Abstract
Tumour hypoxia is a well-studied phenomenon with implications in cancer progression, treatment resistance, and patient survival. While a clear adverse prognosticator, hypoxia is also a theoretically ideal target for guided drug delivery. This idea has lead to the development of hypoxia-activated prodrugs (HAPs): a class of chemotherapeutics which remain inactive in the body until metabolized within hypoxic regions. In theory, these drugs have the potential for increased tumour selectivity and have therefore been the focus of numerous preclinical studies. Unfortunately, HAPs have had mixed results in clinical trials, necessitating further study in order to harness their therapeutic potential. One possible avenue for the improvement of HAPs is through the selective application of anti angiogenic agents (AAs) to improve drug delivery. Such techniques have been used in combination with other conventional chemotherapeutics to great effect in many studies. A further benefit is theoretically achieved through nanocell administration of the combination, though this idea has not been the subject of any experimental or mathematical studies to date. In the following, a mathematical model is outlined and used to compare the predicted efficacies of separate vs. nanocell administration for AAs and HAPs in tumours. The model is experimentally motivated, both in mathematical form and parameter values. Preliminary results of the model are highlighted throughout which qualitatively agree with existing experimental evidence. The novel prediction of our model is an improvement in the efficacy of AA/HAP combination therapies when administered through nanocells as opposed to separately. While this study specifically models treatment on glioblastoma, similar analyses could be performed for other vascularized tumours, making the results potentially applicable to a range of tumour types.
Highlights
Hypoxia is a common feature of solid tumours resulting from an inadequate oxygen supply and has been associated with many negative cancer behaviours including increased metastasis and aggressive phenotypes, promotion of genetic instability, and decreased treatment effectiveness for immunotherapy, radiotherapy, and chemotherapy [1,2,3,4,5,6,7,8,9,10,11]
We focus on the nitroimidazole-based hypoxia-activated prodrugs (HAPs), TH-302 (Evofosfamide), which undergoes a 1e− reduction to form the DNA cross-linking bromo-isophosphoramide mustard (Br-IPM) under hypoxia [15, 16]
We focus on the HAP, TH-302, and the angiogenic agents (AAs), combretastatin, for the purposes of model form and parameter values
Summary
Hypoxia is a common feature of solid tumours resulting from an inadequate oxygen supply and has been associated with many negative cancer behaviours including increased metastasis and aggressive phenotypes, promotion of genetic instability, and decreased treatment effectiveness for immunotherapy, radiotherapy, and chemotherapy [1,2,3,4,5,6,7,8,9,10,11]. HAPs are bioreductive compounds which remain inactive under normoxic conditions, but are metabolized under hypoxic conditions within the body into their cytotoxic forms. Their hypoxic selectivity is achieved through a 1e− or 2e− reduction reaction which is rapidly reversed under an abundance of oxygen, but serves as the first step in a reduction cascade under hypoxia. This activation exclusively in hypoxic zones does not prevent HAPs from attacking non-hypoxic tumour cells. We focus on the nitroimidazole-based HAP, TH-302 (Evofosfamide), which undergoes a 1e− reduction to form the DNA cross-linking bromo-isophosphoramide mustard (Br-IPM) under hypoxia [15, 16]
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