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Open AccessArticle
Targeting Hypoxia-Inducible Factor-1α in Pancreatic Cancer: siRNA Delivery Using Hyaluronic Acid-Displaying Nanoparticles
by
Alice Spadea
Alice Spadea
Alice Spadea received her PhD in Pharmacy from the University of Manchester, UK in 2018, and she is [...]
Alice Spadea received her PhD in Pharmacy from the University of Manchester, UK in 2018, and she is currently working as a postdoctoral researcher at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany. She was recently awarded the MSCA postdoctoral fellowship and the DFG Walter Benjamin postdoctoral fellowship. She previously worked as a Research Associate at the North West Centre of Advanced Drug Delivery (NoWCADD), co-funded by AstraZeneca and the University of Manchester, from 2018 to 2022. In 2022, she joined the Max Planck Institute, focusing on endosomal escape of lipid-based nanoparticles for nucleic acid delivery. Her research topics primarily include nanomedicine, tumor targeting, and gene therapy, with a particular emphasis on endosomal escape mechanisms and the development of nanoparticles for gene editing. Dr. Spadea has considerable experience in both in vitro and in vivo experiments and has contributed to several high-impact publications in the field.
,
Annalisa Tirella
Annalisa Tirella
Julio Manuel Rios de la Rosa
Julio Manuel Rios de la Rosa
Enrique Lallana
Enrique Lallana
Manal Mehibel
Manal Mehibel
Brian Telfer
Brian Telfer
Nicola Tirelli
Nicola Tirelli
Margaret Jayne Lawrence
Margaret Jayne Lawrence
Prof. Margaret Jayne Lawrence is currently Director of the University of Manchester at Harwell, she [...]
Prof. Margaret Jayne Lawrence is currently Director of the University of Manchester at Harwell, where she is responsible for the management of University activities at Harwell, and for promoting its activities to external stakeholders and funders. She is also Director of the North West Centre for Advanced Drug Delivery based in the Division of Pharmacy and Optometry at Manchester University. Before taking up the Harwell role, Prof. Lawrence was Head of the Division of Pharmacy and Optometry at the University (2017–2023). Prior to joining the University in 2017, she was Professor and Head of the Pharmaceutical Biophysics Group, Institute of Pharmaceutical Science, King’s College London (2003–2017) while concurrently serving as Chief Scientist at the Royal Pharmaceutical Society (2007–2016) where she was responsible for promoting pharmacy and pharmacy science to other related professionals, to government and other policy makers, and in the media. Prof. Lawrence was member of the Pharmacy Unit of Assessment for the 2008 Research Assessment Exercise and of Unit of Assessment 3 in the 2021 Research Excellence Framework. She was awarded a Member of Order of the British Empire for services to Pharmaceutical Science in the 2020 Queen’s Birthday Honours (2020).
Kaye J. Williams
Kaye J. Williams
Prof. Kaye j Williams is the Leader of the Hypoxia and Therapeutics Group within the Division of and [...]
Prof. Kaye j Williams is the Leader of the Hypoxia and Therapeutics Group within the Division of Pharmacy and Optometry at the University of Manchester. Prof. Williams joined DPO in November 1996. Following back-to-back research associate and research fellow positions funded by the MRC, she gained tenure in January 2006, and was promoted to Chair in Experimental Therapeutics and Imaging in August 2012. Her research focuses on the tumour microenvironment, investigating therapeutic targets, vascular biology and molecular interactions that influence tumour response to radiotherapy. Prof. Williams also leads pre-clinical imaging development within the Manchester Cancer Research Centre, and has leadership for preclinical imaging within Imaging@Manchester. Externally, she has had significant roles in the NCRI Clinical and Translational Radiotherapy Research Working Group, in particular through association with the RadCom initiative that aimed to expedite novel drug radiation combinations into clinical trials. She continues to provide leadership in this area via the CRUK Drug–Radiotherapy Working Group. She is part of the team that secured £16.5 million for the University of Manchester towards infrastructure funding in radiation-related research via the CRUK RadNET initiative and currently acts as Deputy Director of CRUK RadNET Manchester. She was awarded the British Association for Cancer
Research/AstraZeneca Frank Rose Young Scientist Award in 2005.
Ian J. Stratford
Ian J. Stratford
Prof. Ian J Stratford obtained a B.Sc in Chemistry from the University of Exeter and subsequently a [...]
Prof. Ian J Stratford obtained a B.Sc in Chemistry from the University of Exeter and subsequently a PhD in Radiation Biology from Manchester University where he is now Professor of Pharmacy. He secured continuous programme grant support from the Medical Research Council between 1981 and 2010 and in addition, secured sustantive funding from the cancer charities and industry. He currently leads a small team of post-graduates and research associates and the focus of their research is twofold: 1. to enhance the effects of radiotherapy by using molecularly targeted drugs and 2. to exploit tumour energy metabolism to improve cancer therapy. In 2015, Prof. Stratford was awarded the Weiss Medal at the quadrennial International Congress for Radiation Research for contributions to and achievements in radiation research.
Marianne Ashford
Marianne Ashford
Dr. Marianne Ashford is an Honorary Professor at the University of Nottingham and serves on numerous [...]
Dr. Marianne Ashford is an Honorary Professor at the University of Nottingham and serves on numerous academic and industrial scientific committees and advisory boards in the field of drug delivery. In her role in AstraZeneca, she is responsible for applying drug delivery approaches which have the potential to enable the progression of innovative medicines. She has been instrumental in introducing nanomedicines into the AstraZeneca portfolio, and initiated several key collaborations, building internal capability in nanomedicines and drug targeting. She has a PhD in oral drug delivery to the colon, and a degree in Pharmacy from the University of Manchester.
1
NorthWest Centre for Advanced Drug Delivery (NoWCADD), School of Health Science, University of Manchester, Oxford Road, Manchester M13 9PT, UK
2
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany
3
Division of Pharmacy and Optometry, School of Health Science, University of Manchester, Oxford Road, Manchester M13 9PT, UK
4
BIOtech Research Centre, Department of Industrial Engineering, University of Trento, 38122 Trento, Italy
5
Instituto de Investigacion e Innovacion Biomedica de Cadiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cadiz, Spain
6
EM Analytical Ltd., Media House, Adlington SK10 4NL, UK
7
Precision Medicine Oncology, Abbvie Bay Area, 1000 Gateway Boulevard, South San Francisco, CA 94080, USA
8
Laboratory of Polymers and Biomaterials, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
9
Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield M13 9PT, UK
*
Author to whom correspondence should be addressed.
Pharmaceutics 2024, 16(10), 1286; https://doi.org/10.3390/pharmaceutics16101286 (registering DOI)
Submission received: 20 August 2024
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Revised: 16 September 2024
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Accepted: 29 September 2024
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Published: 30 September 2024
Abstract
Background/Objectives: Conventional anticancer therapies often lack specificity, targeting both cancerous and normal cells, which reduces efficacy and leads to undesired off-target effects. An additional challenge is the presence of hypoxic regions in tumors, where the Hypoxia Inducible Factor (HIF) transcriptional system drives the expression of pro-survival and drug resistance genes, leading to radio- and chemo-resistance. This study aims to explore the efficacy of targeted nanoparticle (NP)-based small interfering RNA (siRNA) therapies in downregulating these genes to enhance treatment outcomes in pancreatic cancer, a tumor type characterized by high CD44 expression and hypoxia. Methods: We utilized hyaluronic acid (HA)-displaying nanoparticles composed of positively charged chitosan (CS) complexed with siRNA to target and knock down HIF-1α in pancreatic cancer cells. Two NP formulations were prepared using either low molecular weight (LMW) or high molecular weight (HMW) CS. These formulations were evaluated for their internalization by cells and their effectiveness in gene silencing, both in vitro and in vivo. Results: The study found that the molecular weight (MW) of CS influenced the interaction between HA and CD44, as well as the release of siRNA upon internalization. The LMW CS formulation shows faster uptake kinetics, while HMW CS is more effective in gene knockdown across different cell lines in vitro. In vivo, both were able to significantly knockdown HIF-1α and some of its downstream genes. Conclusions: The results suggest that HMW and LMW CS-based NPs exhibit distinct characteristics, showing that both MWs have potential for targeted pancreatic cancer therapy by influencing different aspects of delivery and gene silencing, particularly in the hypoxic tumor microenvironment.
Share and Cite
MDPI and ACS Style
Spadea, A.; Tirella, A.; Rios de la Rosa, J.M.; Lallana, E.; Mehibel, M.; Telfer, B.; Tirelli, N.; Lawrence, M.J.; Williams, K.J.; Stratford, I.J.;
et al. Targeting Hypoxia-Inducible Factor-1α in Pancreatic Cancer: siRNA Delivery Using Hyaluronic Acid-Displaying Nanoparticles. Pharmaceutics 2024, 16, 1286.
https://doi.org/10.3390/pharmaceutics16101286
AMA Style
Spadea A, Tirella A, Rios de la Rosa JM, Lallana E, Mehibel M, Telfer B, Tirelli N, Lawrence MJ, Williams KJ, Stratford IJ,
et al. Targeting Hypoxia-Inducible Factor-1α in Pancreatic Cancer: siRNA Delivery Using Hyaluronic Acid-Displaying Nanoparticles. Pharmaceutics. 2024; 16(10):1286.
https://doi.org/10.3390/pharmaceutics16101286
Chicago/Turabian Style
Spadea, Alice, Annalisa Tirella, Julio Manuel Rios de la Rosa, Enrique Lallana, Manal Mehibel, Brian Telfer, Nicola Tirelli, Margaret Jayne Lawrence, Kaye J. Williams, Ian J. Stratford,
and et al. 2024. "Targeting Hypoxia-Inducible Factor-1α in Pancreatic Cancer: siRNA Delivery Using Hyaluronic Acid-Displaying Nanoparticles" Pharmaceutics 16, no. 10: 1286.
https://doi.org/10.3390/pharmaceutics16101286
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