TY - JOUR
T1 - Delivery of Intercellular Adhesion Molecule-1 Antisense Oligonucleotides Using a Topical Hydrogel Tissue Sealant in a Murine Partial Nephrectomy/Ischemia Model
AU - Phull, Hardeep
AU - Lien, Yeong Hau H.
AU - Salkini, Mohamed W.
AU - Escobar, Christina
AU - Lai, Li Wen
AU - Ramakumar, Sanjay
N1 - Funding Information:
This work was supported by a University Physicians Experimental Research for Clinical Care grant from the University of Arizona; a grant from the Dialysis Clinic Inc., a non-profit organization, and the Medical Student Research Program fellowship from the National Institutes of Health Science Education Partnership Awards (grant R25RR15670).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/9
Y1 - 2008/9
N2 - Objectives: Ischemia/reperfusion injury is a leading cause of renal damage which can be improved with antisense oligonucleotide gene therapy. We have shown that polyethylene glycol (PEG) hydrogel, which also functions as a tissue sealant, is an effective topical delivery vehicle for oligonucleotides in a murine partial nephrectomy model. The objective of this study was to use and evaluate this method against intercellular adhesion molecule-1 (ICAM-1) to prevent tissue damage. Methods: Sixty mice underwent left upper pole partial nephrectomy with 45 minutes of warm ischemia, randomized to treatment with 50 μg ICAM-1 antisense oligonucleotides embedded in PEG hydrogel, no therapy, or sham surgery. Kidneys were harvested at 24 hours and 3, 4, and 5 days. The specimens were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) for ICAM-1 messenger ribonucleic acid (mRNA), immunohistochemical staining for ICAM-1 protein, and standard histology. Results: At 24 hours, qRT-PCR and immunohistochemistry data showed a significant reduction in ICAM-1 mRNA and protein expression in the antisense group versus the ischemia group, but no difference at 3 to 5 days. Histologically there was reduced inflammation and necrosis in the cortex at 24 hours. The outer and inner medulla also showed improvement at 3 to 5 days in the antisense group as opposed to the ischemia group. Conclusions: Topical PEG hydrogel delivery of antisense ICAM-1 oligonucleotides demonstrated decreased ICAM-1 mRNA expression, reduced ICAM-1 protein staining, and decreased cellular damage. The application of gene therapy through this novel topical delivery system holds potential for a highly specific, localized method of preventing tissue damage after ischemia/reperfusion injury.
AB - Objectives: Ischemia/reperfusion injury is a leading cause of renal damage which can be improved with antisense oligonucleotide gene therapy. We have shown that polyethylene glycol (PEG) hydrogel, which also functions as a tissue sealant, is an effective topical delivery vehicle for oligonucleotides in a murine partial nephrectomy model. The objective of this study was to use and evaluate this method against intercellular adhesion molecule-1 (ICAM-1) to prevent tissue damage. Methods: Sixty mice underwent left upper pole partial nephrectomy with 45 minutes of warm ischemia, randomized to treatment with 50 μg ICAM-1 antisense oligonucleotides embedded in PEG hydrogel, no therapy, or sham surgery. Kidneys were harvested at 24 hours and 3, 4, and 5 days. The specimens were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) for ICAM-1 messenger ribonucleic acid (mRNA), immunohistochemical staining for ICAM-1 protein, and standard histology. Results: At 24 hours, qRT-PCR and immunohistochemistry data showed a significant reduction in ICAM-1 mRNA and protein expression in the antisense group versus the ischemia group, but no difference at 3 to 5 days. Histologically there was reduced inflammation and necrosis in the cortex at 24 hours. The outer and inner medulla also showed improvement at 3 to 5 days in the antisense group as opposed to the ischemia group. Conclusions: Topical PEG hydrogel delivery of antisense ICAM-1 oligonucleotides demonstrated decreased ICAM-1 mRNA expression, reduced ICAM-1 protein staining, and decreased cellular damage. The application of gene therapy through this novel topical delivery system holds potential for a highly specific, localized method of preventing tissue damage after ischemia/reperfusion injury.
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U2 - 10.1016/j.urology.2007.12.042
DO - 10.1016/j.urology.2007.12.042
M3 - Article
C2 - 18336877
AN - SCOPUS:50249132726
VL - 72
SP - 690
EP - 695
JO - Urology
JF - Urology
SN - 0090-4295
IS - 3
ER -