Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect

Mayu Yamamoto, Taiki Kurino, Reiko Matsuda, Haleigh Sakura Jones, Yoshito Nakamura, Taisei Kanamori, Atushi B. Tsuji, Aya Sugyo, Ryota Tsuda, Yui Matsumoto, Yu Sakurai, Hiroyuki Suzuki, Makoto Sano, Kensuke Osada, Tomoya Uehara, Yukimoto Ishii, Hidetaka Akita, Yasushi Arano, Akihiro Hisaka, Hiroto Hatakeyama

Research output: Contribution to journalArticlepeer-review


Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.v.) administration. i.p. chemotherapy has been investigated to improve drug delivery to tumors; however, the efficacy continues to be debated. As anticancer drugs have low molecular weight and are rapidly excreted through the peritoneal blood vessels, maintaining the i.p. concentration as high as expected is a challenge. In this study, we examined whether i.p. administration is an efficient route of administration of high-molecular-weight immune checkpoint inhibitors (ICIs) for the treatment of peritoneal dissemination using a model of peritoneal disseminated carcinoma. After i.p. administration, the amount of anti-PD-L1 antibody transferred into i.p. tumors increased by approximately eight folds compared to that after i.v. administration. Intratumoral distribution analysis revealed that anti-PD-L1 antibodies were delivered directly from the i.p. space to the surface of tumor tissue, and that they deeply penetrated the tumor tissues after i.p. administration; in contrast, after i.v. administration, anti-PD-L1 antibodies were only distributed around blood vessels in tumor tissues via the enhanced permeability and retention (EPR) effect. Owing to the enhanced delivery, the therapeutic efficacy of anti-PD-L1 antibody in the peritoneal dissemination models was also improved after i.p. administration compared to that after i.v. administration. This is the first study to clearly demonstrate an EPR-independent delivery of ICIs to i.p. tumors by which ICIs were delivered in a massive amount to the tumor tissue via direct penetration after i.p. administration.

Original languageEnglish
Pages (from-to)328-337
Number of pages10
JournalJournal of Controlled Release
Publication statusPublished - 2022 Dec


  • Immune checkpoint inhibitors
  • Intraperitoneal administration
  • PD-L1
  • Peritoneal dissemination

ASJC Scopus subject areas

  • Pharmaceutical Science


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