The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery—Personal Remarks and Future Prospects

Abstract

This Special Issue on the enhanced permeability and retention (EPR) effect commemorates the 35th anniversary of its discovery, the original 1986 Matsumura and Maeda finding being published in Cancer Research as a new concept in cancer chemotherapy. My review here describes the history and heterogeneity of the EPR effect, which involves defective tumor blood vessels and blood flow. We reported that restoring obstructed tumor blood flow overcomes impaired drug delivery, leading to improved EPR effects. I also discuss gaps between small animal cancers used in experimental models and large clinical cancers in humans, which usually involve heterogeneous EPR effects, vascular abnormalities in multiple necrotic foci, and tumor emboli. Here, I emphasize arterial infusion of oily formulations of nanodrugs into tumor-feeding arteries, which is the most tumor-selective drug delivery method, with tumor/blood ratios of 100-fold. This method is literally the most personalized medicine because arterial infusions differ for each patient, and drug doses infused depend on tumor size and anatomy in each patient. Future developments in EPR effect-based treatment will range from chemotherapy to photodynamic therapy, boron neutron capture therapy, and therapies for free radical diseases. This review focuses on our own work, which stimulated numerous scientists to perform research in nanotechnology and drug delivery systems, thereby spawning a new cancer treatment era.

EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect

“…Also, Lee et al reported that nanoparticles conjugated with positron-emitting radionuclei such as 64 Cu resulted the EPR effect in breast cancer, including metastatic cancer [20]. We demonstrated similar results by using arterial angiography of the polymer-conjugate drug SMANCS, i.e., neocarzinostatin (NCS) conjugated to poly(styrene-co-maleic acid) (SMA), in lipiodol [21][22][23][24]. In these situations, restoration of tumor blood flow led to successful treatments with nanomedicines [1,23,24].…”

Stimuli-Responsive Polymeric Nanoplatforms for Cancer Therapy

“…Passive targeting in cancer refers to the preferential accumulation of nanoparticles to the tumor tissues. Due to the leaky tumor vasculature and impaired lymphatic drainage, and the unique microenvironment surrounding the cancer cells, theranostic nanomaterials can accumulate and be retained in tumor tissues longer than in normal tissues, which is also called EPR effect (Overchuk and Zheng, 2018;He et al, 2019;Maeda, 2021). Passive targeting is directly associated with the nanoparticles' inherent properties, including size, shape, charge, flexibility, etc.…”

Ferrocifen Loaded Lipid Nanocapsules: A Promising Anticancer Medication against Multidrug Resistant Tumors

“…In the 1970s, the first nanomedicines were biodegradable but accumulated mainly in the liver. The second generation is characterized by the surface modification with hydrophilic molecules, mainly polyethylene glycol (PEG), in order to confer stealth properties and to passively accumulate in solid tumor tissues via the so-called enhanced permeation and retention (EPR) effect [ 14 , 15 ]. However, the EPR effect still divides the scientific community [ 16 , 17 ].…”