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08:52
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Diffusion-limited binding explains binary dose response for local arterial and tumour drug delivery
A R Tzafriri1, A D Levin, E R Edelman
1Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ramitz@mit.edu
Cell Proliferation
|May 15, 2009
Summary
Drug efficacy depends on dose, diffusion, and binding. High binding potential (B(p)) drugs penetrate deeper at higher concentrations, explaining threshold dose effects for therapies like paclitaxel.
Area of Science:
- Pharmacology
- Biophysics
- Drug Delivery
Background:
- Local drug delivery is crucial but its efficacy related to physicochemical properties and kinetics is unclear.
- Sustained clinical benefit observed after local bolus endovascular delivery challenges prolonged release assumptions.
Purpose of the Study:
- To investigate the relationship between drug dose, diffusion, and binding in determining tissue penetration and effect.
- To quantify the interplay of these factors for optimized local drug delivery.
Main Methods:
- Developed a quantitative framework integrating dose, saturable binding, and diffusion.
- Measured drug-specific binding parameters to target tissues.
- Employed model reduction and numerical simulations.
Main Results:
- The binding potential (B(p)) dictates drug transport and retention, defined as binding capacity over equilibrium dissociation constant times accessible tissue volume fraction.
- At low B(p) (< 1), drug transport is linear with concentration.
- At high B(p) (> 40), drug transport shows threshold dependence on applied surface concentration.
Conclusions:
- Drugs and antibodies with high B(p) exhibit enhanced tissue penetration at higher concentrations.
- Observed threshold dependence in tissue transport for paclitaxel and rapamycin may explain their in vivo efficacy thresholds.
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