Modeling the Distribution of Diprotic Basic Drugs in Liposomal Systems: Perspectives on Malaria Nanotherapy

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.

Altered Drug Transport by Plasmodium falciparum Chloroquine Resistance Transporter Isoforms Harboring Mutations Associated with Piperaquine Resistance

“…In any case, weak base trapping dictates that weak polyprotic bases like CQ and PPQ will accumulate approximately 1000-fold in the acidic environment of the parasitic DV relative to the cytosol. , Given plasma concentrations for CQ (1–10 μM) , and PPQ (100–1500 nM), , the drug concentrations used in this study to assay PfCRT-mediated drug transport correspond to concentrations of drug found within the parasite DV. These DV concentrations (which are not near the IC 50 concentrations typically measured in parasite growth inhibition assays) are the concentrations of drug to which the DV-disposed face of PfCRT that is believed to initially bind the drug is exposed .…”

Phytosomes as Innovative Delivery Systems for Phytochemicals: A Comprehensive Review of Literature

“…[72][73][74] Liposomes are used in different pathological conditions, such as cancer, inflammation, eye and skin disease, malaria, and osteosarcomas. [75][76][77][78][79][80] The liposomes can be designed using various techniques. 81,82 Overall, most liposome preparatory methods are based on (1) solvation of the lipids in an organic solvent; (2) getting lipid thin film by evaporation; (3) hydration of lipid layer by a hydrophilic solvent; (4) liposome purification (5) and characterize the properties of the final liposome.…”

Liposomes for malaria management: the evolution from 1980 to 2020

“…Noteworthy, these three anti-malarial agents are polyprotic drugs that exhibit multiple ionization states and different degree of lipophilicity as a function of physiological conditions. In this context, Fernàndez-Busquets and colleagues designed distribution models that precisely describe the partitioning behaviour of these drugs in liposome vesicular systems [ 142 ]. These models have the capacity to predict the interactions of polyprotic drugs with biological and synthetic membranes depending on the pH, lipid composition and phospholipid charge.…”

“…These models have the capacity to predict the interactions of polyprotic drugs with biological and synthetic membranes depending on the pH, lipid composition and phospholipid charge. Importantly, these anti-malarial drug distribution modelling improved the effective drug delivery strategies such as liposome-based active drug encapsulation methods driven by transmembrane pH gradients [ 142 ].…”