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

Abstract

For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers—isosorbide dinitrate (ISDN, Nitrol®) and sildenafil citrate—strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin® (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.

Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible “EPR Effect Enhancer” to Improve Cancer Nanomedicine Efficacy

“…However, in the last few years, many studies have shown that in human advanced cancers, there is strong heterogeneity of the EPR effect [22]. For example, Ding et al showed that about 90% of human renal tumors have an EPR effect that is significantly heterogeneous [23].…”

“…A possible reason for the insufficient results of the EPR effect in humans is that human tumors are often diagnosed when they are larger than 3 mm and up to 10 cm or more and such large tumors can present with occluded blood vessels owing to vascular clots and thrombi and consequently partially suppressed blood flow [22]. Islam et al claimed that this blood flow suppression is a key feature of late-stage cancers and, consequently, determines "little or no drug delivery and, therefore, a highly limited EPR effect" after systemic administration of the nanomedicine [22].…”

EPR Effect-Based Tumor Targeted Nanomedicine: A Promising Approach for Controlling Cancer

“…A critical issue should be addressed is that the EPR effect is the phenomenon of blood vessels, which is largely dependent on tumor blood flow. While most animal solid tumor models that are rich in blood flow exhibit good EPR effect, many clinical cancers, especially advanced late-stage cancers and refractor cancers, are poor in tumor blood flow due to high coagulation activity and thrombi formation, thus showing unsatisfactory EPR effect [1,2,[10][11][12][13]. Thus, further augmentation of the EPR effect is of great importance and necessity.…”

“…Thus, further augmentation of the EPR effect is of great importance and necessity. In this regard, we should understand that the EPR effect is not a static phenomenon, it is a dynamic event, which could be enhanced by modulating vascular mediators in tumor such as using angiotensin II, NO/nitroglycerin, and angiotensin II, converting enzyme inhibitors and carbon monoxide [1,2,10,11]. A combination of vascular mediators with nanomedicines may become useful strategies for more effective antitumor nanomedicine.…”

“…The discoverer of EPR effect, Professor Hiroshi Maeda, and his former students and colleagues summarized the history; principle; the progress and prospects of EPR effect-based tumor targeting strategies; and the application of nanomedicines [1,2,6,8], in which the concept of EPR effect is not only applied to the development of targeted anticancer drugs [3,4,9] but is also applicable for radiation therapy [5], bacterial therapy of cancer [7], and nucleic acid medicine [14]. Moreover, more papers in the Special Issue emphasized the significance of EPR enhancement, discussing the usefulness of potential EPR enhancers [1,2,[10][11][12][13], which I believe to be an essential issue for successful anticancer therapy using nanomedicine.…”