A Retrospective 30 Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next‐Generation Chemotherapeutics and Photodynamic Therapy—Problems, Solutions, and Prospects

Abstract

Solid tumor has unique vascular architecture, excessive production of vascular mediators, and extravasation of macromolecules from blood vessels into the tumor tissue interstitium. These features comprise the phenomenon named the EPR effect of solid tumors, described in 1986. Our investigations on the EPR revealed that many mediators, such as bradykinin, NO, and prostaglandins, are involved in the EPR effect, which is now believed to be the most important element for cancer-selective drug delivery. However, tumors in vivo manifest great diversity, and some demonstrate a poor EPR effect, for example, because of impaired vascular flow involving thrombosis, with poor drug delivery and therapeutic failure. Another important element of this effect is that it operates in metastatic cancers. Because few drugs are currently effective against metastases, the EPR effect offers a great advantage in nanomedicine therapy. The EPR effect can also be augmented two to three times via nitroglycerin, ACE inhibitors, and angiotensin II-induced hypertension. The delivery of nanomedicines to tumors can thereby be enhanced. In traditional PDT, most PSs had low MW and little tumor-selective accumulation. Our hydroxypropylmetacrylamide-polymer-conjugated-PS, zinc protoporphyrin (apparent MW >50 kDa) showed tumor-selective accumulation, as revealed by fluorescent imaging of autochthonous cancers. After one i.v. injection of polymeric PS followed by two or three xenon light irradiation/treatments, most tumors regressed. Thus, nanoprobes with the EPR effect seem to have remarkable effects. Enhancing the EPR effect by using vascular modulators will aid innovations in PDT for greater tumor-targeted drug delivery.

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…16 Although the limitations of EPR effect have been extensively discussed, 17 it remains the main process of passive tumor targeting by NPs, resulting in an increased drug accumulation in tumor while sparing healthy tissues. 18 This selective accumulation and retention of NPs in solid tumor by EPR effect, contrary to small molecules International Journal of Nanomedicine 2017:12 submit your manuscript | www.dovepress.com…”

Porphyrin-based cationic amphiphilic photosensitisers as potential anticancer, antimicrobial and immunosuppressive agents

“…Photosensitiser (PS) is usually non-toxic in the absence of light, and is passively accumulated and retained in the tumour tissue (Vaidya et al 2006). The mechanism that conferes this therapeutically advantageous feature is known as enhanced permeability and retention effect (EPR) (Maeda et al 2016). Once a PS is accumulated in the tumour, it is activated with local application of light of the appropriate wavelength, which leads to the formation of the cytotoxic singlet oxygen ( 1 O 2 ) that can kill tumour cells.…”

Nanoparticles for Delivery of Vitamin D: Challenges and Opportunities

“…These nanosystems also showed the ability to reduce and destroy tumor cells, taking advantage of the EPR effect verified in tumor tissues. As the EPR effect does not occur in healthy tissues, it is thus possible to target tumor cells, reducing VD's toxicity in healthy tissue [44]. None of the works here discussed reported the use of functionalized NPs.…”

“…The NPs take advantage of the increased permeability of blood vessels in tumor tissues, whereas lymphatic drainage is decreased which increases the concentration of loaded nanoparticles in the tumor tissue. As the EPR effect does not occur in healthy tissues, it is thus possible to target tumor cells, reducing VD's toxicity in healthy tissue [44].…”