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      Intra-colonic administration of a polymer-bound NIRF probe for improved colorectal cancer detection during colonoscopy.

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          Abstract

          There is increasing interest in the use of nanoparticle imaging probes for cancer diagnosis. However, various biological barriers limit the efficient delivery of nanoparticles to tumors following parenteral administration. We have investigated the applicability of a water-soluble polymeric imaging probe for improving the detection of gastrointestinal (GI) tumors after intra-luminal (colonic) administration. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing either fluorescein-isothiocyanate (FITC) or near-infrared fluorescence (NIRF) dye (IR-783) were conjugated with EPPT1 peptide, derived from the CDR3 Vh region of a monoclonal antibody (ASM2) raised against human epithelial cancer cells, for targeting under-glycosylated mucin-1 (uMUC-1) expressed in neoplastic tissues. The targeted FITC-labeled copolymer, P-(EPPT1)-FITC, was investigated for its ability to bind human CRC cells and tissue specimens in vitro. The uMUC-1-targeted NIRF-labeled copolymer, P-(EPPT1)-IR783, was assessed for its ability to detect colonic lesions in vivo. P-(EPPT1)-FITC demonstrated superior binding to colorectal cancer (CRC) cells that over-express the uMUC-1 antigen and exhibited selectivity towards human CRC tissue specimens, as compared to adjacent normal tissues from the same patient. When applied intra-colonically, P-(EPPT1)-IR783 significantly accumulated in cancerous tissue, relative to the adjacent normal mucosa of HT29 and LS174T tumor-bearing mice, and demonstrated higher signal intensities in colonic tumors, as compared to the non-targeted P-(GG-OH)-IR783 probe (i.e., without EPPT1). We found that P-(GG-OH)-IR783 can also accumulate specifically at tumor sites. The cancer-specific uptake and retention of P-(GG-OH)-IR783 was not mediated by organic anion transporting peptides (OATPs). Our findings indicate that the polymer-bound NIRF probe can successfully detect solid tumors in the GI tract following intra-colonic administration, and could be used in conjunction with colonoscopic procedures to improve the sensitivity of colonoscopies for polyp detection.

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          Author and article information

          Journal
          J Control Release
          Journal of controlled release : official journal of the Controlled Release Society
          Elsevier BV
          1873-4995
          0168-3659
          Oct 28 2014
          : 192
          Affiliations
          [1 ] Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
          [2 ] Surgical Oncology Laboratory, Department of Surgery, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem 91120, Israel.
          [3 ] Given Imaging Ltd., New Industrial Park, Yoqneam 20692, Israel.
          [4 ] Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: ayeletda@bgu.ac.il.
          Article
          S0168-3659(14)00467-2
          10.1016/j.jconrel.2014.06.058
          25008468

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