title: A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis.
abstract: Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Surgery, Columbia University College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, 1130St Nicholas Avenue, New York, NY 10032, USA. Electronic address: sugahara@sanfordburnham.org.
authors.forename: Kazuki N
authors.initials: KN
authors.lastname: Sugahara
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: pscodeller@sanfordburnham.org.
authors.forename: Pablo
authors.initials: P
authors.lastname: Scodeller
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Center of Nanomedicine and Department of Cell, Molecular and Developmental Biology, 2203 Life Sciences Building, MCDB, University of California, Santa Barbara, CA 93106-9625, USA. Electronic address: gbraun@sanfordburnham.org.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Braun
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: thurtado@sanfordburnham.org.
authors.forename: Tatiana Hurtado
authors.initials: TH
authors.lastname: de Mendoza
authors.affiliation: Department of Surgery, Columbia University College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, 1130St Nicholas Avenue, New York, NY 10032, USA. Electronic address: ct2621@cumc.columbia.edu.
authors.forename: Chisato M
authors.initials: CM
authors.lastname: Yamazaki
authors.affiliation: Department of Surgery, Columbia University College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, 1130St Nicholas Avenue, New York, NY 10032, USA. Electronic address: mk2462@cumc.columbia.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kluger
authors.affiliation: Department of Surgical Oncology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: kitayama-1SU@h.u-tokyo.ac.jp.
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.affiliation: Department of Reproductive Medicine, Division of Gynecologic Oncology, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0987, USA. Electronic address: Edwin.alvarez@ucdmc.ucdavis.edu.
authors.forename: Edwin
authors.initials: E
authors.lastname: Alvarez
authors.affiliation: Department of Medicine, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, USA. Electronic address: showell@ucsd.edu.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Center of Nanomedicine and Department of Cell, Molecular and Developmental Biology, 2203 Life Sciences Building, MCDB, University of California, Santa Barbara, CA 93106-9625, USA; Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, Ravila 14b, Tartu 50411, Estonia. Electronic address: tteesalu@sanfordburnham.org.
authors.forename: Tambet
authors.initials: T
authors.lastname: Teesalu
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Center of Nanomedicine and Department of Cell, Molecular and Developmental Biology, 2203 Life Sciences Building, MCDB, University of California, Santa Barbara, CA 93106-9625, USA. Electronic address: ruoslahti@sanfordburnham.org.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0987, USA. Electronic address: alowy@ucsd.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage* / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D012039:Regional Blood Flow
chemical_list: D057846:Cell-Penetrating Peptides; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D004317:Doxorubicin
keywords: integrin; intraperitoneal chemotherapy; neuropilin; peritoneal carcinomatosis; tumor-penetrating peptide