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

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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 33926

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Dr. Jun Fang

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Guest Editor

Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
Interests: nanomedicine; tumor-targeting; EPR effect; carbon monoxide; inflammation; reactive oxygen species
Special Issues, Collections and Topics in MDPI journals

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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

Jump to: Research, Review

3 pages, 178 KiB

Open AccessEditorial

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 17 | Viewed by 2930

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 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

3 pages, 178 KiB

Open AccessEditorial

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 2144

Abstract

In the mid-70s of the last century, Prof [...] Full article

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

Research

Jump to: Editorial, Review

11 pages, 2324 KiB

Open AccessArticle

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 2651

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 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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12 pages, 1618 KiB

Open AccessArticle

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 2343

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, 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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18 pages, 4307 KiB

Open AccessArticle

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 2243

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 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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12 pages, 3099 KiB

Open AccessArticle

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 2207

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 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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20 pages, 5651 KiB

Open AccessArticle

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 2817

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 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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Review

Jump to: Editorial, Research

25 pages, 6517 KiB

Open AccessReview

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 3306

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 (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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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20 pages, 2985 KiB

Open AccessEditor’s ChoiceReview

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 25 | Viewed by 5399

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 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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36 pages, 2100 KiB

Open AccessReview

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 63 | Viewed by 6799

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, 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

(This article belongs to the Special Issue EPR Effect-Based Cancer Targeted Therapy: Commemorative Issue in Honor of Professor Hiroshi Maeda)

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