An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

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Abstract

The enhanced permeability and retention (EPR) effect in cancer treatment is one of the key mechanisms that enables drug accumulation at the tumor site. However, despite a plethora of virus/inorganic/organic-based nanocarriers designed to rely on the EPR effect to effectively target tumors, most have failed in the clinic. It seems that the non-compliance of research activities with clinical trials, goals unrelated to the EPR effect, and lack of awareness of the impact of solid tumor structure and interactions on the performance of drug nanocarriers have intensified this dissatisfaction. As such, the asymmetric growth and structural complexity of solid tumors, physicochemical properties of drug nanocarriers, EPR analytical combination tools, and EPR description goals should be considered to improve EPR-based cancer therapeutics. This review provides valuable insights into the limitations of the EPR effect in therapeutic efficacy and reports crucial perspectives on how the EPR effect can be modulated to improve the therapeutic effects of nanomedicine.

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To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?

F Danhier (2016)

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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Nanoparticle Uptake: The Phagocyte Problem.

Heather Herd Gustafson, Dolly Holt-Casper, David Grainger … (2015)

Phagocytes are key cellular participants determining important aspects of host exposure to nanomaterials, initiating clearance, biodistribution and the tenuous balance between host tolerance and adverse nanotoxicity. Macrophages in particular are believed to be among the first and primary cell types that process nanoparticles, mediating host inflammatory and immunological biological responses. These processes occur ubiquitously throughout tissues where nanomaterials are present, including the host mononuclear phagocytic system (MPS) residents in dedicated host filtration organs (i.e., liver, kidney spleen, and lung). Thus, to understand nanomaterials exposure risks it is critical to understand how nanomaterials are recognized, internalized, trafficked and distributed within diverse types of host macrophages and how possible cell-based reactions resulting from nanomaterial exposures further inflammatory host responses in vivo. This review focuses on describing macrophage-based initiation of downstream hallmark immunological and inflammatory processes resulting from phagocyte exposure to and internalization of nanomaterials.

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The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo.

Hiroshi Maeda, Hideaki Nakamura, Jun Fang (2013)

The EPR effect results from the extravasation of macromolecules or nanoparticles through tumor blood vessels. We here provide a historical review of the EPR effect, including its features, vascular mediators found in both cancer and inflamed tissue. In addition, architectural and physiological differences of tumor blood vessels vs that of normal tissue are commented. Furthermore, methods of augmentation of the EPR effect are described, that result in better tumor delivery and improved therapeutic effect, where nitroglycerin, angiotensin I-converting enzyme (ACE) inhibitor, or angiotensin II-induced hypertension are employed. Consequently, better therapeutic effect and reduced systemic toxicity are generally observed. Obviously, the EPR effect based delivery of nanoprobes are also useful for tumor-selective imaging agents with using fluorescent or radio nuclei in nanoprobes. We also commented a key difference between passive tumor targeting and the EPR effect in tumors, particularly as related to drug retention in tumors: passive targeting of low-molecular-weight X-ray contrast agents involves a retention period of less than a few minutes, whereas the EPR effect of nanoparticles involves a prolonged retention time-days to weeks. Copyright © 2012 Elsevier B.V. All rights reserved.