Correlating quantitative tumor accumulation and gene knockdown using SPECT/CT and bioluminescence imaging within an orthotopic ovarian cancer model

Jones, Steven K.; Douglas, Kirk; Shields, Anthony F. und Merkel, Olivia M. (2018): Correlating quantitative tumor accumulation and gene knockdown using SPECT/CT and bioluminescence imaging within an orthotopic ovarian cancer model. In: Biomaterials, Bd. 178: S. 183-192

Abstract

Using an orthotopic model of ovarian cancer, we studied the delivery of siRNA in nanoparticles of triblock copolymers consisting of hyperbranched polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (hyPEI-g-PCL-b-PEG) with and without a folic acid targeting ligand. A SKOV-3/LUC FR alpha overexpressing cell line was employed to mimic the clinical manifestations of ovarian cancer. Both targeted and non-targeted micelleplexes were able to effectively deliver siRNA to the primary tumor and its metastases, as measured by gamma scintillation counting and confocal microscopy. Stability of the micelleplexes was demonstrated with a serum albumin binding study. Regarding biodistribution, intravenous (I.V.) administration showed a slight advantage of FR alpha targeted over non-targeted micelleplex accumulation within the tumor. However, both formulations displayed significant liver uptake. On the other hand, intraperitoneally (I.R) injected mice showed a modest 6% of the injected dose per gram (ID/g) uptake within the primary and most interestingly also in the metastatic lesions which subsequently resulted in a 62% knockdown of firefly luciferase expression in the tumor after a single injection. While this is, to the best of our knowledge, the first paper that correlates quantitative tumor accumulation in an orthotopic tumor model with in vivo gene silencing, these data demonstrate that PEI-g-PCL-b-PEG-Fol conjugates are a promising option for gene knockdown in ovarian cancer.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0142-9612
• Sprache: Englisch