Optimal therapy design with tumor microenvironment normalization

Tumor microenvironment (TME) normalization improves efficacy by increasing anticancer nanocarrier delivery by restoring transvascular pressure gradients that induce convection. However, transport depends on TME biophysics, normalization dose, and nanocarrier size. With increased understanding, we could use computation to personalize normalization amount and nanocarrier size. Here, we use deterministic global dynamic optimization with novel bounding routines to validate mechanistic models against in vivo data. We find that normalization with dexamethasone increases the maximum transvascular convection rate of nanocarriers by 48-fold, the tumor volume fraction with convection by 61%, and the total amount of convection by 360%. Nonetheless, 22% of the tumor still lacks convection. These findings underscore both the effectiveness and limits of normalization. Using artificial neural network surrogate modeling, we demonstrate the feasibility of rapidly determining the dexamethasone dose and nanocarrier size to maximize accumulation. Thus, this digital testbed quantifies transport and performs therapy design.

Automated summary

Tumor microenvironment (TME) normalization enhances the delivery of anticancer nanocarriers by restoring transvascular pressure gradients and inducing convection. The effectiveness of this normalization depends on TME biophysics, normalization dose, and nanocarrier size. By using computation, we can personalize the dose and size of normalization. Experimental results show that normalization with dexamethasone significantly increases the convection rate of nanocarriers, tumor volume fraction with convection, and total amount of convection. However, a portion of the tumor still lacks convection. Artificial neural network surrogate modeling can be used to rapidly determine the optimal dose and size of nanocarriers for maximum accumulation. This digital testbed provides a quantitative evaluation of transport and allows for therapy design.