(4al) Rational, Model-Guided Design and Experimental Evaluation of Targeted Drug Delivery Vehicles

The success of a therapeutic drug is directly related to its ability to be safely and effectively delivered to its intended site of action within the body. Given the complexity of drug delivery systems and the steps required to achieve their desired activity in a biological organism, mathematical modeling is becoming an increasingly important tool to complement experimental approaches in the drug development process. Here, specific examples from my research will be presented demonstrating how this model-based approach, accompanied by in vitro and in vivo experimental studies, has been applied toward the design of nanoparticle delivery systems for nucleic acid therapeutics and chemotherapeutics.

During my time as a graduate student in the laboratory of Professor Mark E. Davis at the California Institute of Technology, we employed a novel experimental technique using noninvasive bioluminescence imaging and positron emission tomography (PET) to quantify the pharmacokinetic and pharmacodynamic parameters of targeted siRNA nanoparticles. Mathematical models were developed to guide and interpret the experimental studies performed in vitro and in vivo. This analysis revealed how cell doubling time profoundly impacts the kinetics of siRNA-mediated gene silencing, providing important guidelines for the design of optimized dosing regimens using siRNA. Furthermore, these studies demonstrated that targeting ligands may have a minimal impact on the overall tumor localization of nanoparticles, but they can be critical for achieving intracellular delivery of a therapeutic payload. More recently, a similar model-based approach is being applied to my current research at Abraxis BioScience on nanoparticle delivery systems for water-insoluble chemotherapeutics. These studies aim to understand how a drug's formulation impacts its interaction with biological systems.

Technological advances, such as noninvasive molecular imaging, are making biological systems increasingly amenable to quantitative engineering analysis. This will enable a paradigm shift in which novel drug delivery systems will be rationally and efficiently designed through the integration of quantitative mathematical models with experimental approaches.

REFERENCES

Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proceedings of the National Academy of Sciences USA. 2007;104(39):15549-54.

Bartlett DW, Davis ME. Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Research. 2006;34(1):322-33.