EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Personalized Therapy and Drug Delivery".

Deadline for manuscript submissions: closed (10 November 2022) | Viewed by 32846

Special Issue Editor

Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
Interests: nanomedicine; tumor-targeting; EPR effect; carbon monoxide; inflammation; reactive oxygen species
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Special Issue Information

Dear Colleagues,

This Special Issue of the Journal of Personalized Medicine entitled “EPR Effect-Based Cancer Targeted Therapy” is dedicated to Professor Hiroshi Maeda, the founder of the concept of the EPR effect, on the occasion of his unexpected passing.

Professor Maeda (1938–2021) was one of the most distinguished and influential scientists in the field of tumor targeting and nanomedicine, as well as in the field of reactive oxygen species (ROS) and viral infection. He graduated from Tohoku University, Japan (1962), followed by a master’s degree and PhD at the University of California, Davis (1962–1964), and Tohoku University (1964–1968), respectively. He carried out his postdoc study at the Dana-Farber Cancer Institute, Harvard University (1968–1971), which paved the way to his professorship at Tohoku University (1971–1981) and then Kumamoto University School of Medicine (1981–2004), where he developed the first polymer anticancer drug SMANCS and discovered the EPR effect with his colleague Dr. Matsumura. Now, the EPR effect has been becoming the basic concept of tumor targeting using nanomedicine and a standard for designing nanomedicine. In addition to the EPR effect, he was also the one who first reported that ROS is the major cause of pneumonia in influenza infection and that removal of ROS could effectively improve the progression of the disease, which I believe is a mechanism that could be applied to COVID-19-induced pneumonia. His scientific excellence and integrative personality were internationally recognized with numerous awards, including the Asagawa Award of the Japanese Society for Bacteriology (1995), Princess Takamatsu Cancer Research Fund Prizes (1997), Frey-Werle Award/Commemorative Gold Medal (1998), Life Time Achievement Award of the Royal Society of Pharmacy (2007), Nagai Award of the Japan Society of Drug Delivery System (2011), the Tomizo Yoshida Prize of the Japanese Cancer Association (2011), Thomson Reuters Citation Laureate (2016), Wayne State University Roland T. Lakey Award (2017), and the Order of the Sacred Treasure, Gold Rays with Neck Ribbon, Cabinet Office, Japan (2018).

Professor Maeda was a real scientist and excellent mentor. He developed various anticancer nanomedicines and carried out efforts for clinical application until his last day. Conquering Cancer and helping cancer patients were his lifelong dream, and we strongly believe this dream will become true, and EPR-based nanomedicine will be a solution to cancer.

We invite researchers to submit review articles and original articles for an in-depth understanding of the EPR effect and further exploitation of its effect on human cancer. New strategies for enhancement of the EPR effect using nanomedicine and imaging technology with the help of nanosize fluorogenic agents will be welcome.

Dr. Jun Fang
Guest Editor

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Keywords

  • EPR effect
  • nanomedicine macromolecular drugs
  • tumor delivery
  • tumor targeting
  • tumor imaging
  • tumor selectivity
  • tumor vasculature
  • drug retention

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Published Papers (10 papers)

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Editorial

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3 pages, 178 KiB  
Editorial
Thinking about Enhanced Permeability and Retention Effect (EPR)
by Stefano Leporatti
J. Pers. Med. 2022, 12(8), 1259; https://doi.org/10.3390/jpm12081259 - 30 Jul 2022
Cited by 16 | Viewed by 2834
Abstract
This invited editorial article aims at reporting progress about the enhanced permeability and retention effect (EPR for short), starting from a recent Special Issue in the Journal of Personalized Medicine (namely, “EPR Effect-Based Tumor Targeted Nanomedicine”) and focusing specifically on one of these [...] Read more.
This invited editorial article aims at reporting progress about the enhanced permeability and retention effect (EPR for short), starting from a recent Special Issue in the Journal of Personalized Medicine (namely, “EPR Effect-Based Tumor Targeted Nanomedicine”) and focusing specifically on one of these contributing articles, a review from Jun Wu entitled “The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application”, which has recently acquired the rank of a highly cited paper [...] Full article
3 pages, 178 KiB  
Editorial
The Journey of an Outstanding Scientific Mind: Prof Hiroshi Maeda (1938–2021)
by Khaled Greish and Jun Fang
J. Pers. Med. 2021, 11(12), 1362; https://doi.org/10.3390/jpm11121362 - 14 Dec 2021
Viewed by 2105
Abstract
In the mid-70s of the last century, Prof [...] Full article

Research

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11 pages, 2324 KiB  
Article
Singlet Oxygen In Vivo: It Is All about Intensity
by Steffen Hackbarth, Rayhanul Islam, Vladimír Šubr, Tomáš Etrych and Jun Fang
J. Pers. Med. 2022, 12(6), 891; https://doi.org/10.3390/jpm12060891 - 28 May 2022
Cited by 5 | Viewed by 2597
Abstract
The presented work addresses the influence of illumination intensity on the amount and locations of singlet oxygen generation in tumor tissue. We used time-resolved optical detection at the typical emission wavelength around 1270 nm and at 1200 nm where there is no singlet [...] Read more.
The presented work addresses the influence of illumination intensity on the amount and locations of singlet oxygen generation in tumor tissue. We used time-resolved optical detection at the typical emission wavelength around 1270 nm and at 1200 nm where there is no singlet oxygen phosphorescence to determine the phosphorescence kinetics. The discussed data comprise in vivo measurements in tumor-laden HET-CAM and mice. The results show that illumination that is too intense is a major issue, affecting many PDT treatments and all singlet oxygen measurements in vivo so far. In such cases, photosensitization and oxygen consumption exceed oxygen supply, limiting singlet oxygen generation to the blood vessels and walls, while photosensitizers in the surrounding tissue will likely not participate. Being a limitation for the treatment, on one hand, on the other, this finding offers a new method for tumor diagnosis when using photosensitizers exploiting the EPR effect. In contrast to high-intensity PDT, some papers reported successful treatment with nanoparticular drugs using much lower illumination intensity. The question of whether, with such illumination, singlet oxygen is indeed generated in areas apart from vessels and walls, is addressed by numerical analysis. In addition, we discuss how to perform measurements at such low intensities. Full article
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12 pages, 1618 KiB  
Article
Effect of Tumor Targeted-Anthracycline Nanomedicine, HPMA Copolymer-Conjugated Pirarubicin (P-THP) against Gynecological Malignancies
by Shintaro Yanazume, Jun Fang, Rayhanul Islam, Shanghui Gao and Hiroaki Kobayashi
J. Pers. Med. 2022, 12(5), 814; https://doi.org/10.3390/jpm12050814 - 18 May 2022
Cited by 1 | Viewed by 2279
Abstract
Anthracyclines are important for the treatment of gynecological malignancies, but their effects are modest, and one of the major reasons is the lack of a tumor-targeting property. To overcome this drawback, a poly (hydroxypropyl meta-acrylamide) conjugated with tetrahydropyraryl doxorubicin (P-THP) has been developed, [...] Read more.
Anthracyclines are important for the treatment of gynecological malignancies, but their effects are modest, and one of the major reasons is the lack of a tumor-targeting property. To overcome this drawback, a poly (hydroxypropyl meta-acrylamide) conjugated with tetrahydropyraryl doxorubicin (P-THP) has been developed, which exhibits a highly tumor-specific accumulation owing to the enhanced permeability and retention effect. The effect of P-THP has been confirmed by using various cell lines and solid tumor models, while its effect on gynecological malignancies have not been investigated. In this regard, human uterine sarcoma cell line with metastatic potential MEA-SA C9 high, epithelial ovarian cancer cell line A2780 and its cisplatin-resistant line A2780cis, and DOX-resistant line A2780ADR were used in this study, and the therapeutic effect as well as the safety profiles of P-THP were investigated compared to native THP, cisplatin, and paclitaxel, which are commonly used for gynecological malignancies, both in vitro and in vivo. Similar to native THP, a dose-dependent toxicity of P-THP was identified in all cell lines. Moreover, the IC50 values in the 3 h following P-THP were 1.5–10 times higher than those at 72 h, though the intracellular uptake of P-THP in all cells were 2–10-fold less than THP. In vivo studies using xenograft tumor models revealed that P-THP significantly suppressed the MES-SA C9 high, A2780, and A2780cis tumor growth at the dose of 15 mg/kg (THP equivalent), which is three times above the maximal tolerance dose of native THP, while no body weight loss or acute death occurred. However, in A2780ADR cells and the xenograft model, no significant difference in the therapeutic effect was observed between THP and P-THP, suggesting that P-THP exhibits its effect depending on the release of the active free THP in tumor tissues, and thus the internalization into tumor cells. These findings indicates that P-THP has the potential as a therapeutic for gynecological malignancies to improve the therapeutic outcomes and survival rates of patients, even in refractory patients. Full article
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18 pages, 4307 KiB  
Article
Tumor Stimulus-Responsive Biodegradable Diblock Copolymer Conjugates as Efficient Anti-Cancer Nanomedicines
by Vladimír Šubr, Robert Pola, Shanghui Gao, Rayhanul Islam, Takuma Hirata, Daiki Miyake, Kousuke Koshino, Jian-Rong Zhou, Kazumi Yokomizo, Jun Fang and Tomáš Etrych
J. Pers. Med. 2022, 12(5), 698; https://doi.org/10.3390/jpm12050698 - 27 Apr 2022
Viewed by 2207
Abstract
Biodegradable nanomedicines are widely studied as candidates for the effective treatment of various cancerous diseases. Here, we present the design, synthesis and evaluation of biodegradable polymer-based nanomedicines tailored for tumor-associated stimuli-sensitive drug release and polymer system degradation. Diblock polymer systems were developed, which [...] Read more.
Biodegradable nanomedicines are widely studied as candidates for the effective treatment of various cancerous diseases. Here, we present the design, synthesis and evaluation of biodegradable polymer-based nanomedicines tailored for tumor-associated stimuli-sensitive drug release and polymer system degradation. Diblock polymer systems were developed, which enabled the release of the carrier drug, pirarubicin, via a pH-sensitive spacer allowing for the restoration of the drug cytotoxicity solely in the tumor tissue. Moreover, the tailored design enables the matrix-metalloproteinases- or reduction-driven degradation of the polymer system into the polymer chains excretable from the body by glomerular filtration. Diblock nanomedicines take advantage of an enhanced EPR effect during the initial phase of nanomedicine pharmacokinetics and should be easily removed from the body after tumor microenvironment-associated biodegradation after fulfilling their role as a drug carrier. In parallel with the similar release profiles of diblock nanomedicine to linear polymer conjugates, these diblock polymer conjugates showed a comparable in vitro cytotoxicity, intracellular uptake, and intratumor penetration properties. More importantly, the diblock nanomedicines showed a remarkable in vivo anti-tumor efficacy, which was far more superior than conventional linear polymer conjugates. These findings suggested the advanced potential of diblock polymer conjugates for anticancer polymer therapeutics. Full article
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12 pages, 3099 KiB  
Article
Decrease of Hyaluronidase Activity and Suppression of Mouse CD4+ T Lymphocyte Activation by Tomato Juice Saponin Esculeoside B, and Its Sapogenol Esculeogenin B
by Jian-Rong Zhou, Nozomi Kitahara, Honami Nakamura, Takuya Ono, Ryohei Karashima, Jun Fang, Toshihiro Nohara and Kazumi Yokomizo
J. Pers. Med. 2022, 12(4), 579; https://doi.org/10.3390/jpm12040579 - 5 Apr 2022
Cited by 1 | Viewed by 2154
Abstract
(1) Background: A naturally occurring glycoside, esculeoside B (EsB), has been identified as a major component in juice or canned tomato. We reported how EsB ameliorated mice experimental atopic dermatitis by a decrease in serum IgE levels. However, the underlying immunologic molecular mechanisms [...] Read more.
(1) Background: A naturally occurring glycoside, esculeoside B (EsB), has been identified as a major component in juice or canned tomato. We reported how EsB ameliorated mice experimental atopic dermatitis by a decrease in serum IgE levels. However, the underlying immunologic molecular mechanisms are unknown. (2) Methods: The present study tested the effects of EsB on hyaluronidase activity and CD4+ T lymphocyte activation using concanavalin A (ConA)-blast mouse splenocyte primary culture. (3) Results: We found that EsB and its sapogenol esculeogenin B (Esg-B) decreased hyaluronidase activity by a modified Morgan–Elson method. We demonstrated that EsB/Esg-B dose-dependently suppressed T-lymphoproliferation using CFSE-labeled flow-cytometry and water-soluble tetrazolium (WST) assay. Using ELISA and q-PCR methods, EsB/Esg-B suppressed the cytokine secretion and mRNA expression of Th2-relevant IL-4 and Th1-relevant IFN-γ. Moreover, both EsB/Esg-B showed a reduction in IL-10 secretion, but only Esg-B decreased IL-2 secretion. (4) Conclusions: Our study is the first to demonstrate how EsB/Esg-B inhibit hyaluronidase activity and reduce CD4+ T-lymphocyte activation via a reduction in Th2-lymphocyte activity by modulation of Th2/Th1/Treg subunits differentiation. Full article
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20 pages, 5651 KiB  
Article
Poly(styrene-co-maleic acid) Micelle of Photosensitizers for Targeted Photodynamic Therapy, Exhibits Prolonged Singlet Oxygen Generating Capacity and Superior Intracellular Uptake
by Gahininath Yadavrao Bharate, Haibo Qin and Jun Fang
J. Pers. Med. 2022, 12(3), 493; https://doi.org/10.3390/jpm12030493 - 18 Mar 2022
Cited by 3 | Viewed by 2757
Abstract
Targeted therapy by using nanomedicines based on the enhanced permeability and retention (EPR) effect is becoming a promising anticancer strategy. Many nano-designed photosensitizers (PSs) for photodynamic therapy (PDT) have been developed which show superior therapeutic potentials than free PS. To further understand the [...] Read more.
Targeted therapy by using nanomedicines based on the enhanced permeability and retention (EPR) effect is becoming a promising anticancer strategy. Many nano-designed photosensitizers (PSs) for photodynamic therapy (PDT) have been developed which show superior therapeutic potentials than free PS. To further understand the advantages of nano-designed PS, in this study, we used styrene-co-maleyl telomer (SMA) as a polymer platform to prepare a micellar type of PS with two well-characterized PSs—rose bengal (RB) and methylene blue (MB)—and evaluated the outmatching benefits of SMA-PS micelles, especially focusing on the singlet oxygen (1O2) generation capacity and intracellular uptake profiles. In aqueous solutions, SMA-PS self-assembles to form micelles by non-covalent interactions between PS and SMA. SMA-PS micelles showed discrete distributions by dynamic light scattering having a mean particle size of 18–30 nm depending on the types of SMA and different PSs. The hydrodynamic size of SMA-PS was evaluated by Sephadex chromatography and it found to be 30–50 kDa. In the presence of human serum albumin, the sizes of SMA-PS remarkably increased, suggesting the albumin-binding property. 1O2 generation from the SMA-PS micelle was determined by electron spin resonance, in which the SMA-PS micelle showed comparatively more photo-stable, and consequently a more durable and constant, 1O2 generation capability than free PS. Moreover, intracellular uptake of SMA-PS micelles was extensively faster and higher than free PS, especially in tumor cells. Taken together, SMA-PS micelles appear highly advantageous for photodynamic therapy in addition to its capacity in utilizing the EPR effect for tumor targeted delivery. Full article
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Review

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25 pages, 6517 KiB  
Review
Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis
by Md Abdus Subhan, Farzana Parveen, Nina Filipczak, Satya Siva Kishan Yalamarty and Vladimir P. Torchilin
J. Pers. Med. 2023, 13(3), 389; https://doi.org/10.3390/jpm13030389 - 23 Feb 2023
Cited by 22 | Viewed by 3159
Abstract
The innovative development of nanomedicine has promised effective treatment options compared to the standard therapeutics for cancer therapy. However, the efficiency of EPR-targeted nanodrugs is not always pleasing as it is strongly prejudiced by the heterogeneity of the enhanced permeability and retention effect [...] Read more.
The innovative development of nanomedicine has promised effective treatment options compared to the standard therapeutics for cancer therapy. However, the efficiency of EPR-targeted nanodrugs is not always pleasing as it is strongly prejudiced by the heterogeneity of the enhanced permeability and retention effect (EPR). Targeting the dynamics of the EPR effect and improvement of the therapeutic effects of nanotherapeutics by using EPR enhancers is a vital approach to developing cancer therapy. Inadequate data on the efficacy of EPR in humans hampers the clinical translation of cancer drugs. Molecular targeting, physical amendment, or physiological renovation of the tumor microenvironment (TME) are crucial approaches for improving the EPR effect. Advanced imaging technologies for the visualization of EPR-induced nanomedicine distribution in tumors, and the use of better animal models, are necessary to enhance the EPR effect. This review discusses strategies to enhance EPR effect-based drug delivery approaches for cancer therapy and imaging technologies for the diagnosis of EPR effects. The effort of studying the EPR effect is beneficial, as some of the advanced nanomedicine-based EPR-enhancing approaches are currently undergoing clinical trials, which may be helpful to improve EPR-induced drug delivery and translation to clinics. Full article
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20 pages, 2985 KiB  
Review
Enhanced Permeability and Retention Effect as a Ubiquitous and Epoch-Making Phenomenon for the Selective Drug Targeting of Solid Tumors
by Waliul Islam, Takuro Niidome and Tomohiro Sawa
J. Pers. Med. 2022, 12(12), 1964; https://doi.org/10.3390/jpm12121964 - 28 Nov 2022
Cited by 24 | Viewed by 5187
Abstract
In 1979, development of the first polymer drug SMANCS [styrene-co-maleic acid (SMA) copolymer conjugated to neocarzinostatin (NCS)] by Maeda and colleagues was a breakthrough in the cancer field. When SMANCS was administered to mice, drug accumulation in tumors was markedly increased compared with [...] Read more.
In 1979, development of the first polymer drug SMANCS [styrene-co-maleic acid (SMA) copolymer conjugated to neocarzinostatin (NCS)] by Maeda and colleagues was a breakthrough in the cancer field. When SMANCS was administered to mice, drug accumulation in tumors was markedly increased compared with accumulation of the parental drug NCS. This momentous result led to discovery of the enhanced permeability and retention effect (EPR effect) in 1986. Later, the EPR effect became known worldwide, especially in nanomedicine, and is still believed to be a universal mechanism for tumor-selective accumulation of nanomedicines. Some research groups recently characterized the EPR effect as a controversial concept and stated that it has not been fully demonstrated in clinical settings, but this erroneous belief is due to non-standard drug design and use of inappropriate tumor models in investigations. Many research groups recently provided solid evidence of the EPR effect in human cancers (e.g., renal and breast), with significant diversity and heterogeneity in various patients. In this review, we focus on the dynamics of the EPR effect and restoring tumor blood flow by using EPR effect enhancers. We also discuss new applications of EPR-based nanomedicine in boron neutron capture therapy and photodynamic therapy for solid tumors. Full article
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36 pages, 2100 KiB  
Review
The Promise of Nanotechnology in Personalized Medicine
by Maha Ali Alghamdi, Antonino N. Fallica, Nicola Virzì, Prashant Kesharwani, Valeria Pittalà and Khaled Greish
J. Pers. Med. 2022, 12(5), 673; https://doi.org/10.3390/jpm12050673 - 22 Apr 2022
Cited by 58 | Viewed by 6465
Abstract
Both personalized medicine and nanomedicine are new to medical practice. Nanomedicine is an application of the advances of nanotechnology in medicine and is being integrated into diagnostic and therapeutic tools to manage an array of medical conditions. On the other hand, personalized medicine, [...] Read more.
Both personalized medicine and nanomedicine are new to medical practice. Nanomedicine is an application of the advances of nanotechnology in medicine and is being integrated into diagnostic and therapeutic tools to manage an array of medical conditions. On the other hand, personalized medicine, which is also referred to as precision medicine, is a novel concept that aims to individualize/customize therapeutic management based on the personal attributes of the patient to overcome blanket treatment that is only efficient in a subset of patients, leaving others with either ineffective treatment or treatment that results in significant toxicity. Novel nanomedicines have been employed in the treatment of several diseases, which can be adapted to each patient-specific case according to their genetic profiles. In this review, we discuss both areas and the intersection between the two emerging scientific domains. The review focuses on the current situation in personalized medicine, the advantages that can be offered by nanomedicine to personalized medicine, and the application of nanoconstructs in the diagnosis of genetic variability that can identify the right drug for the right patient. Finally, we touch upon the challenges in both fields towards the translation of nano-personalized medicine. Full article
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