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J Control Release. 2015 Aug 28;212:59-69. doi: 10.1016/j.jconrel.2015.06.009. Epub 2015 Jun 11.

A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis.

Author information

1
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.
2
Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: pscodeller@sanfordburnham.org.
3
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.
4
Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: thurtado@sanfordburnham.org.
5
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.
6
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.
7
Department of Surgical Oncology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: kitayama-1SU@h.u-tokyo.ac.jp.
8
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.
9
Department of Medicine, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, USA. Electronic address: showell@ucsd.edu.
10
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.
11
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.
12
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.

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.

KEYWORDS:

integrin; intraperitoneal chemotherapy; neuropilin; peritoneal carcinomatosis; tumor-penetrating peptide

PMID:
26071630
PMCID:
PMC4508207
DOI:
10.1016/j.jconrel.2015.06.009
[Indexed for MEDLINE]
Free PMC Article

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