that SMDC products, obtained by the coupling of acetazolamide with monomethyl auristatin E (MMAE) using dipeptide linkers, display a potent anti-tumoral activity in mice bearing xenografted SKRC-52 renal cell carcinomas. A comparative evaluation of four dipeptides revealed that SMDCs featuring valine-citrulline and valine-alanine linkers exhibited greater serum stability and superior therapeutic activity, compared to the counterparts with valine-lysine or valine-arginine linkers. The most active products substantially inhibited tumor growth over a prolonged period of time, in a tumor model for which sunitinib and sorafenib do not display therapeutic activity. However, complete tumor eradication was not possible even after ten intravenous injection. Macroscopic near-infrared imaging procedures confirmed that ligands had not lost the ability to selectively localize at the tumor site at the end of therapy and that the neoplastic masses continued to express CAIX. The findings are of mechanistic and of therapeutic significance, since CAIX is a non-internalizing membrane-associated antigen, which can be considered for targeted drug delivery applications in kidney cancer patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.