Abstract
The delivery of blood-borne therapeutic agents to solid tumours depends on a broad range of biophysical factors. We present a novel multiscale, multiphysics, in-silico modelling framework that encompasses dynamic tumour growth, angiogenesis and drug delivery, and use this model to simulate the intravenous delivery of cytotoxic drugs. The model accounts for chemo-, hapto- and mechanotactic vessel sprouting, extracellular matrix remodelling, mechano-sensitive vascular remodelling and collapse, intra- and extravascular drug transport, and tumour regression as an effect of a cytotoxic cancer drug. The modelling framework is flexible, allowing the drug properties to be specified, which provides realistic predictions of in-vivo vascular development and structure at different tumour stages. The model also enables the effects of neoadjuvant vascular normalisation to be implicitly tested by decreasing vessel wall pore size. We use the model to test the interplay between time of treatment, drug affinity rate and the size of the vessels’ endothelium pores on the delivery and subsequent tumour regression and vessel remodelling. Model predictions confirm that small-molecule drug delivery is dominated by diffusive transport and further predict that the time of treatment is important for low affinity but not high affinity cytotoxic drugs, the size of the vessel wall pores plays an important role in the effect of low affinity but not high affinity drugs, that high affinity cytotoxic drugs remodel the tumour vasculature providing a large window for the normalisation of the vascular architecture, and that the combination of large pores and high affinity enhances cytotoxic drug delivery efficiency. These results have implications for treatment planning and methods to enhance drug delivery, and highlight the importance of in-silico modelling in investigating the optimisation of cancer therapy on a personalised setting.
Highlights
Inefficient delivery of drugs to solid tumours is one of the main reasons for chemotherapy failure
We find that the time of treatment and vessel permeability are important factors for the efficacy of chemical agents with low binding affinity, that high affinity drugs can impact the tumour vasculature remodelling and bring vascular structure back to a more normalised state, and that the combination of large-sized vessel wall pores and high affinity enhances cytotoxic drug delivery and efficacy
At low affinity a similar trend to tissue hydrostatic pressure (THP) is predicted: only late injection can reduce the interstitial fluid pressure (IFP) monotonically, with the earlier injections showing either monotonically increasing IFP, or decreasing IFP followed by relapse (Fig 5E and 5G). These results propose two main points:(a) THP and IFP are implicitly reduced by cytotoxic drug delivery, and (b) as a result of the reduced IFP, drugs that are dependent on convective transport—such as liposomes or nanoparticles—should not be administered after treatment by cytotoxic drugs
Summary
Inefficient delivery of drugs to solid tumours is one of the main reasons for chemotherapy failure. Apart from heterogeneous and low perfusion, other physiological barriers to the delivery of drugs to solid tumours is the uniform elevation of the interstitial fluid pressure owing to: (i) the hyper-permeability of the tumour blood vessels, (ii) the dysfunction of tumour lymphatics and in some (desmoplastic) tumour types, (iii) the dense interstitial space that resist to interstitial fluid flow [9, 10] All these parameters result in the accumulation of fluid in the tumour and interstitial hypertension, which in term eliminates pressure gradients across the tumour vessel wall and convective transport of drugs [1]. Binding of the drug to cancer cells might change significantly the penetration and intratumoural distribution of the drug, depending on the binding affinity [12, 13]
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