Tumor Targeting Theory: Physiological Limits from Scaling Analyses, and Design Principles for Better Magic Bullets

SBE Webinar
Originally delivered Sep 26, 2011

For the past two decades the capability of protein engineers to devise clever tumor-targeting molecules has outstripped our understanding of how these agents distribute through the body and permeate through tumors. Classical chemical engineering reaction/diffusion analyses help illustrate the definitive tradeoffs with respect to size and binding affinity of these 'magic bullets.'Theoretical analyses of targeting agent pharmacokinetics provides specific guidance with respect to desirable design objectives such as agent size, affinity, and target antigen. These analyses suggest that IgG-sized macromolecular constructs exhibit the most favorable balance between systemic clearance and vascular extravasation, resulting in maximal tumor uptake. Quantitative predictions of the effects of dose and binding affinity on tumor uptake and penetration are also provided. The single bolus dose required for saturation of xenografted tumors in mice can be predicted from knowledge of antigen expression level and metabolic half life. The role of high binding affinity in tumor uptake can be summarized as: essential for small peptides, less important for antibodies, and negligible for nanoparticles.

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