Impact of Tumor-Specific Targeting and Dosing Schedule on Tumor Growth Inhibition After Intravenous Administration of siRNA-Containing Nanoparticles

Impact of Tumor-Specific Targeting and Dosing Schedule on Tumor Growth Inhibition After Intravenous Administration of siRNA-Containing Nanoparticles

Impact of Tumor-Specific Targeting and Dosing Schedule on Tumor Growth Inhibition After Intravenous Administration of siRNA-Containing Nanoparticles

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 nontargeted 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.
KEYWORDS: RNAi; targeted delivery; mathematical modeling; ribonucleotide reductase; Neuro2A

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