Efficacy and Safety Assessment of 5‐Fluorouracil, Irinotecan and Oxaliplatin‐Loaded Implants in Mouse and Pig Models for Pancreatic Cancer Therapy
Abstract
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to treatment, with mortality rates largely unchanged despite advances in cancer therapies. For ∼80% of borderline, non‐resectable, or metastatic cases, chemotherapy is predominantly palliative, underscoring the need for improved drug delivery approaches. This study presents the development, characterization and in vivo evaluation of a novel polymeric implant loaded with 5‐fluorouracil, irinotecan, and oxaliplatin (FIRINOX). Scanning electron microscopy of FIRINOX implants showed internal microstructure was preserved upon drug loading, while micro‐CT and X‐ray imaging revealed valuable insights into the morphology and degradation of implants retrieved from in vivo experiments. In murine PDAC models, dose‐escalation identified 4 × FIRINOX implants as the maximum tolerated dose, while 2 × implants achieved significant therapeutic efficacy at lower doses than IV administration, without compromising animal safety. In healthy pigs, 20 × FIRINOX implants were well‐tolerated, as confirmed by histopathology and blood analysis. Finally, laser ablation‐inductively coupled plasma‐mass spectrometry imaging and microbiome analysis confirmed localized drug perfusion within tissues, and minimal off‐target effects, including preservation of gut microbiota diversity. These findings support the potential of this implantable platform to improve outcomes in borderline or non‐resectable PDAC and enhance tolerability of cytotoxic chemotherapy through localized, controlled delivery, addressing a key gap where current treatment options are limited.
Article Details
Authors (20)
Samantha J. Wade
School of Science, Molecular Horizons University of Wollongong Wollongong NSW Australia
Ashna A. Kumar
School of Science, Molecular Horizons Research Institute University of Wollongong Wollongong New South Wales Australia
Samuel O. Nitschke
School of Pharmacy and Biomedical Science Adelaide University Adelaide SA Australia
Paul Joyce
School of Pharmacy and Biomedical Science Adelaide University Adelaide SA Australia
Elahe Minaei
School of Science, Molecular Horizons University of Wollongong Wollongong NSW Australia
Stephanie E. Reuter
School of Pharmacy and Biomedical Science Adelaide University Adelaide SA Australia
Chelsea Penney
School of Science, Molecular Horizons University of Wollongong Wollongong NSW Australia
Holly Warren
School of Science, Molecular Horizons University of Wollongong Wollongong NSW Australia
Ruby Shepherd
School of Science, Molecular Horizons University of Wollongong Wollongong NSW Australia
Jeremy N. Dinoro
Intelligent Polymer Research Institute and Australian National Fabrication Facility ‐ Materials Node Innovation Campus University of Wollongong Wollongong NSW Australia
Gordon G. Wallace
Anthony Dosseto
Sameera Ansar
Southern IML Pathology Sonic Healthcare Coniston NSW Australia
Naila Islam
Southern IML Pathology Sonic Healthcare Coniston NSW Australia
Alistair Lochhead
Southern IML Pathology Sonic Healthcare Coniston NSW Australia
George Sharbeen
Phoebe A. Phillips
Morteza Aghmesheh
Nelune Comprehensive Cancer Centre Bright Building Prince of Wales Hospital Sydney NSW Australia
Wayne J. Hawthorne
Faculty of Medicine and Health University of Sydney Westmead NSW Australia
Kara L. Vine‐Perrow
School of Science, Molecular Horizons University of Wollongong Wollongong NSW Australia