caa a22 4500 445313358 CHVBK 20180317142637.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s11095-010-0330-4 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0330-4 Actively Targeted Low-Dose Camptothecin as a Safe, Long-Acting, Disease-Modifying Nanomedicine for Rheumatoid Arthritis [Elektronische Daten] [Otilia Koo, Israel Rubinstein, Hayat Önyüksel] ABSTRACT: Purpose: Camptothecin (CPT), a potent topoisomerase I inhibitor, was originally discovered as an anticancer agent to induce programmed cell death of cancer cells. Recent evidence suggests that, similar to cancer, alterations in apoptosis and over-proliferation of key effector cells in the arthritic joint result in rheumatoid arthritis (RA) pathogenesis. Initial in vitro studies have suggested that camptothecin inhibits synoviocyte proliferation, matrix metalloproteinases expression in chrondrocytes and angiogenesis. This study is one of the first to test, in vivo, RA as a new indication for CPT. Methods: To circumvent insolubility, instability and toxicity of CPT, we used biocompatible, biodegradable and targeted sterically stabilized micelles (SSM) as nanocarriers for CPT (CPT-SSM). We also surface-modified CPT-SSM with vasoactive intestinal peptide (VIP) for active targeting. We then determined whether this nanomedicine abrogated collagen-induced arthritis (CIA) in mice. Results: Based on our findings, this is the first study to report that CPT was found to be efficacious against CIA at concentrations significantly lower than usual anti-cancer dose. Furthermore, a single subcutaneous injection of CPT-SSM-VIP (0.1mg/kg) administered to CIA mice mitigated joint inflammation for at least 32days thereafter without systemic toxicity. CPT alone needed at least 10-fold higher dose to achieve the same effect, albeit with some vacuolization in liver histology. Conclusion: We propose that CPT-SSM-VIP is a promising targeted nanomedicine and should be further developed as a safe, long-acting, disease-modifying pharmaceutical product for RA. Springer Science+Business Media, LLC, 2010 camptothecin nationallicence phospholipid micelles nationallicence rheumatoid arthritis nationallicence targeted drug delivery nationallicence vasoactive intestinal peptide nationallicence CIA : collagen-induced arthritis nationallicence CMC : critical micelle concentration nationallicence CPT : camptothecin nationallicence CPT-SSM : sterically stabilized micelles loaded with camptothecin nationallicence CPT-SSM-VIP : sterically stabilized micelles loaded with camptothecin and surface-modified with vasoactive intestinal peptide nationallicence MTX : methotrexate nationallicence PEG : polyethylene glycol nationallicence RA : rheumatoid arthritis nationallicence SSM : sterically stabilized micelles nationallicence VIP : vasoactive intestinal peptide nationallicence Koo Otilia Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., 60612-7231, Chicago, Illinois, USA aut Rubinstein Israel Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., 60612, Chicago, Illinois, USA aut Önyüksel Hayat Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., 60612-7231, Chicago, Illinois, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/4(2011-04-01), 776-787 0724-8741 28:4<776 2011 28 11095 https://doi.org/10.1007/s11095-010-0330-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0330-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Koo Otilia Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., 60612-7231, Chicago, Illinois, USA aut NATIONALLICENCE 700 1- Rubinstein Israel Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., 60612, Chicago, Illinois, USA aut NATIONALLICENCE 700 1- Önyüksel Hayat Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., 60612-7231, Chicago, Illinois, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/4(2011-04-01), 776-787 0724-8741 28:4<776 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer