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Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells.

Publication ,  Journal Article
Talbot, LJ; Mi, Z; Bhattacharya, SD; Kim, V; Guo, H; Kuo, PC
Published in: Surgery
August 2011

BACKGROUND: We report pharmacokinetic (PK) data, evaluation of modifications for increased stability, evaluation for cellular uptake, and mediation of regression of breast cancer for the aptamer OPN-R3. METHODS: The OPN-R3 aptamer was assessed for PK data in vivo with additional comparison of IV and subcutaneous dosing. Five aptamer variants were generated by differential 2'-O-methylation for comparison with parent. OPN-R3-Cy3 was incubated with MDA-MB231 cells and cellular uptake evaluated under confocal microscopy. Mice were treated with OPN-R3, mutant, or saline 3 weeks after inoculation with MDA-MB231 cells and tumor size was evaluated. RESULTS: OPN-R3 PK data were: t(1/2) 7.76 hours, T(max) 3 hours, C(max) 13.2 mmol/L, mean residence time 9 hours, AUC (0-t) 161.9 mmol/hr/L, and K(d) 57.2 nmol/L. The half-life was higher when given intravenously versus subcutaneously (E(1/2) 7.93 vs 0.74 hours). The 2' methylation of all available bases increased unmodified aptamer stability and affinity (t(1/2) 6.2 hours; K(d) 520 nmol/L), but this did not improve on parent aptamer (t(1/2) 7.78 hours, K(d) 18 nmol/L). The aptamer remained extracellular. OPN-R3 caused regression of tumor to levels seen at 1 week after tumor inoculation. CONCLUSION: We show the efficacy of OPN-R3 for reversing growth of breast cancer cells with adequate PK stability for clinical application.

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Published In

Surgery

DOI

EISSN

1532-7361

Publication Date

August 2011

Volume

150

Issue

2

Start / End Page

224 / 230

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Treatment Outcome
  • Surgery
  • Osteopontin
  • Mice
  • Humans
  • Female
  • Disease Models, Animal
  • Breast Neoplasms
  • Aptamers, Nucleotide
 

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Talbot, L. J., Mi, Z., Bhattacharya, S. D., Kim, V., Guo, H., & Kuo, P. C. (2011). Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells. Surgery, 150(2), 224–230. https://doi.org/10.1016/j.surg.2011.05.015
Talbot, Lindsay Jones, Zhiyong Mi, Syamal Dave Bhattacharya, Victoria Kim, Hongtao Guo, and Paul C. Kuo. “Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells.Surgery 150, no. 2 (August 2011): 224–30. https://doi.org/10.1016/j.surg.2011.05.015.
Talbot, Lindsay Jones, et al. “Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells.Surgery, vol. 150, no. 2, Aug. 2011, pp. 224–30. Pubmed, doi:10.1016/j.surg.2011.05.015.
Journal cover image

Published In

Surgery

DOI

EISSN

1532-7361

Publication Date

August 2011

Volume

150

Issue

2

Start / End Page

224 / 230

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Treatment Outcome
  • Surgery
  • Osteopontin
  • Mice
  • Humans
  • Female
  • Disease Models, Animal
  • Breast Neoplasms
  • Aptamers, Nucleotide