EPR‐effect enhancers strongly potentiate tumor‐targeted delivery of nanomedicines to advanced cancers: further extension to enhancement of the therapeutic effect

Waliul Islam, Shintaro Kimura, Rayhanul Islam, Ayaka Harada, Katsuhiko Ono, Jun Fang, Takuro Niidome, Tomohiro Sawa, Hiroshi Maeda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
16 Downloads (Pure)

Abstract

For more than three decades, enhanced permeability and retention (EPR)‐effect‐based na-nomedicines 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) pol-ymer‐conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosa-mine‐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.

Original languageEnglish
Article number487
Number of pages13
JournalJournal of Personalized Medicine
Volume11
Issue number6
DOIs
Publication statusPublished - 28 May 2021
Externally publishedYes

Keywords

  • EPR effect
  • EPR‐effect enhancers
  • Heterogeneity of the EPR effect
  • Isosorbide dinitrate
  • Nitric oxide donors
  • Sildenafil citrate
  • Tumor blood flow

ASJC Scopus subject areas

  • Medicine (miscellaneous)

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