Microfluidic investigation of the effect of liposome surface charge on drug delivery in micro-circulation

Abstract

Nano-carrier drug transport in blood microcirculation is one of the hotspots of current research in drug development due to many advantages over traditional therapies, such as reduced sideeffects, target delivery, controlled release, improved pharmacokinetics and therapeutic index. Despite the substantial efforts made in the design of nanotherapeutics, the big majority of the used strategies failed to overcome the biological barriers to drug transport encountered in human microvasculature, such as transport by blood flow via the microcirculatory network and margination, the mechanism according to which particles migrate along vessel radius to the wall. In fact, drug transport efficiency in microvasculature is affected by both the particulate nature of blood and drug carrier properties, such as size, shape and surface charge. In this work, the effect of the surface charge of liposomes on their margination in blood flow in microcapillaries was experimentally evaluated. By high-speed video microscopy and image analysis it was found that the two custom-made liposomes (one neuter and the other positively charged) tend to drift laterally, moving towards the wall and accumulating in the cell-free layer. In particular, neuter and cationic liposomes showed a comparable margination propensity, suggesting that the presence of blood cells governs the flow behavior independently on liposome surface charge.

Margination of Fluorescent Polylactic Acid–Polyaspartamide based Nanoparticles in Microcapillaries In Vitro: the Effect of Hematocrit and Pressure

“…As shown in Figure 6 , the average value of the CFL at Hct 10% is about 6 μm at 20/40 mmHg and 7 μm at 75 mmHg, while at Hct 15% it is about 4 μm at 20/40 mmHg and 5 μm at 75 mmHg, finding a very good agreement with the results from numerical simulations and experiments in similar flow conditions [ 3 , 9 , 12 , 22 ].…”

“…The velocity profiles have been determined as previously reported [ 3 , 9 , 12 ]. FNP/RBC velocity profiles at 20 mmHg are shown in Figure 2 as a function of the distance from the centerline for the two hematocrit values investigated: Hct 10% ( Figure 2 A) and Hct 15% ( Figure 2 B).…”

“…In physiology, the term refers to the flow behavior of white blood cells (WBCs) and platelets, which 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 [ 5 , 6 , 7 ]. In analogy with platelets and WBCs, drug carriers within the bloodstream are also expected to migrate in the RBC-FL near the vessel wall [ 8 , 9 , 10 ]. The phenomenon of margination has been studied either by numerical simulations [ 8 , 11 ] or by experimental studies in vitro, the latter being focused on the dependence of micro-particles (μ-Ps) distribution and delivery efficacy on the presence of RBCs, shear rate, particle size, shape and surface charge [ 3 , 9 , 12 , 13 ].…”

“…In analogy with platelets and WBCs, drug carriers within the bloodstream are also expected to migrate in the RBC-FL near the vessel wall [ 8 , 9 , 10 ]. The phenomenon of margination has been studied either by numerical simulations [ 8 , 11 ] or by experimental studies in vitro, the latter being focused on the dependence of micro-particles (μ-Ps) distribution and delivery efficacy on the presence of RBCs, shear rate, particle size, shape and surface charge [ 3 , 9 , 12 , 13 ]. It has been shown 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.…”

“…Margination is also affected by μ-P size and shape, larger spherical/discoid particles being more effectively marginated both in vitro and in vivo [ 14 ]. 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 charge [ 9 ]. Moreover, the chemical nature of μ-P could be another important aspect to take into account when designing drug delivery strategies.…”