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

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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.

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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

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ACKNOWLEDGMENTS

We thank J. Artwohl for his advice on the CIA mouse model and for analyzing our histology and radiographic slides in a blinded fashion, T. Valli and the veterinarian pathology laboratory at University of Illinois at Urbana Champion for preparing the immunohistochemical slides and analyzing them in a blinded fashion, R. Gemeinhart’s laboratory for use of microscope equipment, H. Radloff at the Radiology Department at UIC Hospital for help in taking the radiographs. This study was supported, in part, by DOD grant BCRP, #DAMD 17-02-1-0415, VA Merit Review and NIH grants R01 AG024026, R01 HL72323 and C06RR15482. This investigation was conducted in a facility constructed with support from grant C06RR15482 from the NIH National Center for Research Resources. O.M.K. was a recipient of the UIC University Fellowship.

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Authors and Affiliations

  1. 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 May Yue Koo & Hayat Önyüksel

  2. Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Chicago, Illinois, 60612, USA

    Israel Rubinstein

  3. Jesse Brown VA Medical Center, 820 S. Damen Ave., Chicago, Illinois, 60612, USA

    Israel Rubinstein

  4. Department of Bioengineering, University of Illinois at Chicago, 851 S Morgan St., Chicago, Illinois, 60607, USA

    Hayat Önyüksel

  5. Biopharmaceutics R&D, Bristol-Myers Squibb Company, 1 Squibb Dr., New Brunswick, New Jersey, 08903, USA

    Otilia May Yue Koo

Authors
  1. Otilia May Yue Koo
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Correspondence to Hayat Önyüksel.

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All research was conducted by author at University of Illinois at Chicago

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Koo, O.M.Y., Rubinstein, I. & Önyüksel, H. Actively Targeted Low-Dose Camptothecin as a Safe, Long-Acting, Disease-Modifying Nanomedicine for Rheumatoid Arthritis. Pharm Res 28, 776–787 (2011). https://doi.org/10.1007/s11095-010-0330-4

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  • DOI: https://doi.org/10.1007/s11095-010-0330-4

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