Lasse Murtomäki

Barrier analysis of periocular drug delivery to the posterior segment

Periocular administration is a potential way of delivering drugs to their targets in posterior eye segment (vitreous, neural retina, retinal pigment epithelium (RPE), choroid). Purpose of this study was to evaluate the role of the barriers in periocular drug delivery. Permeation of FITC-dextrans and oligonucleotides in the bovine sclera was assessed with and without Pluronic gel in the donor compartment. Computational model for subconjunctival drug delivery to the choroid and neural retina/vitreous was built based on clearance concept. Kinetic parameters for small hydrophilic and lipophilic drug molecules, and a macromolecule were obtained from published ex vivo and in vivo animal experiments. High negative charge field of oligonucleotides slows down their permeation in the sclera. Pluronic does not provide adequate rate control to modify posterior segment drug delivery. Theoretical calculations for subconjunctival drug administration indicated that local clearance by the blood flow and lymphatics removes most of the drug dose which is in accordance with experimental results. Calculations suggested that choroidal blood flow removes most of the drug that has reached the choroid, but this requires experimental verification. Calculations at steady state using the same subconconjunctival input rate showed that the choroidal and vitreal concentrations of the macromolecule is 2-3 orders of magnitude higher than that of small molecules. The evaluation of the roles of the barriers augments to design new drug delivery strategies for posterior segment of the eye.

Estimation of the pore size and charge density in human cadaver skin

Abstract Streaming potential and the ction transport number were measured in human cadaver skin. The transport number was used to estimate the charge density in aqueous pores of skin using both Donnan equilibrium and Langmuir adsorption isotherm. A microscopic model was employed to evaluate the pore radius from the streaming potential and charge density data. The capillary pore model was extended to account for any distribution of pore size, and applied particularly to the gaussian distribution. The mean radius of the distribution appeared to be slightly less than that of the single pore model. In both cases the radii were ca. 20 nm.

Light induced cytosolic drug delivery from liposomes with gold nanoparticles

Externally triggered drug release at defined targets allows site- and time-controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH-sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site-specific drug delivery into the target cells.

Hydrogen evolution catalyzed by electrodeposited nanoparticles at the liquid/liquid interface

Aqueous protons reduction by decamethylferrocene in 1,2-dichloroethane can be catalyzed efficiently by platinum and palladium nanoparticles electrogenerated in situ at the liquid-liquid interface.

Inhibitive Effect of Benzotriazole on Copper Surfaces Studied by SECM

The inhibitive effect of benzotriazole on a commercial copper surface phosphorus-deoxidized copper was studied by a scanning electrochemical microscope SECM in an aqueous sodium sulfate solution using ferrocenemethanol FcMeOH as the redox mediator. The formation of the inhibitive film was followed as a function of time and as a function of the potential of the copper substrate. The results were analyzed using the existing models in the literature. The results show that the potential has a crucial effect on the growth of the CuI-BTA film. At a potential close to the dissolution range of copper, the surface changes gradually from almost ideally conductive to almost ideally insulating surface in the presence of benzotriazole, but at more negative potentials the effect is diminished and finally deceased. Quartz crystal microbalance experiments showed that the mass of an adsorbed layer must correspond to a multilayer.

Estimation of pore size and pore density of biomembranes from permeability measurements of polyethylene glycols using an effusion-like approach

Abstract Biomembranes restrict adsorption and distribution of hydrophilic molecules, like many peptides and oligonucleotides, in the body. The paracellular pathway occupies a very small surface area and is sealed by the junctional complex. In many cases the paracellular pore size (rp) is comparable with the radius of diffusing molecule (rd) and so called Renkin correction is used to model the transmembrane diffusion in a quantitative way. In this approach a crucial parameter rd/rp must not be greater than 0.3–0.4; a requirement that is not often fulfilled by experimental data. Consequently, an effusion-like approach was used to estimate pore sizes of the paracellular route and the porosity of the effective barrier of biomembranes. The model membranes were the cornea and conjunctiva of a rabbit eye and the permeating paracellular probes were a mixture of 17 polyethylene glycols of different sizes. It was concluded that the rate determining step for the permeability of the drug through the studied membranes is the probability of finding hydrophilic pores. Another criteria for the effusion-like process was that the effective barrier thickness is small. The effusion-like approach yielded realistic values for the paracellular pore diameter and for the number of the pores in the cornea and conjunctiva. The theory will evidently also be applicable to several other biomembranes, enabling calculation of paracellular pore sizes and porosities; for example nasal, tracheal and intestinal epithelia should fulfill the criteria.

Ion-exchange fibers and drugs: a transient study

The objective of this study was to theoretically model and experimentally measure the kinetics and extent of drug release from different ion-exchange materials using an in-house-designed flow-cell. Ion-exchange fibers (staple fibers and fiber cloth) were compared with commercially available ion-exchange materials (resins and gels). The functional ion-exchange groups in all the materials were weak -COOH or strong -SO3H groups. The rate and extent of drug release from the fibers (staple fiber>fiber cloth) was much higher than that from the resin or the gel. An increase in the hydrophilicity of the model drugs resulted in markedly higher rates of drug release from the fibers (nadolol>metoprolol>propranolol>tacrine). Theoretical modelling of the kinetics of ion exchange provided satisfactory explanations for the experimental observations: firstly, a change in the equilibrium constant of the ion-exchange reaction depending on the drug and the ion-exchange material and, secondly, a decrease in the Peclet number (Pe) with decreasing flow-rate of the drug-releasing salt solution.

Controlled complexation of plasmid DNA with cationic polymers: Effect of surfactant on the complexation and stability of the complexes

The aggregation of the cationic polymer-plasmid DNA complexes of two commonly used polymers, polyethyleneimine (PEI) and poly-l-lysine (PLL) were systematically compared. The complexation was studied in 5% glucose solution at 25 degrees C using dynamic light scattering and isothermal titration calorimetry. The aggregation of the complexes was controlled by addition of the surfactant polyoxyethylene stearate (POES). The stability of the complexes was evaluated using dextran sulphate (DS) as relaxing agent. The relaxation of the complexes in the presence of DS was studied using agarose gel electrophoresis. This study elucidates the role of surfactant in controlling the size of the PEI/pDNA complex and reveals the differences of the two polymers as complexing agents.

Electrochemical Characterization of Human Skin by Impedance Spectroscopy: The Effect of Penetration Enhancers

The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model with modern fractal mathematics, the effect of enhancers on the surface of skin is demonstrated. The enhancers appeared to open new penetration routes and increase the ohmic resistance, capacitive properties, and fractal dimension of skin, which means a rougher or more heterogeneous surface.

Transdermal iontophoresis of sotalol and salicylate; the effect of skin charge and penetration enhancers

Abstract Transdermal iontophoresis of sotalol was studied in horizontal diffusion chambers in the presence and absence of penetration enhancers dodecyl N , N -dimethyl amino acetate (DDAA) and Azone using the constant potential drop of 0.5 V across human cadaver skin, and the results were compared with the ones of shed snake skin, Elaphe obsoleta . DDAA and Azone improved the permeation of sotalol in human cadaver skin equally to that of iontophoresis with 0.5 V potential drop, i.e., 6–13-fold in comparison to the control without enhancement. Combination of iontophoresis and penetration enhancers did not further increase the permeation; in fact, the combination seemed to decrease it slightly when compared to iontophoresis or enhancers alone. The effect of skin charge on the transport was studied comparing the permeabilities of cationic sotalol and anionic salicylate in human and snake skin which have different ion selective properties. Sotalol appeared to penetrate better through human skin while salicylate penetrated better through snake skin. The principal route of charged drugs during iontophoresis is proposed to be through the skin appendages while neutral solutes are transported through the lipid matrix of skin. The permeation of tritiated water increased slightly during iontophoresis and in a more pronounced manner in the presence of DDAA and Azone.