Capillary-Wall Collagen as a Biophysical Marker of Nanotherapeutic Permeability into the Tumor Microenvironment

Abstract

The capillary wall is the chief barrier to tissue entry of therapeutic nanoparticles, thereby dictating their efficacy. Collagen fibers are an important component of capillary walls, affecting leakiness in healthy or tumor vasculature. Using a computational model along with in vivo systems, we compared how collagen structure affects the diffusion flux of a 1 nm chemotherapeutic molecule (doxorubicin [DOX]) and an 80 nm chemotherapy-loaded pegylated liposome (DOX-PLD) in tumor vasculature. We found a direct correlation between the collagen content around a tumor vessel to the permeability of that vessel permeability to DOX-PLD, indicating that collagen content may offer a biophysical marker of extravasation potential of liposomal drug formulations. Our results also suggested that while pharmacokinetics determined the delivery of DOX and DOX-PLD to the same tumor phenotype, collagen content determined the extravasation of DOX-PLD to different tumor phenotypes. Transport physics may provide a deeper view into how nanotherapeutics cross biological barriers, possibly helping explain the balance between biological and physical aspects of drug delivery.

A multi-scale FE model for convective–diffusive drug transport within tumor and large vascular networks

“…We here emphasize that the goal of the paper was to formulate a computational framework for modeling complex problems such as convective-diffusive transport in organs or tumors, so that the presented results give basically a qualitative confirmation of the methodology. Quantitative verification of accuracy of models, which are incorporated into the methodology of this study, was partly given in our previous references [27,32,19,34], and the results are in agreement with general observations in experiments. We present two examples which demonstrate applicability of the developed computational model to two very different conditions, one is a tumor with extremely small dimensions and the other is an organ with an order-ofmagnitude larger dimensions and different material parameters.…”

“…can dominate the transport through the wall. This interaction on a molecular level may be incorporated into a continuum transport model by evaluation of the effective diffusion coefficients (or scaling functions) using MD procedures and a numerical homogenization (within a multiscale-hierarchical concept); such a multiscale model has been applied to various bioengineering problems [19,[27][28][29][30][31][32][33][34][35]. Briefly, the following steps are undertaken in formulating the multiscale model.…”

“…A generalization of this concept is given in [18]. [19]); (c) use of molecular dynamics (MD) for evaluation of scaling functions to account for interaction between diffusing molecules and microstructural solid surfaces.…”

“…Computational procedure consists in the following steps: (a) Eqs (26). are assembled and solved for pressures; (b) fluxes are calculated from(19), using values for fluxes in(20) from previous iteration; (c) the fluxes obtained in step (b) are used in evaluation of the next iteration. If the terms corresponding to pressure derivatives in(24) are neglected (accounting for inertial effects), the governing equation(24) reduces to kp ,x x = 0, and the FE equation(26) reduces to…”

Physics-based multiscale mass transport model in drug delivery and tumor microenvironment

“…Our in vivo and in silico study revealed that phenotypic differences of tumor microenvironment can negate enhanced PK properties of nanotherapeutics [3]. There, capillary collagen of type-IV can be a biophysical marker determining the extravasation of doxorubicin (DOX) by using its liposomal formulation (PLD) as a nanotherapeutic formulation of DOX.…”