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Final Report Summary - NANOLEM (Understanding the physico-chemical basis of transdermal drug delivery using nanomaterials)

Skin has high potential in systemic drug delivery and provides the advantage of avoidance of the first-pass effect, ease of use and withdrawal, and better patient compliance. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum (SC). The SC consists of enucleated dead cells (corneocytes) that are surrounded by lipid lamellae (being a mixture of ceramides (CER), cholesterol (CHOL) and free fatty acids (FA)). Several studies have shown that the lipid matrix is the major diffusion-rate limiting pathway, as most of the drugs applied topically pass the SC through the multilamellar organized lipids. The knowledge and comprehension of the interaction of drug carriers and SC lipids are essential for the understanding of drug penetration through the SC, as well as for the development of the new dermal drug delivery systems. In this regard, model lipid membranes which mimic many aspects of skin lipids are very useful models and that a lipid matrix based on CER/CHOL/FA is able to mimic the lipid organization of human SC to a large extent.
The main goal of this project was to clarify the mechanisms involved in the interactions between nanogels and dermal membranes and find out how these are influenced by physico-chemical conditions and the morphology of the nanogels. It was realised by synthesis (deliverables D1.1) and characterisation (D1.2) of thermo-responsive nanogels which because of their tuneable size, biocompatibility, a large surface area, and an interior network for the incorporation of biomolecules offer unique advantages for effective drug delivery systems. As the main monomer used in those studies the N-isopropylacrylamide (NIPAM) was chosen as it’s known to be able to alter size, volume occupied and hydrophobic character as a result of changes in the temperature of the solution (with volume transition temperature of 32 °C). By incorporating different amount of cross-linker into NIPAM-based nanogels the size, particle rigidity and transition temperature of nanogels were tuned. Additionally nanoparticles with different monomers (N-n-propylacrylamide and N-isopropylmethacrylamide) and with addition of charged co-monomers were prepared to gain a library of particles with various chemical structure, size, polarity and charge. The size (measured by dynamic light scattering), morphology (AFM, TEM) and charge (laser electrophoresis) were measured for all nanogels to identify candidates the most suitable as drug delivery agents. One of the very important characteristics of NIPAM nanogels was their surface activity and their behaviour at the interfaces (D2.1) which was studied in details by means of surface tension and neutron reflectivity (NR) measurements in the function of percentage of cross-linker, nanogel concentration and temperature. Application of NR allowed obtaining detailed information on nanogels structure and conformation at the interface. It was found that the structure of the nanogels differs significantly when nanogels are adsorbed at the interface causing their deformation and partial dehydration. It was proven as well that the degree of cross-linking, nanogel bulk concentration and temperature has a profound effect on their adsorption kinetics, adsorbed amount and structures created. Those finding become a subject of two papers (one already published and second submitted).
The next stage of the project was to study the interaction of nanogels with selected skin models. As mentioned above the most representative models of dermal transport are based on ceramides and ceramide/cholesterol/fatty acid mixtures. In this project we implemented ceramide (D2.2) and CER/CHOL/FA (D2.3) monolayers at air/water interface together with supported lipid bilayers (D3.1) to study their interactions and transport mechanisms with both neutral and charged (D2.4) nanogels. Studies on lipid monolayers at air/water interface showed that ability of NIPAM nanogels to penetrate monolayer depends strongly on the surface pressure. As NR measurements show at 31.0 mN/m nanogels are not able to penetrate membrane, however even small decrease in pressure (and at the same time at lipid packing) allows particles to enter lipid layer. We can conclude that as expected the type (e.g. part of the body) and condition (dermal diseases) of skin will have huge impact on the ability of nanogels to permeate skin. Experiments with CER/FA/CHOL indicated that fatty acid play important role in transport through the membranes since they can create complexes with gels and facilitate their transport.
To gain more insight into transport mechanisms the supported lipid bilayers (SLB) were used as a skin model. Before exposition to thermo-responsive nanogels SLBs were characterised by means of atomic force microscopy (AFM) and by NR. Those studies proved that morphology and organisation (e.g. distance between bilayers) of SLB depends strongly on the presence of fatty acids and cholesterol. In this part of the project the nanogels with different hydrophobicity, elasticity and charge were studied. Simultaneous AFM and NR studies proved that nanogels do not cause creation of holes in the lipid membrane (as suggested by some researchers) and do not influence lipid conformation but are still able to penetrate them. It was found that gels with intermediate (20 and 30%) degree of cross-linking penetrate the SLBs in the most effective way. Obtained data show as well that charged particles partitioning into membranes quite effectively but this process is depend on particles charge density and pH.
In the last part of the project the nanogels were uploaded (D4.1) with model drug (flufenamic acid) and the drug-nanogel complex morphology was studied (D4.2). Obtained data showed that drug can be effectively uploaded into nanogels and encapsulation efficiency depends on the nanogel structure. In general nanogels with lower degree of cross-linking allowed incorporating more drug but its release was faster and addition of hydrophobic co-monomers to gel structure increased the ability of nanogels to bond drug. It was proven as well that addition of drug did not influence significantly the nanogel size and morphology but was changing significantly the temperature at which polymer was undergoing transition from swollen to collapsed state. In general it was found that particles with higher hydrophobicity and ability to adapt their conformation are the best candidates for effective transdermal transport.
Data obtained in this project helps to understand the relationships between the structure of the nanoparticles and their efficiency as a drug delivery vehicle and brings the new light into clarifying mechanisms involved in nanoparticle transport through the lipid membranes (all mile stones achieved). The outcome of this research will aid the design of the next generation of effective dermal delivery systems and also contribute to the risk assessment of skin exposure to nanoparticles.

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