D'Apolito, Rosa (2016) Transport of drug carriers in microcirculation. [Tesi di dottorato]

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Nanomedicine holds great promises in the treatment of a wide range of diseases, such as cancer, pain, infections and inflammatory disorders. In fact, the primary aim of nanomedicine is the improvement of human health delivering drug molecules within the body to their final biological target with minimal toxicit and in a controlled manner. For this purpose, the use of nano- and micro-particulate Drug Delivery Systems (DDSs) has emerged as a valuable potential tool for performing the main goals of nanomedicine (i.e. targeted delivery, stability of the drug, high permeability, controlled release-kinetic and reduced side-effects). To evaluate the delivery efficiency of drug carriers, it is crucial to study their transport, adhesion and distribution in blood flow. In particular, for particle transport and distribution in microcirculation (i.e. capillaries, arterioles and venules, where most of the exchange with tissues takes place), the particulate nature of blood and the deformability of Red Blood Cells (RBCs) needs to be considered. A key step in particle-based drug delivery through microcirculation is particle migration from blood flow to vessel walls, also known as “margination”, which promotes particle contact and adhesion to the vessel wall. In physiology, the term refers to the flow behaviour of white blood cells (WBCs) and platelets, that concentrate in the RBC-free-layer (RBC-FL), a near-wall region depleted of RBCs, which originates from the migration of RBCs toward the vessel centerline due to a hydrodynamic lift. In analogy with platelets and WBCs, drug carriers within the bloodstream are also expected to migrate in the RBC-FL near the vessel wall. Margination and adhesion should be independently addressed as two distinct phenomena, considering that the former is a fundamental prerequisite to achieve particle adhesion and subsequent extravasation. Although margination has been modeled by numerical simulations and investigated in model systems in vitro, experimental studies including RBCs and environmental conditions mimicking human microcirculation are currently lacking. Here, we evaluate the effect of several parameters on margination through microfluidic studies in vitro and by intravital microscopy in vivo. In particular, the dependence of micro-particles (μ-Ps) distribution and delivery efficacy on the presence of RBCs, shear rate, particle size, shape, surface charge and stiffness is examined. We show that margination, which is almost absent when particles are suspended in a cell-free medium, is drastically enhanced by RBCs, in a pressure drop-dependent manner. In particular, as the shear rate increases, the μ-P concentration near the wall increases. The margination is also affected by μ-P size and shape, larger spherical/discoid particles being more effectively marginated both in vitro and in vivo. μ-Ps with different surface charge, instead, show a comparable margination propensity, suggesting that the presence of RBCs governs suspension flow behavior independently on μ-P surface properties. Finally, margination of carriers decreases when their stiffness decreases. Our findings can be explained by the collision of particles with RBCs that induces the drifting of the particles towards the vessel walls where they become trapped in the cell-free layer. These results are relevant for the design of drug delivery strategies based on systemically administered carriers, providing a quantitative analysis on how the particulate nature of blood, particle properties and physiological conditions influence μ-P delivery and distribution.

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