Actively targeted low-dose camptothecin as a safe, long-acting, disease-modifying nanomedicine for rheumatoid arthritis.
OBJECTIVE
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 (0.1 mg/kg) administered to CIA mice mitigated joint inflammation for at least 32 days 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.


CONCLUSIONS
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.
Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., Chicago, Illinois 60612-7231, USA. otilia.koo@bms.com
Otilia May Yue
OM
Koo
Israel
I
Rubinstein
Hayat
H
Onyüksel
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D011859:Radiography; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry*
D004337:Drug Carriers; D008823:Micelles; D059004:Topoisomerase I Inhibitors; D014660:Vasoactive Intestinal Peptide; D002166:Camptothecin