Abstract

This perspective focuses on the hyper-permeable vasculature, contributing to the passive accumulation of drugs or NP-drug combinations through the paracellular and/or transcellular pathways. This unique, cardinal, pathological feature of the vasculature in solid tumors is a major determinant for the entry of anti-cancer macromolecules, with longer drug retention, attributable to imperfections in the lymphatic drainage system. However, the desmoplastic reaction, another challenge in terms of drug delivery, is attributable to the collagen-dense, heterogeneous accumulation of stromal components in the Tumour Microenvironment (TME). Thus, the consequent increases in the Interstitial Fluid Pressure (IFP) have been determined by experimental and computational techniques. This back-flow can contribute to decrements in the drug/NP-drug conjugate reaching the tumour site, warranting strategies to be adopted that can lower this pressure. However, the translational potential of the EPR-effect-mediated drug delivery in humans is limited. The tumour-specific, spatiotemporal differences in the EPR effect require human-relevant tumour models as well as their analysis based on advanced imaging, including MRI-based studies. This development, validation, and refinement of an iterative strategy can lead to the optimization of such customized models for personalised, tailormade medicine.

Keywords: EPR effect, disorganized vasculature, desmoplasia, increased fluid pressure, PDX models, MRI-based imaging.