Cameron Meaney, Sander Rhebergen, Mohammad Kohandel
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.
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 [1–11]. Accordingly, strategies to combat tumour hypoxia are in high demand. On the other hand, tumour hypoxia has gained significant interest in recent years for its potential as a target for selective drug delivery in cancer.
Materials and methods
The mathematical model presented here is a combination of existing mathematical models, used here to investigate a novel problem; namely, AA/HAP combinations. It incorporates results from previously published experimental data, informing selections for equation forms and parameter values. It consists of a system of reaction-diffusion equations for the essential components of the tumour growth and treatment system. The parameter meanings, values, and sources for separate administration can be found in Table 1 and for nanocell administration in Table 2. Most of the parameters are taken directly from previous mathematical modelling studies which estimated the parameters from experimental data. Parameters describing tumour cell growth, vasculature development, and oxygen distribution were taken from Kohandel et al 2007  who estimated the parameters based off of the experimental results of Winkler et al 2004  who examined mouse xenograft models from the U87 MG cell line (glioblastoma). This experimental work showed that selective VEGF blockade can induce a normalization window during which chemotherapy and radiotherapy achieves the best outcome
Our model simulations suggest a novel, advantageous method for administration of HAPs: a combination with AAs through nanocell administration. To our knowledge, no other models—mathematical or experimental—have investigated the combination of HAPs and AAs through nanocell delivery. The results of our model clearly show that the nanocell delivery method results in an increase in the efficacy of TH-302, shown through an increase in the total cell kill of the tumour. The model was also used to reproduce the results of previous experiments, which are summarized and compared in more detail below.
Citation: Meaney C, Rhebergen S, Kohandel M (2020) In silico analysis of hypoxia activated prodrugs in combination with anti angiogenic therapy through nanocell delivery. PLoS Comput Biol 16(5): e1007926. https://doi.org/10.1371/journal.pcbi.1007926
Editor: Natalia L. Komarova, University of California Irvine, UNITED STATES
Received: December 4, 2019; Accepted: May 5, 2020; Published: May 28, 2020
Copyright: © 2020 Meaney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: MK acknowledges the financial support from the Natural Sciences and Engineering Research Council (NSERC) of Canada as well as the Canadian Institutes of Health Research (CIHR). SR acknowledges support from the Natural Sciences and Engineering Research Council of Canada through the Discovery Grant program (RGPIN-05606-2015). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.