The role of the microvascular network structure on diffusion and consumption of anticancer drugs

We investigate the impact of microvascular geometry on the transport of drugs in solid tumors, focusing on the diffusion and consumption phenomena. We embrace recent advances in the asymptotic homogenization literature starting from a double Darcy—double advection-diffusion-reaction system of partial differential equations that is obtained exploiting the sharp length separation between the intercapillary distance and the average tumor size. The geometric information on the microvascular network is encoded into effective hydraulic conductivities and diffusivities, which are numerically computed by solving periodic cell problems on appropriate microscale representative cells. The coefficients are then injected into the macroscale equations, and these are solved for an isolated, vascularized spherical tumor. We consider the effect of vascular tortuosity on the transport of anticancer molecules, focusing on Vinblastine and Doxorubicin dynamics, which are considered as a tracer and as a highly interacting molecule, respectively. The computational model is able to quantify the treatment performance through the analysis of the interstitial drug concentration and the quantity of drug metabolized in the tumor. Our results show that both drug advection and diffusion are dramatically impaired by increasing geometrical complexity of the microvasculature, leading to nonoptimal absorption and delivery of therapeutic agents. However, this effect apparently has a minor role whenever the dynamics are mostly driven by metabolic reactions in the tumor interstitium, eg, for highly interacting molecules. In the latter case, anticancer therapies that aim at regularizing the microvasculature might not play a major role, and different strategies are to be developed

Transport Phenomena with Reactions in Drug Delivery: towards a Quantitative Description

A Distributed System Called a Krogh Cylinder is Used Here to Quantify the Transport of a Solute from the Capillary into the Extravascular Tissue. the Capillary Network is Broken Down into Cylindrical Cells, Each Containing a Capillary and an Appropriate Amount of Extravascular Tissue. the Flow in the Cylinder Model Has Two-Dimensional Velocities, Which Are in the Axial and Radial Directions. All Parameters of the System, together with the Geometric Ones, Have Been Included in the Model. for a Given Bioavailability, the Uptakes of Reactive and Nonreactive Solutes Have Been Obtained. Very Large or Massive Molecules Have Been Considered. the Diffusion in the Tissue is Found to Be Very Low. Most of the Drug Uptake Happens through Convection, which is Slowed Down in the Presence of a Reaction. Further, This Convection is Entirely Due to the Flow Out into the Lymphatic System. for the Case Where a Reaction Takes Place, Local Equilibrium is Assumed, Which Both Cuts Down the Computation Times and Provides Good Results in the Case of Reactive Solutes. the Full Results of a Distributed System Have Been Obtained for the First Time, and the Mechanics of How the Area-Under-The-Curve Can Be Used to Calculate the Actual Solute Uptake Have Been Determined

In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability

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

Numerical simulation of transdermal delivery of drug nanocarriers using solid microneedles and medicated adhesive patch

Open Access via the Elsevier agreementPeer reviewedPublisher PD