To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?
Abstract
Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the "royal gate" in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine.
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Optimization of nanomedicine design to enhance the EPR effect is one of the strategies proposed, as well as combination with external stimuli, including ultrasounds, radiotherapy or hyperthermia or usage of nanomedicine modified with cell-penetrating peptides.
“Optimization of nanomedicine design to enhance the EPR effect is also one of the strategies that are proposed, as well as a combination of the nanomedicine with the external stimuli, including ultrasounds, radiotherapy or hyperthermia or usage of nanomedicine modified with the cell-penetrating peptides [157].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [157]
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- Authors
- Danhier, F.
- Affiliations
- UCLouvain (BE)
- Corresponding author
- Danhier, F.
- ORCID
- Danhier, F.
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 244
- Issue
- Pt A
- Pages
- 108-121
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2549628327
- Cited by
- 1,288
- References
- 108
- Citations by year
- 2026: 91 · 2025: 101 · 2024: 113 · 2023: 130 · 2022: 153 · 2021: 197 · 2020: 208 · 2019: 125 · 2018: 102 · 2017: 57
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Funders
- Fonds National de la recherché Scientifique (F.R.S.-FNRS)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- tumor microenvironment, enhanced permeability and retention effect, nanomedicine, anticancer drug delivery, tumor targeting, nanoparticle delivery
- MeSH terms
- Tumor Hypoxia, Antineoplastic Agents, Extracellular Matrix, Humans, Neoplasms, Permeability, Biomarkers, Tumor, Drug Delivery Systems, Nanostructures, Nanomedicine, Tumor Microenvironment
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