"Nanostructured Oxidic Materials for Drug Delivery"
* Research contract No.: 2CEEX-06-D11-104
* Project director: Dr. Ruxandra Bîrjega
* Institutes participating in project:
• INFLPR -NILPRP National Institute for Lasers, Plasma and Radiation Physics; OPAM research group
• IB – Institute of Biochemistry of the Romanian Academy
• INCDFM -NIMP National Institute for Materials Physics
• ICF - Institute of Physical Chemistry "I. G. Murgulescu" of the Romanian Academy
• UB, FCh - University Of Bucharest, Chemistry Department.
* People involved at the beginning of the project in 2006
• PhD's - 27 persons
• PhD Students - 21 persons;
• MSc - 5 persons;
• Students - 3 persons;
• technicians - 7 persons.
At the conclusion of the project 5 PhD students became Phd’s by defeating their thesis.
1. Deposition of oxidic thin films (SiO2, TiO2 and/or Al2O3, ZrO2. using metalic targets. Chatarectization and biocomatibility tests on the as deposited thin films.
2. Syntheses of nanostructured oxides or mixed oxides powders e.g. SiO2, Al2O3, TiO2, ZrO2, MgO-Al2O3, Mg(Al)O) şi LDH-Mg-Al. Thin films deposition by PLD from ceramic targets obtained from the as-prepared powders.
3. Structural, microstructural, morphological characterization of the nanostructured materials prepared in the previous report. Dieletric and hidrophobic properties evaluations. Tests on the enzymathic SOD activity and on the contolled release of ampicillin on the above prepared and characterized materials.
3 extra. Functionalization and chracterization of selected mezoporous powders and thin films.
4. Post-synthesis treatments. Aminofunctionalization of SiO2 and/or TiO2 nanopowders. UV laser treatment of TiO2 thin films. Tests of SOD enzymatic activity and of ampicillin conrtolled release from the post-synthesized treated nanostructured materials.
5. Evaluations on the ability of teh above prepared nonostructured materials to act as drug deliver carriers. Elaborations of nanostructured materials synthesis and adequate biocompatibility tests. protocols
The goals and the results of the project were:
The project aimed to evaluate the prospects of a series of nanostructured oxidic materials ( e.g. SiO2, TiO2, ZrO2, Mg(Al)O ) prepared by different routes to be use as drug vehicles for controlled drug release. The main scientific goal was to emphasize correlations between synthesis methods with physical, (micro)structural and chemical properties and therefore to the ability of as-prepared materials to act as drugs delivery. The long term objectiv was the search for low cost material, exhibiting properties and synthesis procedures easy to monitorized , nontoxic and tolerated by the organism, ecological friendly, to be used for bio applications as: drugs, implants ets. The studies performed in the framework of this project produced a large amount of data concerning the properties of a series of materials prepared via different protocols developed by physicist and chemists as well, will help to gain a better understanding of the mechanims decisive in monitorising a synthesis and to detect the particular properties to be addressed for bio-applications.
A large number of samples, powders and thin films, were prepared. The samples were characterized by X-ray diffraction (XRD), atomic force microscopy (AFM), transmission electron microscopy (TEM), contact angle, thermal analysis, textural analysis. The biocompatibility of as- prepared thin films was tested by fluorescence microscopy with markers survaying the viability and the morphological changes of in vitro grown cells. For powdered samples the loading and contolled release of a drug- molecule test, (ampicillin) were studied. For silica powered the loading of an enzyme (SOD) and a proteine (BSA) were also investigated. It was a complex study allowing us to develop a common approach in the analysis of the results and in establishing further work strategies for this boundary field of research.
The systems thoroughly and deeply studied were for powders: the mesoporous silica and titania and the hydrotacites clays and for the thin films the TiO2 thin films. The MCM-41 structure was selected as reference sample for the powdered oxidic materials. It was used in order to establish protocols for : the ampicillin up-take kinetics, the degree of ampicillin loading, the cumulative precentage release kinetics in different types of release media.
The perfomed studies allow us to formulate some conclusions and results already presented in different scientific meetings.
There are briefly presented:
- For the ordered mesoporous silica, both MCM-41 (cationic surfactant) and SBA-15 (neutral surfactant) types are good candidates for the adsorption and controlled release of ampicillin. Encouraging results were obtained especially for the SBA-15 specimen. Although, exhibiting less ordered structured porosity at long range distance, due to its very good textural properties and pores particularly morphology, with ink-bottle effect, the SBA-15 sample manifests a higher adsorption capacity and a sensible slower rate of ampicillin release in comparison with the highly ordered mesoporous structured MCM-41 sample. The ampicillin loading tests revealed the sensitivity of the silica to moisture and ambient conditions therefore further studies will be interesting to be developed on functionalized ordered mesoporous silicas or on other nanostructures oxides host materials (e.g. TiO2). Our studies on functionalized MCM-41 and SBA-15 samples revealed the effect of amine functionalization on the textural properties and consequently on the up-take ampicillin.
- For the TiO2 systems our studies reveal the effect of structural slight differences as a lower overall crystallinity and the presence of defects, on the ampicillin loading and release. For a specimen of TiO2 synthesized via a sol-gel procedure which exhibits higher crystallinity, the ampicillin loading is more efficient but the release rate is higher due to a weak interaction of the drug molecule with its host titania matrix. On the other hand, for a titania sample less crystalline (surfactant assisted synthesis) and with a higher number of defects, although exposing the same surface area and mean pore size, due to the presence of cavities with different morphologies including ink-bottle like pores, the interaction of the drug molecule with the TiO2 surface in much stronger and consequently,the ampicillin up-take is lower and the delivery rate is much slower.
- For the hydrotalcites system the aim of the studies was to select the advantageous procedure to intercalate ampicillin in the interlayer spaces. Three types of methods were used on a parent hydrotalcite sample: HT3 (Mg/Al=3) prepared by co-precipitation at low supersaturation. : a) impregnation, b) reconstruction via the « memory effect » and c) direct synthesis. Reconstruction was selected as the suitable method in term of loading degree and reproducibility.
- For TiO2 thin films the aim of the studies was to investigate the biocompatibility of thin films obtained via two laser techniques : pulsed laser deposition (PLD ) and matrix assisted pulsed laser evaporation (MAPLE). The biocompatibility tests were performed by fluorescence microscopy with markers using a HEK 293 cells line. Our study emphasized that the TiO2 thin films obtained by both laser techniques are nontoxic and biocompatible. MAPLE leads to the formation of thin films exhibiting higher roughness and a granular character, which apparently enhanced the adhrence of cells to film surface.