Influence of systemic administration of atelocollagen on mouse livers: an ideal biomaterial for systemic drug delivery

• Published in: Journal of toxicological sciences Vol. 36; no. 6; pp. 751 - 762
• Main Authors: Ogawa, Shingo, Onodera, Jun, Honda, Rika, Fujimoto, Ichiro
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2011
• Subjects: Adenylate cyclase; Amyloid; Animals; Apoptosis; Atelocollagen; Atelocollagen (AC); Biomaterials; Cationic liposome; Cholesterol - toxicity; Collagen - toxicity; cyclin-dependent kinase inhibitors; Cytokines; DNA; Drug Carriers - toxicity; Drug delivery; Drug delivery system (DDS); Fatty Acids, Monounsaturated - toxicity; Gene expression; Gene Expression - drug effects; Gene Expression Profiling; Gene ontology (GO); granzyme B; Immune response; Lipocalin; Liposomes; Liposomes - toxicity; Liver; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; miRNA; Oligonucleotide Array Sequence Analysis; Plasmids; Quaternary Ammonium Compounds - toxicity; RNA, Messenger - metabolism; siRNA; Systemic administration; Toxicity
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.36.751

Atelocollagen (AC), a biomaterial with low antigenicity and high bioaffinity, has been widely used in implantable materials in clinical practice. Preclinical studies have demonstrated that AC is a potential drug carrier for local and systemic delivery of cytokines, growth factors, plasmid DNA, small interfering RNA, and microRNA. AC is also believed to have low systemic toxicity on the basis of the safety of implant usage; however, this is not enough determined. Therefore, we performed whole genome expression profiling in mouse liver after systemic administration of AC or the cationic liposome carrier DOTAP/cholesterol (LP) and compared the changes of gene expressions associated with hepatotoxicity. Microarray analysis revealed that systemic LP administration significantly increased expression of toxicity-related genes, i.e., those for lipocalin-2, cyclin-dependent kinase inhibitor 1A, serum amyloid A isoforms, chemokine ligands, and granzyme B. Alternatively, AC administration did not alter the expression of any of these genes. Further gene ontology (GO) enrichment analysis highlighted the characteristic annotations extracted from genes upregulated after LP administration, and most of them were related to toxicity annotations such as immune response, inflammatory response, and apoptosis induction. In contrast, GO enrichment analysis of genes induced after AC administration revealed that only three annotations, all of which were unrelated to toxicity. These findings indicate that AC is potentially far less hepatotoxic than LP after systemic administration, suggesting that AC may be an excellent biomaterial for nontoxic drug delivery system carriers.