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Project: Drug Delivery Control at the Molecular Level

Main Objective: The objective of this project is to follow the process of drug delivery on a biocompatible monolayer controlling the mechanism at the molecular level, using scanning tunnelling microscopy(STM). More specifically, nanostructured monolayers of a heparin disaccharide unit will be deposited on a titanium (Ti) surface over which a monolayer with an ocular drug encapsulated in cyclodextrin(CD) will be put together by a self-assembling process. The drug release process will then be followed.

The motivation for this research is rooted on the concern of physicians collaborating in this project for an alternative solution to the drugs administration system used in the glaucoma therapeutics. The conventional methods consist on eye drops administration, for which only 20% of the active drug in one droplet achieves the ocular anterior chamber, the remaining being drained through the nasolacrimal duct or run down the chin. Another problem relates to the patient noncompliance since half of glaucoma patients do not use their ophthalmic medication properly.

A potentially alternative solution to the current therapeutics could be the delivery of drugs into the eye using intraocular devices similar which are already used in glaucoma treatment. These devices could be coated with self-assembled monolayers as proposed for investigation in this project, incorporating the same drugs as those used in the conventional therapeutics.

The idea is to use STM to prepare the self-assembled monolayers and to control the release of the drug (â -blockers and/or á2 adrenergic agonist) from the CD carriers, using a stepwise procedure which is commonly used by the team work of this project to investigate supramolecular structures. In particular, the PI of this project showed that the CDs form inclusion complexes with these drugs. The STM uses a droplet of a non volatile solvent between the STM tip and the substrate where it is possible to inject molecules sequentially until the desired supramolecular structure is obtained. During the process, images with molecular resolution are obtained in real time from the moment the molecules are injected until a fully packed monolayer is achieved. Images can also be obtained to follow and control the release process. More specifically, the images which will be obtained and examined are those of the
i) heparin on the titanium surface,
ii) the CD+drug complex,
iii) release of the drug from the CD.
Using this method, a dissacharide unit of heparin will be assembled on a Ti substrate to obtain a nanostructured monolayer. Then, CD+drug complexes will assembly on the heparin. The fact that we have molecular resolution will enable the real time observation of the release of the drug at this scale in a biological environment, and that was never done. To control the process under the biological conditions and without loosing the molecular level detail, an electrochemical STM cell will be used at a later stage. The method is similar to the one used in STM at the solid/liquid interface but in this case the monolayers will be prepared and characterized in water. The experiments will be made in conditions similar to those in the human body, namely, pH, temperature, salt concentration. This environment will allow a realistic study of the processes in the drug release mechanism.

This research addresses a new strategy to study drug delivery, since usually such systems are evaluated by spectroscopy in solution to study drug delivery systems in a large scale. They don’t take into account the interactions at the molecular level that occur between drug and carrier. The detailed knowledge of the system at the molecular scale will allow its optimization in large scale and potentiate the development of new devices or therapeutics.
Reference: EXPL/CTM-NAN/0837/2012
Funding: FCT
Start Date: 01-05-2013
End Date: 01-04-2014
Team: Quirina Alexandra Tavares Ferreira, Luís Joaquim Alcácer, Rita França de Sousa Rodrigues
Groups: Organic Electronics – Lx, Organic Electronics – Lx, Organic Electronics – Lx
Local Coordinator: Quirina Alexandra Tavares Ferreira
Links: Internal Page
Associated Publications