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Cited by 167Nanoparticle-Based Drug DeliveryUltrasound and Hyperthermia ApplicationsAngiogenesis and VEGF in Cancer

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

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Maeda, Hiroshi·2021·Journal of Personalized Medicine
DOI 10.3390/jpm11030229PMC PMC8004895
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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.

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Figures

Figure 1 The enhanced permeability and retention (EPR) effect in tumor vasculature. The mechanism of this tumor-selective macromolecular drug targeting depends on various effectors affecting vascular tone, as shown here. Aprotinin is an inhibitor of kallikrein; HOE-140 is a peptide antagonist of kinin. SBTI, soybean trypsin inhibitor; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; iNOS, inducible form of nitric oxide synthase; COXs, cyclooxygenases; PGs, prostaglandins; MMP, metalloproteinase; ONOO−, peroxynitrite; O2−, superoxide anion radical; MΦ, macrophage; VEGF, vascular endothelial growth factor; VPF, vascular permeability factor; uPA, urokinase plasminogen activator; IL, interleukin; TNF, tumor necrosis factor; B2 receptor, bradykinin B2 receptor (see also Supplementary Figure S1, adapted from ref [23]).
Figure 1 The enhanced permeability and retention (EPR) effect in tumor vasculature. The mechanism of this tumor-selective macromolecular drug targeting depends on various effectors affecting vascular tone, as shown here. Aprotinin is an inhibitor of kallikrein; HOE-140 is a peptide antagonist of kinin. SBTI, soybean trypsin inhibitor; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; iNOS, inducible form of nitric oxide synthase; COXs, cyclooxygenases; PGs, prostaglandins; MMP, metalloproteinase; ONOO−, peroxynitrite; O2−, superoxide anion radical; MΦ, macrophage; VEGF, vascular endothelial growth factor; VPF, vascular permeability factor; uPA, urokinase plasminogen activator; IL, interleukin; TNF, tumor necrosis factor; B2 receptor, bradykinin B2 receptor (see also Supplementary Figure S1, adapted from ref [23]).CC BY · PubMed Central
Figure 2 Comparison of the cellular uptake of P-THP—the poly(hydroxypropylmethaacrylamide [HPMA]) conjugate of pirarubicin (THP)—and P-DOX (HPMA polymer-DOX conjugate) by human pancreatic cancer cells (SUIT-2) in vitro. (A) Polymeric P-THP shows a far greater uptake by tumor cells compared with P-DOX: at 30 min, P-THP had a 33.2-fold higher uptake, and its cytotoxicity had greatly increased (see Table at lower left). (B) Penetration of P-DOX, DOX, P-THP, and THP into spheroidal tumor colon cancer (Adapted with permission from ref. [39,40]. 2016 American Chemical Society, 2019 American Chemical Society). Far greater penetration of P-THP into the tumor spheroid (similar to Figure 2, Table) is seen.
Figure 2 Comparison of the cellular uptake of P-THP—the poly(hydroxypropylmethaacrylamide [HPMA]) conjugate of pirarubicin (THP)—and P-DOX (HPMA polymer-DOX conjugate) by human pancreatic cancer cells (SUIT-2) in vitro. (A) Polymeric P-THP shows a far greater uptake by tumor cells compared with P-DOX: at 30 min, P-THP had a 33.2-fold higher uptake, and its cytotoxicity had greatly increased (see Table at lower left). (B) Penetration of P-DOX, DOX, P-THP, and THP into spheroidal tumor colon cancer (Adapted with permission from ref. [39,40]. 2016 American Chemical Society, 2019 American Chemical Society). Far greater penetration of P-THP into the tumor spheroid (similar to Figure 2, Table) is seen.CC BY · PubMed Central
Figure 3 Self-assembling PS polymer conjugates of HPMA and ZnPP. (A) Chemical structure of the HPMA-PS polymer conjugate. (B) Polymer-ZnPP in solution. Spontaneous micelles were formed. Quenching occurs in the self-forming micellar form of P-ZnPP, which leads to a lack of fluorescence in the micellar form. When tumor cells take up these micelles, the micelles disintegrate during the traversing lipid bilayer due to its amphiphilic nature. Then, fluorescence becomes positive and singlet oxygen (ROS) are generated in the tumor upon light irradiation (B). ZnPP itself also inhibits heme oxygenase-1 (HO-1) and suppresses tumors (see text for details).
Figure 3 Self-assembling PS polymer conjugates of HPMA and ZnPP. (A) Chemical structure of the HPMA-PS polymer conjugate. (B) Polymer-ZnPP in solution. Spontaneous micelles were formed. Quenching occurs in the self-forming micellar form of P-ZnPP, which leads to a lack of fluorescence in the micellar form. When tumor cells take up these micelles, the micelles disintegrate during the traversing lipid bilayer due to its amphiphilic nature. Then, fluorescence becomes positive and singlet oxygen (ROS) are generated in the tumor upon light irradiation (B). ZnPP itself also inhibits heme oxygenase-1 (HO-1) and suppresses tumors (see text for details).CC BY · PubMed Central
Figure 4 Fluorescence imaging of breast cancer in a rat and of implanted S180 tumor in a mouse, after intravenous injection of P-ZnPP. (A) DMBA (7,12-dimethylbenz[a]anthracene)-induced breast cancer in a rat. Under fluorescent light (left) and under normal light (right). (B) Fluorescent image of nano-PSs: polymeric HPMA-ZnPP (P-HPMA-ZnPP) and free ZnPP. (C) Rhodamine-conjugated bovine albumin (BSA) vs. free rhodamine. Images show no accumulation of LMW free PSs in tumors (B,C). (A, adapted from [58]; B,C, adapted from ref. [4]).
Figure 4 Fluorescence imaging of breast cancer in a rat and of implanted S180 tumor in a mouse, after intravenous injection of P-ZnPP. (A) DMBA (7,12-dimethylbenz[a]anthracene)-induced breast cancer in a rat. Under fluorescent light (left) and under normal light (right). (B) Fluorescent image of nano-PSs: polymeric HPMA-ZnPP (P-HPMA-ZnPP) and free ZnPP. (C) Rhodamine-conjugated bovine albumin (BSA) vs. free rhodamine. Images show no accumulation of LMW free PSs in tumors (B,C). (A, adapted from [58]; B,C, adapted from ref. [4]).CC BY · PubMed Central
Figure 5 Photodynamic therapy (PDT) with polymeric PSs. (A) View of the light source for the endoscope; a xenon lamp was used. (B) Dose dependence of P-ZnPP dosage, marked D. (C) Dose of light irradiation intensity. The D indicates the time of drug injection of P-ZnPP in B and C. The power of irradiation light (%) is relative to full power output of the endoscope (100%). (D) Results of PDT treatment of DMBA-induced breast cancer in rats. L, light irradiation. D, drug injection. Control received only light. Boxed images at right show growth and suppression of tumor after PDT and P-ZnPP treatment (right) and tumor without treatment (left).
Figure 5 Photodynamic therapy (PDT) with polymeric PSs. (A) View of the light source for the endoscope; a xenon lamp was used. (B) Dose dependence of P-ZnPP dosage, marked D. (C) Dose of light irradiation intensity. The D indicates the time of drug injection of P-ZnPP in B and C. The power of irradiation light (%) is relative to full power output of the endoscope (100%). (D) Results of PDT treatment of DMBA-induced breast cancer in rats. L, light irradiation. D, drug injection. Control received only light. Boxed images at right show growth and suppression of tumor after PDT and P-ZnPP treatment (right) and tumor without treatment (left).CC BY · PubMed Central
Figure 6 This represents the mode of action of poly(styrene-co-maleic acid) conjugated glucosamine (SGB-complex), which forms complex with boric acid, then forms micelles (~15 nm) and exhibits the EPR effect, about 10 times more boron accumulation in the tumor than other normal tissue [67]. When this SGB-complex is used, it exhibits three different cell killing mechanisms as denoted by “①, ②, and ③” in this figure. By neutron irradiation at right, ③, it elicits the production of α-particles which will kill the tumor cells within 10 micron radius. SGB-complex is rapidly incorporated into the tumor cells and inhibit both glycolysis ① and production of lactic acid; ② it also affects the structural integrity of mitochondria, and its size will shrink and suppress ATP production in the cells (Reprinted with permission from ref. [67]. 2020 Elsevier Ltd.).
Figure 6 This represents the mode of action of poly(styrene-co-maleic acid) conjugated glucosamine (SGB-complex), which forms complex with boric acid, then forms micelles (~15 nm) and exhibits the EPR effect, about 10 times more boron accumulation in the tumor than other normal tissue [67]. When this SGB-complex is used, it exhibits three different cell killing mechanisms as denoted by “①, ②, and ③” in this figure. By neutron irradiation at right, ③, it elicits the production of α-particles which will kill the tumor cells within 10 micron radius. SGB-complex is rapidly incorporated into the tumor cells and inhibit both glycolysis ① and production of lactic acid; ② it also affects the structural integrity of mitochondria, and its size will shrink and suppress ATP production in the cells (Reprinted with permission from ref. [67]. 2020 Elsevier Ltd.).CC BY · PubMed Central
Figure 7 Body distribution of boron-containing drugs. (A) Body distribution of a macromolecular 10B compound (e.g., SGB-complex). (B) Distribution of an LMW 10B compound. In (A), boron-containing micelles such as the SGB-complex accumulates predominantly in tumor tissue (T), with the accumulation being about 10 times greater than that of a LMW compound or all other normal tissues in (B). (A’,B’) at right represent enlarged views of the neutron irradiation sites. In (A’), only tumor tissue is damaged: boron micelles (back dots) are evident only in the tumor (T). In (B’), neighboring normal tissue to tumor the boron compound are distributed in most normal tissues such as skin, which will be then be damaged. Red specks around black dots indicate the area of emission of α-particles. (B’) shows that a wide area of tissue is damaged in (B’) (adverse effect).
Figure 7 Body distribution of boron-containing drugs. (A) Body distribution of a macromolecular 10B compound (e.g., SGB-complex). (B) Distribution of an LMW 10B compound. In (A), boron-containing micelles such as the SGB-complex accumulates predominantly in tumor tissue (T), with the accumulation being about 10 times greater than that of a LMW compound or all other normal tissues in (B). (A’,B’) at right represent enlarged views of the neutron irradiation sites. In (A’), only tumor tissue is damaged: boron micelles (back dots) are evident only in the tumor (T). In (B’), neighboring normal tissue to tumor the boron compound are distributed in most normal tissues such as skin, which will be then be damaged. Red specks around black dots indicate the area of emission of α-particles. (B’) shows that a wide area of tissue is damaged in (B’) (adverse effect).CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Pasut, G., and Zalipsky, S. (2020). Overcoming barriers for tumor-targeted drug delivery: The power of macromo-lecular anticancer drugs with the EPR effect and the modulation of vascular physiology. Polymer-Protein Conjugation: From PEGylation and Beyond, Elsevier.
  2. Maeda, 2015, Great expectations for innovative PDT and tumor imaging using fluorescing nanophotosensitizers that utilizes EPR effect, JSMI Rep., 9, 3

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Metadata

Authors
Maeda, H.
Affiliations
Tohoku University (JP)
Corresponding author
Maeda, Hiroshi
ORCID
Maeda, Hiroshi
Venue
Journal of Personalized Medicine
Publisher
MDPI AG
Published
2021-03-22
Volume
11
Issue
3
Pages
229
ISSN
2075-4426 (ISSN-L)
DOI
10.3390/jpm11030229
PMC
PMC8004895
OpenAlex
W3138405372
Cited by
167
References
87
Citations by year
2026: 24 · 2025: 23 · 2024: 29 · 2023: 35 · 2022: 40 · 2021: 15
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Personalized Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Japan Society for the Promotion of Science (18H04059, 29400001)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
enhanced permeability and retention effect, anticancer drug delivery, nanomedicine, tumor perfusion, tumor vasculature, arterial infusion, tumor emboli, tumor necrosis, photodynamic therapy, boron neutron capture therapy, cancer chemotherapy, personalized medicine

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