Search for: All records

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 againstin vivodata. 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.

 

We present a deterministic global optimization method for nonlinear programming formulations constrained by stiff systems of ordinary differential equation (ODE) initial value problems (IVPs). The examples arise from dynamic optimization problems exhibiting both fast and slow transient phenomena commonly encountered in model‐based systems engineering applications. The proposed approach utilizes unconditionally stable implicit integration methods to reformulate the ODE‐constrained problem into a nonconvex nonlinear program (NLP) with implicit functions embedded. This problem is then solved to global optimality in finite time using a spatial branch‐and‐bound framework utilizing convex/concave relaxations of implicit functions constructed by a method which fully exploits problem sparsity. The algorithms were implemented in the Julia programming language within the EAGO.jl package and demonstrated on five illustrative examples with varying complexity relevant in process systems engineering. The developed methods enable the guaranteed global solution of dynamic optimization problems with stiff ODE–IVPs embedded.

 

An extensible open-source deterministic global optimizer (EAGO) programmed entirely in the Julia language is presented. EAGO was developed to serve the need for supporting higher-complexity user-defined functions (e.g. functions defined implicitly via algorithms) within optimization models. EAGO embeds a first-of-its-kind implementation of McCormick arithmetic in an Evaluator structure allowing for the construction of convex/concave relaxations using a combination of source code transformation, multiple dispatch, and context-specific approaches. Utilities are included to parse userdefined functions into a directed acyclic graph representation and perform symbolic transformations enabling dramatically improved solution speed. EAGO is compatible with a wide variety of local optimizers, the most exhaustive library of transcendental functions, and allows for easy accessibility through the JuMP modelling language. Together with Julia’s minimalist syntax and competitive speed, these powerful features make EAGO a versatile research platform enabling easy construction of novel meta-solvers, incorporation and utilization of new relaxations, and extension to advanced problem formulations encountered in engineering and operations research (e.g. multilevel problems, user-defined functions). The applicability and flexibility of this novel software is demonstrated on a diverse set of examples. Lastly, EAGO is demonstrated to perform comparably to state-of-the-art commercial optimizers on a benchmarking test set.