title: Synthesis of a cell penetrating peptide modified superparamagnetic iron oxide and MRI detection of bladder cancer.
abstract: Bladder cancer is the most common malignancy of the urinary tract for which the accurate measurement of minimal residual disease is critical to treatment and determining prognosis. Although cystoscope examination and voided urine cytology remain the current standard of care for detecting residual disease, these approaches are limited by mechanical trauma and lack sensitivity. To develop a new accurate noninvasive method, we developed a novel contrast agent where the surface of superparamagnetic iron oxide (SPIO) nanoparticles is functionalized with a bladder cancer-specific fluorescein isothiocyanate (FITC) labeled cell penetrating peptide (CPP)-polyarginine peptides (R11) for active targeting and imaging. The stable nanoparticles have an average hydrodynamic diameter of 51 nm, surface charge of -21 mV and MRI r2 relaxivity 135 mM-1s-1. In vitro cell studies demonstrated that the R11-conjugated SPIO (SPIO-R11) nanoparticles were taken up by bladder cancer cells (T24) in a dose-dependent manner, which was higher than unconjugated SPIO. TEM showed that SPIO-R11 was mainly concentrated on cell vesicle and lysosome, not in cell nucleus, and no obvious damage was seen on cell ultrastructure. Moreover, uptake of the nanoparticles showed significantly more SPIO-R11 accumulation in bladder cancer cells than in immortalized bladder epithelial cells unlike control SPIO. Further, SPIO-R11 was compatible with immortalized bladder epithelial cells at all tested concentrations up to 200 μg/mL after 72 h incubation. Moreover, SPIO-R11 decreased the magnetic resonance T2 relaxation time by 73% in tumors cells in vitro compared to 12% with SPIO. These results indicate great potential of SPIO-R11 as contrast agent to target bladder cancer for diagnostic and therapeutic applications.
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.|Department of Urology, Xiangyang Central Hospital, Hubei University of Arts and Science, Hubei Province, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, The Forth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Oncology Research Laboratory, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.|Oncology Research Laboratory, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Fan
mesh_terms: D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003287:Contrast Media / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000737:chemistry; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry; D018365:Neoplasm, Residual; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000000981:diagnostic imaging*
chemical_list: D057846:Cell-Penetrating Peptides; D003287:Contrast Media; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; D009842:Oligopeptides; C568793:R11 peptide; C000499:ferric oxide; D016650:Fluorescein-5-isothiocyanate
keywords: bladder cancer; cell penetrating peptide; magnetic resonance imaging; superparamagnetic iron oxide; targeted diagnosis