Rational Design of Metal–Organic Frameworks for Pancreatic Cancer Therapy - from Machine Learning Screening to In Vivo Efficacy

Aug 5, 2026

Despite advances in oncology, metastatic and drug-resistant pancreatic cancer continues to cause poor outcomes and limited treatment options. Enhancing intratumoral drug bioavailability while limiting off-target toxicity is critical. This study integrates machine learning with molecular simulations to screen metal–organic frameworks for gemcitabine, paclitaxel, and SN-38 encapsulation and identifies PCN-222 as optimal. After formulation optimization, experiments show high biocompatibility, efficient cellular internalization, sustained release, and strong in vivo antitumor and anti-metastatic effects in tumor-bearing mice.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Pancreatic cancer challenge and current therapies

Need for improved drug delivery systems

MOF-based delivery and study approach

RESEARCH ARTICLE [www.advmat.de](www.advmat.de) Rational Design of Metal–Organic Frameworks for Pancreatic Cancer Therapy: from Machine Learning Screening to In Vivo Eﬃcacy Francesca Melle, Dhruv Menon, João Conniot, Jon Ostolaza-Paraiso, Sergio Mercado, Jhenifer Oliveira, Xu Chen, Bárbara B. Mendes, João Conde,* and David Fairen-Jimenez* Despite improvements in cancer survival rates, metastatic and surg ery-resistant cancers, such as pancreatic cancer, remain challenging, with poor prognoses and limited treatment options. Enhancing drug bioavailability in tumors, while minimizing oﬀ-target eﬀects, is crucial. Metal–organic frameworks (MOFs) have emerged as promising drug delivery vehicles owing to their high loading capacity, biocompatibility, and functional tunability. However, the vast chemical diversity of MOFs complicates the rational design of biocompatible materials. This study employed machine learning and molecular simulations to identify MOFs suitable for encapsulating gemcitabine, paclitaxel, and SN-38, and identiﬁed PCN-222 as an optimal candidate. Following drug loading, MOF formulations are improved for colloidal stability and biocompatibility. In vitro studies on pancreatic cancer cell lines have shown high biocompatibility, cellular internalization, and delayed drug release. Long-term stability tests demonstrated a consistent performance over 12 months. In vivo studies in pancreatic tumor-bearing mice revealed that paclitaxel-loaded PCN-222, particularly with a hydrogel for local administration, signiﬁcantly reduced metastatic spread and tumor growth compared to the free drug. These ﬁndings underscore the potential of PCN-222 as an eﬀective drug delivery system for the treatment of hard-to-treat cancers. expected to rise to over 16 million by 2040 . [1] Despite advancements in cancer treatmentsand improved survival rates in recent years, the heterogeneous nature of cancer demands the development of new therapeutic strategies. This is particularly relevant for the so-called “hard-to-treat” cancers, which continue to exhibit alarmingly high mortality rates with little to no progress in outcomes over the past 20 years. [2] An example is pancreatic ductal adenocarcinoma (PDAC), the most common and deadly form of pancreatic cancer known for its exceptionally high mortality rate. [2,3] Despite accounting for only 3.3% of all new cancer cases in the United States, pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in males and females, with almost 7% of all cancer deaths. [4,5] The 5-year relative survival rate for pancreatic cancer remains below 10%, starkly contrasting the higher survival rates seen in other common cancers such as breast (90.8%), prostate (97.1%), and thyroid (98.5%) . [6] This disparity highlights the aggressive nature of pancreatic cancer and the signiﬁcant challenges it poses 1. Introduction Cancer remains the second leading cause of mortality worldwide, responsible for ≈10 million deaths annually—a number in early diagnosis and eﬀective treatment. Pancreatic cancer is often diagnosed in later stages, which signiﬁcantly limits treatment options. Only a small percentage of patients (15-20%) are eligible for surgery, needing to rely on combination chemotherapy as the F. Melle, D. Menon, J. Ostolaza-Paraiso, S. Mercado, X. Chen, D. Fairen-Jimenez The Adsorption & Advanced Materials Laboratory (AAML) Department of Chemical Engineering & Biotechnology University of Cambridge Philippa Fawcett Drive, Cambridge CB3 0AS, UK E-mail: [df334@cam.ac.uk](df334@cam.ac.uk) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/adma.202412757](https://doi.org/10.1002/adma.202412757)[ ](https://doi.org/10.1002/adma.202412757)© 2025 The Author(s). Advanced Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use,

FAQs

Why is drug delivery optimization important for pancreatic cancer therapy?

Pancreatic tumors often require higher intratumoral drug availability while avoiding systemic toxicity and off-target effects. Current chemotherapeutics also face limitations such as resistance, poor solubility, and stability issues.

How did the study identify suitable MOFs for drug encapsulation?

The work used machine learning together with molecular simulations to screen MOFs for encapsulating gemcitabine, paclitaxel, and SN-38, leading to PCN-222 as an optimal candidate.

What evidence supports the effectiveness of the PCN-222 formulations?

In vitro results show high biocompatibility, cellular internalization, and delayed drug release. Long-term stability was consistent over 12 months, and in vivo studies in tumor-bearing mice demonstrated reduced metastatic spread and tumor growth, especially with hydrogel-assisted local administration of paclitaxel-loaded PCN-222.

Aug 5, 2026

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