Modeling the Release Kinetics of Poorly Water-Soluble Drug Molecules from Liposomal Nanocarriers

Liposomes are frequently used as pharmaceutical nanocarriers to deliver poorly water-soluble drugs such as temoporfin, cyclosporine A, amphotericin B, and paclitaxel to their target site. Optimal drug delivery depends on understanding the release kinetics of the drug molecules from the host liposomes during the journey to the target site and at the target site. Transfer of drugs in model systems consisting of donor liposomes and acceptor liposomes is known from experimental work to typically exhibit a first-order kinetics with a simple exponential behavior. In some cases, a fast component in the initial transfer is present, in other cases the transfer is sigmoidal. We present and analyze a theoretical model for the transfer that accounts for two physical mechanisms, collisions between liposomes and diffusion of the drug molecules through the aqueous phase. Starting with the detailed distribution of drug molecules among the individual liposomes, we specify the conditions that lead to an apparent first-order kinetic behavior. We also discuss possible implications on the transfer kinetics of (1) high drug loading of donor liposomes, (2) attractive interactions between drug molecules within the liposomes, and (3) slow transfer of drugs between the inner and outer leaflets of the liposomes

Influence of Monolayer-Monolayer Coupling on the Phase Behavior of a Fluid Lipid Bilayer

AbstractWe suggest a minimal model for the coupling of the lateral phase behavior in an asymmetric lipid membrane across its two monolayers. Our model employs one single order parameter for each monolayer leaflet, namely its composition. Regular solution theory on the mean-field level is used to describe the free energy in each individual leaflet. Coupling between monolayers entails an energy penalty for any local compositional differences across the membrane. We calculate and analyze the phase behavior of this model. It predicts a range of possible scenarios. A monolayer with a propensity for phase separation is able to induce phase separation in the apposed monolayer. Conversely, a monolayer without this propensity is able to prevent phase separation in the apposed monolayer. If there is phase separation in the membrane, it may lead to either complete or partial registration of the monolayer domains across the membrane. The latter case which corresponds to a three-phase coexistence is only found below a critical coupling strength. We calculate that critical coupling strength. Above the critical coupling strength, the membrane adopts a uniform compositional difference between its two monolayers everywhere in the membrane, implying phase coexistence between only two phases and thus perfect spatial registration of all domains on the apposed membrane leafs. We use the lattice Boltzmann simulation method to also study the morphologies that form during phase separation within the three-phase coexistence region. Generally, domains in one monolayer diffuse but remain fully enclosed within domains in the other monolayer

Attraction between Like Charged Surfaces Mediated by Uniformly Charged Spherical Colloids in a Salt Solution

Like-charged macromolecules repel in electrolyte solutions that contain small (i.e. point-like) monovalent co- and counterions. Yet, if the mobile ions of one species are spatially extended instead of being point-like, the interaction may turn attractive. This effect can be captured within the mean-field Poisson-Boltzmann framework if the charge distribution within the spatially extended ions is accounted for. This has been demonstrated recently for rod-like ions. In the present work, we consider an electrolyte solution that is composed of monovalent point-like salt ions and uniformly charged spherical colloids, sandwiched between two planar like-charged surfaces. Minimization of the mean-field free energy yields an integral-differential equation for the electrostatic potential that we solve numerically within the linear Debye-Hückel limit. The free energy, which we calculate from the potential, indeed predicts attractive interactions for sufficiently large spherical colloids. We derive an approximate analytical expression for the critical colloid size, above which attraction between like-charged surfaces starts to emerge. (doi: 10.5562/cca1824

Influence of spontaneous curvature on the line tension of phase-coexisting domains in a lipid monolayer: A Landau-Ginzburg model

The line tension between two coexisting phases of a binary lipid monolayer in its fluid state has contributions not only from the chemical mismatch energy between the two different lipid types but also from the elastic deformation of the lipid tails. We investigate to what extent differences in the spontaneous curvature of the two lipids affect the line tension. To this end, we supplement the standard Landau-Ginzburg model for the line tension between coexisting phases by an elastic energy that accounts for lipid splay and tilt. The spontaneous curvature of the two lipids enters into our model through the splay deformation energy. We calculate the structure of the interfacial region and the line tension between the coexisting domains numerically and analytically, the former based on the full non-linear model and the latter upon employing an approximation in the free energy that linearizes the resulting Euler-Lagrange equations. We demonstrate that our analytical approximation is in excellent agreement with the full non-linear model and use it to identify relevant length scales and two physical regimes of the interfacial profile, double-exponential decay, and damped oscillations. The dependence of the line tension on the spontaneous curvatures of the individual lipids is crucially dependent on how the bulk phases are affected. In the special case that the bulk phases remain inert, the line tension decreases when the difference between the spontaneous curvatures of the two lipid types grows.Fil: Rufeil Fiori, Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; ArgentinaFil: Downing, Rachel. North Dakota State University. Department Of Physics.; Estados UnidosFil: Bossa, Guilherme Volpe. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: May, Sylvio. North Dakota State University. Department Of Physics.; Estados Unido

Structure and energy of fusion stalks: the role of membrane edges.

Fusion of lipid bilayers proceeds via a sequence of distinct structural transformations. Its early stage involves a localized, hemifused intermediate in which the proximal but not yet the distal monolayers are connected. Whereas the so-called stalk model most successfully accounts for the properties of the hemifused intermediate, there is still uncertainty about its microscopic structure and energy. We reanalyze fusion stalks using the theory of membrane elasticity. In our calculations, a short (cylindrical micelle-like) tether connects the two proximal monolayers of the hemifused membranes. The shape of the stalk and the length of the tether are calculated such as to minimize the overall free energy and to avoid the formation of voids within the hydrocarbon core. Our free energy expression is based on three internal degrees of freedom of a perturbed lipid layer: thickness, splay, and tilt deformations. Based on exactly the same model, we compare fusion stalks with and without the ability included to form sharp edges at the interfacial region between the hydrocarbon core and the polar environment. Requiring the interface to be smooth everywhere, our detailed calculations recover previous results: the stalk energies are far too high to account for the experimental observation of fusion intermediates. However, if we allow the interface to be nonsmooth, we find a remarkable reduction of the stalk free energy down to more realistic values. The corresponding structure of a nonsmooth stalk exhibits sharp edges at the transition regions between the bilayer and tether parts. In addition to that, a corner is formed at each of the two distal monolayers. We discuss the mechanism how membrane edges reduce the energy of fusion stalks