A spatiotemporal multi-scale computational model for FDG PET imaging at different stages of tumor growth and angiogenesis

Abstract

A deeper understanding of the tumor microenvironment (TME) and its role in metabolic activity at different stages of vascularized tumors can provide useful insights into cancer progression and better support clinical assessments. In this study, a robust and comprehensive multi-scale computational model for spatiotemporal transport of F-18 fluorodeoxyglucose (FDG) is developed to incorporate important aspects of the TME, spanning subcellular-, cellular-, and tissue-level scales. Our mathematical model includes biophysiological details, such as radiopharmaceutical transport within interstitial space via convection and diffusion mechanisms, radiopharmaceutical exchange between intracellular and extracellular matrices by glucose transporters, cellular uptake of radiopharmaceutical, as well as its intracellular phosphorylation by the enzyme. Further, to examine the effects of tumor size by varying microvascular densities (MVDs) on FDG dynamics, four different capillary networks are generated by angiogenesis modeling. Results demonstrate that as tumor grows, its MVD increases, and hence, the spatiotemporal distribution of total FDG uptake by tumor tissue changes towards a more homogenous distribution. In addition, spatiotemporal distributions in tumor with lower MVD have relatively smaller magnitudes, due to the lower diffusion rate of FDG as well as lower local intravenous FDG release. Since mean standardized uptake value (SUVmean) differs at various stages of microvascular networks with different tumor sizes, it may be meaningful to normalize the measured values by tumor size and the MVD prior to routine clinical reporting. Overall, the present framework has the potential for more accurate investigation of biological phenomena within TME towards personalized medicine.

Targeted Nano Sized Drug Delivery to Heterogeneous Solid Tumor Microvasculatures: Implications for Immunoliposomes Exhibiting Bystander Killing Effect

“…4c and 5g, regardless of implemented drug delivery systems, the intracellular concentration of the drug and its therapeutic outcomes (i.e., FKCs and AUC) increase as the MVD decreases. This result is consistent with several experimental 31, 62 and numerical 30, 63 studies. These results also provide evidence that at the initial stages of tumor-induced angiogenesis and growth, the cytotoxic agents have shown higher efficacy during chemotherapy, the phenomenon which is also reported by Vavourakis et al 64 .…”

“…The AUC, a commonly used pharmacokinetic parameter, indicates the actual extracellular drug amount in the interstitium available to the tumor over time, which can be described as 7 : in which T is the period of treatment and C is the drug concentration in the extracellular space. To obtain quantitative representation and additional insight into the dynamic changes taking place in the microvascular architecture over different tumor networks, a new parameter is introduced by 30, 31 : …”

“…Calculating metabolic stimuli and blood hemodynamic according to vascular remodeling. See 28, 30 for details;…”

Clinical significance of 18F-FDG PET/CT imaging in 32 cases of gastrointestinal stromal tumors

“…Among them, 18 F-FDG PET/CT is a non-invasive method to study biochemical and metabolic changes in tumor tissues, which provides useful functional information for identifying surviving tumor tissues [11]. 18 F-FDG metabolic imaging expresses the metabolic level of glucose molecules in the cell [12][13][14]. Tumor cells have increased nucleus division, active cell proliferation, and increased glucose metabolism, which is manifested by increased FDG metabolism and an increased SUV at the lesion.…”

Application of Mathematical Modeling and Computational Tools in the Modern Drug Design and Development Process

“…Researchers can better understand side effect profiles by understanding routes and their relationships. Because most diseases are the consequence of interactions between several stages and elements, any modification made at a different stage or in various tissues will result in different outcomes [38]. As a result, the associated treatments should differ as well.…”