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Aptamer-modified 5-fluorouracil encapsulated metal-organic framework nanodrugs for enhanced therapy of colorectal cancer via peroxidative induced cell death

ABSTRACT: Colorectal cancer (CRC) remains one of the most devastating malignancies worldwide. 5-Fluorouracil (5-FU) is a widely used therapeutic agent in CRC treatment. Here, we report a PTK-7–targeted, MOF-based nanodrug (AFZC) comprising Sgc8 aptamer, 5-FU, and Cu-doped ZIF-8. AFZC was synthesized via stepwise loading and surface functionalization and rigorously characterized by SEM/TEM. Targeting specificity was confirmed in PTK-7–positive colorectal cancer cells: Cy5-Sgc8 showed strong internalization in CRC cells but negligible uptake in normal epithelial cells. Functionally, AFZC suppressed proliferation and lowered 5-FU IC₅₀ across multiple CRC lines, with enhanced apoptosis versus 5-FU alone. Patient-derived organoids demonstrated greater growth inhibition with AFZC than with 5-FU. Transcriptomic profiling of AFZC-treated CRC cells highlighted pro-apoptotic remodeling with upregulation of NECTIN4 and NCF2, and concordant increases by Western blot alongside caspase cleavage. In vivo, AFZC achieved superior tumor control over 5-FU or ZIF-8 in CRC xenografts and a PDX model. No toxicity was found in histopathology of major organs or in liver/renal function markers at the treatment dosage. Collectively, AFZC couples selective PTK-7 targeting, catalytic activity, and sustained drug release to potentiate 5-FU efficacy with a favorable toxicity profile, supporting its translational promise in CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315569 | GEO | 2026/01/06

REPOSITORIES: GEO

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Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer This model is described in the article: Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R. J. Clin. Oncol. 2009 Sep; 27(25): 4103-4108 Abstract: PURPOSE: We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials. METHODS: We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC. RESULTS: The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine. CONCLUSION: The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies. This model is hosted on BioModels Database and identified by: MODEL1708310001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard protocol for treating patients with locally advanced non-metastatic colorectal cancer (CRC) is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU), but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic CRC patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-two patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results: We have highlighted 384 differentially expressed proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially expressed proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Conclusions: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic CRC. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.

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Aptamer-modified 5-fluorouracil encapsulated metal-organic framework nanodrugs for enhanced therapy of colorectal cancer via peroxidative induced cell death

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