An experimental and computational framework for engineering multifunctional nanoparticles: designing selective anticancer therapies.

A key challenge in the treatment of cancer with nanomedicine is to engineer and select nanoparticle formulations that lead to the desired selectivity between tumorigenic and non-tumorigenic cells. To this aim, novel designed nanomaterials, deep biochemical understanding of the mechanisms of interaction between nanomaterials and cells, and computational models are emerging as very useful tools to guide the design of efficient and selective nanotherapies. This works shows, using a combination of detailed experimental approaches and simulations, that the specific targeting of cancer cells in comparison to non-tumorigenic cells can be achieved through the custom design of multivalent nanoparticles. A theoretical model that provides simple yet quantitative predictions to tune the nanoparticles targeting and cytotoxic properties by their degree of functionalization is developed. As a case study, a system that included a targeting agent and a drug and is amenable to controlled experimental manipulation and theoretical analysis is used. This study shows how at defined functionalization levels multivalent nanoparticles can selectively kill tumor cells, while barely affecting non-tumorigenic cells. This work opens a way to the rational design of multifunctionalized nanoparticles with defined targeting and cytotoxic properties for practical applications.

A mathematical model for the rational design of chimeric ligands in selective drug therapies.

Chimeric drugs with selective potential toward specific cell types constitute one of the most promising forefronts of modern Pharmacology. We present a mathematical model to test and optimize these synthetic constructs, as an alternative to conventional empirical design. We take as a case study a chimeric construct composed of epidermal growth factor (EGF) linked to different mutants of interferon (IFN). Our model quantitatively reproduces all the experimental results, illustrating how chimeras using mutants of IFN with reduced affinity exhibit enhanced selectivity against cell overexpressing EGF receptor. We also investigate how chimeric selectivity can be improved based on the balance between affinity rates, receptor abundance, activity of ligand subunits, and linker length between subunits. The simplicity and generality of the model facilitate a straightforward application to other chimeric constructs, providing a quantitative systematic design and optimization of these selective drugs against certain cell-based diseases, such as Alzheimer's and cancer.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e26; doi:10.1038/psp.2013.2; advance online publication 13 February 2013.

Variability in noise-driven integrator neurons.

Neural variability in the presence of noise has been studied mainly in resonator neurons, such as Hodgkin-Huxley or FitzHugh-Nagumo models. Here we investigate this variability for integrator neurons, whose excitability is due to a saddle-node bifurcation of the rest state instead of a Hopf bifurcation. Using simple theoretical expressions for the interspike times distributions, we obtain coefficients of variation in good agreement with numerical calculations in realistic neuron models. The main features of this coefficient as a function of noise depend on the refractory period and on the presence of bistability. The bistability is responsible for the existence of two different time scales in the spiking behavior giving an antiresonance effect.

Collisional line shapes for low frequency vibrations of adsorbates on a metal surface.

The dynamics of atoms or molecules adsorbed on a metal surface, and excited by collisions with an atomic beam, are treated within a theory that includes energy dissipation into lattice vibrations by means of a frequency and temperature dependent friction function. The theory provides dynamic structure factors for energy transfer derived from collisional time correlation functions. It describes the relaxation of a vibrationally excited atom or molecule within a model of a damped quantum harmonic oscillator bilinearly coupled to a bath of lattice oscillators. The collisional time correlation function is generalized to include friction effects and is applied to the vibrational relaxation of the frustrated translation mode of Na adsorbed on a Cu(001) surface, CO on Cu(001), and CO on Pt(111), following excitation by collisions with He atoms. Results for the frequency shift and width of line shapes versus surface temperature are in very good agreement with experimental measurements of inelastic He atom scattering. Our interpretation of the experimental results provides insight on the relative role of phonon versus electron-hole relaxation.

Hamiltonian theory for vibrational line shapes of atoms adsorbed on surfaces.

The vibrational motions of atomic adsorbates on surfaces can be probed by helium atom scattering. The experimental observable is the dynamic structure factor, which shows an inelastic peak around the vibrational frequency of the isolated adsorbates known as the frustrated translational or T-mode peak. In this paper we develop a theory for the line shape of this peak, as well as for its temperature-dependent shift and broadening, based on a Hamiltonian equivalent of the generalized Langevin equation. The theory can be used to infer physical parameters of the adatom-surface interaction, such as the friction coefficient, the barrier height to diffusion, and the anharmonicity parameter. Numerical simulations are used to ascertain the range of validity of the theory, which is also generalized to describe multidimensional systems and to include quantum corrections. We compare the theoretical predictions for the shift and broadening with experimental results for the Na/Cu(001) system, showing quantitative agreement within experimental resolution.

Chaotic transport of particles in two-dimensional periodic potentials driven by ac forces.

The diffusive and directed transport of particles in a two-dimensional periodic potential subjected to frictional and time-periodic forces is analyzed in detail. The model represents diffusion of atoms adsorbed on metal surfaces under an applied ac electric field (surface electromigration) in the low-temperature limit. The second dimension and the potential energy coupling are shown to play an important role on both diffusion and net currents, depending on the direction of the drive. A properly chosen biharmonic field is able to control the directed ratchetlike dynamics of atoms on symmetric surfaces, since current reversals take place by different stabilization of attractors. Reversals identified with hysteresis loops between periodic running attractors are robust against an increase of the second harmonic amplitude, and against temperature effects inside the experimental range for measurements of surface diffusion.