Impact of tumor-specific targeting and dosing schedule on tumor growth inhibition after intravenous administration of siRNA-containing nanoparticles

Authors

  • Derek W. Bartlett,

    1. Chemical Engineering, California Institute of Technology, 1200 E. California Blvd., MC 210-41, Pasadena, California 91125; telephone: 626-395-4251; fax: 626-568-8743
    Search for more papers by this author
  • Mark E. Davis

    Corresponding author
    1. Chemical Engineering, California Institute of Technology, 1200 E. California Blvd., MC 210-41, Pasadena, California 91125; telephone: 626-395-4251; fax: 626-568-8743
    • Chemical Engineering, California Institute of Technology, 1200 E. California Blvd., MC 210-41, Pasadena, California 91125; telephone: 626-395-4251; fax: 626-568-8743
    Search for more papers by this author

Abstract

This study addresses issues of relevance for siRNA nanoparticle delivery by investigating the functional impact of tumor-specific targeting and dosing schedule. The investigations are performed using an experimental system involving a syngeneic mouse cancer model and a theoretical system based on our previously described mathematical model of siRNA delivery and function. A/J mice bearing subcutaneous Neuro2A tumors ∼100 mm3 in size were treated by intravenous injection with siRNA-containing nanoparticles formed with cyclodextrin-containing polycations (CDP). Three consecutive daily doses of transferrin (Tf)-targeted nanoparticles carrying 2.5 mg/kg of two different siRNA sequences targeting ribonucleotide reductase subunit M2 (RRM2) slowed tumor growth, whereas non-targeted nanoparticles were significantly less effective when given at the same dose. Furthermore, administration of the three doses on consecutive days or every 3 days did not lead to statistically significant differences in tumor growth delay. Mathematical model calculations of siRNA-mediated target protein knockdown and tumor growth inhibition are used to elucidate possible mechanisms to explain the observed effects and to provide guidelines for designing more effective siRNA-based treatment regimens regardless of delivery methodology and tumor type. Biotechnol. Bioeng. 2008; 99; 975–985. © 2007 Wiley Periodicals, Inc.

Ancillary

Advertisement