Abstract
Understanding how polyprotic compounds distribute within liposome (LP) suspensions is of major importance to design effective drug delivery strategies. Advances in this research field led to the definition of LP-based active drug encapsulation methods driven by transmembrane pH gradients with evidenced efficacy in the management of cancer and infectious diseases. An accurate modeling of membrane-solution drug partitioning is also fundamental when designing drug delivery systems for poorly endocytic cells, such as red blood cells (RBCs), in which the delivered payloads rely mostly on the passive diffusion of drug molecules across the cell membrane. Several experimental models have been proposed so far to predict the partitioning of polyprotic basic/acid drugs in artificial membranes. Nevertheless, the definition of a model in which the membrane-solution partitioning of each individual drug microspecies is studied relative to each other is still a topic of ongoing research. We present here a novel experimental approach based on mathematical modeling of drug encapsulation efficiency (EE) data in liposomal systems by which microspecies-specific partition coefficients are reported as a function of pH and phospholipid compositions replicating the RBC membrane in a simple and highly translatable manner. This approach has been applied to the study of several diprotic basic antimalarials of major clinical importance (quinine, primaquine, tafenoquine, quinacrine, and chloroquine) describing their respective microspecies distribution in phosphatidylcholine-LP suspensions. Estimated EE data according to the model described here closely fitted experimental values with no significant differences obtained in 75% of all pH/lipid composition-dependent conditions assayed. Additional applications studied include modeling drug EE in LPs in response to transmembrane pH gradients and lipid bilayer asymmetric charge, conditions of potential interest reflected in our previously reported RBC-targeted antimalarial nanotherapeutics.
Highlights
A wide range of therapeutic nanoparticles in the form of nanocarrier-based delivery systems have been developed so far for the management of several medical conditions aiming to improve treatment outcomes while minimizing drug dosages (Anselmo and Mitragotri, 2016; Bobo et al, 2016)
The initial aim of this work was to study the effect of differences in pH and red blood cells (RBCs) membrane-analogous phospholipid compositions over the distribution of polyprotic antimalarials in LP suspensions
Considering our ultimate goal to advance in the design of RBCtargeted, LP-based nanotherapeutics with improved prophylactic activity against P. falciparum intraerythrocytic stages, an alternative lipid composition consisting of 40% cholesterol and 60% phospholipid, mainly PC:phosphatidylserine (PS):PE at mole ratios 23:33:44 (PC:PS:PE-LPs), was studied reproducing the RBC inner membrane leaflet (Maguire et al, 1991; Virtanen et al, 1998; Ingólfsson et al, 2014)
Summary
A wide range of therapeutic nanoparticles in the form of nanocarrier-based delivery systems have been developed so far for the management of several medical conditions aiming to improve treatment outcomes while minimizing drug dosages (Anselmo and Mitragotri, 2016; Bobo et al, 2016). Liposomes (LPs) have proven to be notably effective in the treatment of cancer, fungal infections, and age-related disorders, among other therapeutic purposes, as well as in analgesia and vaccine formulations (Allen and Cullis, 2013; Bulbake et al, 2017) Given their biphasic character analogous to biological membranes, LPs are capable of entrapping both lipophilic and hydrophilic compounds as well as buffer solutions (Torchilin, 2005; Pattni et al, 2015; Sercombe et al, 2015). This assumption has been theorized in a large number of works and is represented in Figure 1 as an adaptation for liposomal systems
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