Pharmaceutical Research

, Volume 28, Issue 4, pp 776–787

Actively Targeted Low-Dose Camptothecin as a Safe, Long-Acting, Disease-Modifying Nanomedicine for Rheumatoid Arthritis

  • Otilia May Yue Koo
  • Israel Rubinstein
  • Hayat Önyüksel
Research Paper

DOI: 10.1007/s11095-010-0330-4

Cite this article as:
Koo, O.M.Y., Rubinstein, I. & Önyüksel, H. Pharm Res (2011) 28: 776. doi:10.1007/s11095-010-0330-4

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 (0.1 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.

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.

KEY WORDS

camptothecinphospholipid micellesrheumatoid arthritistargeted drug deliveryvasoactive intestinal peptide

ABBREVIATIONS

CIA

collagen-induced arthritis

CMC

critical micelle concentration

CPT

camptothecin

CPT-SSM

sterically stabilized micelles loaded with camptothecin

CPT-SSM-VIP

sterically stabilized micelles loaded with camptothecin and surface-modified with vasoactive intestinal peptide

MTX

methotrexate

PEG

polyethylene glycol

RA

rheumatoid arthritis

SSM

sterically stabilized micelles

VIP

vasoactive intestinal peptide

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Otilia May Yue Koo
    • 1
    • 5
  • Israel Rubinstein
    • 2
    • 3
  • Hayat Önyüksel
    • 1
    • 4
  1. 1.Department of Biopharmaceutical Sciences (M/C 865) College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Jesse Brown VA Medical CenterChicagoUSA
  4. 4.Department of BioengineeringUniversity of Illinois at ChicagoChicagoUSA
  5. 5.Biopharmaceutics R&DBristol-Myers Squibb CompanyNew BrunswickUSA