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Scientific background

Drug targeting

Almost a century ago, Paul Ehrlich postulated that targeting of drugs would be a major medical progress. He compared such substances with "Zauberkugeln" (magic bullets) that could be guided to specific locations and tissues in the body. However, targeted delivery of drugs is still a major challenge in pharmacology.
In contrast to systemic, non-targeted drug treatment, targeted drug delivery aims at treating the diseased tissues or organs individually as biological entities. Thereby, targeted delivery would achieve higher drug concentrations at the diseased tissue/organ, while at the same time the total drug dosage as well as the number and severity of side effects would be minimized.
A novel approach to drug targeting is the development of nano-sized drug carriers that allow for guided delivery therapeutic substances and/or controlled release of the drug.

Innovative therapies –Gene and Cell delivery

It is obvious, that site and tissue specific delivery of genes is still a major issue for genebased therapies. Many of the novel pharmaceuticals and innovative therapies arising from advances in pharmacology and biotechnology are macromolecules such as proteins, nucleic acids, oligonucleotides, DNA and RNA expression plasmids. Although these novel therapies would be of relevance for the treatment of a broad spectrum of human diseases, their clinical use may not be possible without carrier systems that allow these new drugs to access target cells and tissues.
Gene therapy can be most broadly defined as the delivery of genes to cells and tissues with the goal of curing a disease or at least to improve the clinical status of the patient (Pfeifer and Verma, 2001; Verma and Weitzman, 2005). Nucleic acids can be efficiently delivered to cells and tissues by viral gene transfer vectors (Kay et al., 2001; Pfeifer and Verma, 2001; Verma and Somia, 1997). However, targeted gene transfer, which is a prerequisite to achieve specific and localized expression of genes, is still a major obstacle. Although the tropism of viral vectors can be modified to some extent by pseudotyping, such modifications achieve only a relatively low degree of specificity and can be applied only to a rather small group of cell types. In addition, the problem of localized delivery of genes to a specific part of
an organ or only a subset of cells remains unsolved. Finally, the fundamental rerequisite for molecular targeting by receptor-ligand interactions is vector-cell contact in the first place.
This initial step is dependent on the presence of cellular attachment factors and incubation times, as well as diffusion rates. Experimental data demonstrate that cell attachment of viral and nonviral vectors can be efficiently enhanced by nanoparticles in vitro and in vivo (Haim et al., 2005; Scherer et al., 2002).
Presently, the most promising concepts for regenerative medicine are cell-based therapies. Progenitors and stem cells are considered ideal candidates for cell-based therapies, because of their unique properties: (i) self renewal, (ii) clonality and (iii) the potential to differentiate into different cell types in vitro and in vivo. Adult stem cells are multipotent and of limited plasticity, whereas embryonic stem cells can differentiate in all different cell types (Anderson et al., 2001). Among the most important diseases where such strategies could be beneficial for the patient, are cardiovascular (i.e. myocardial infarction) disorders (Srivastava and Ivey, 2006) since the underlying pathophysiology and the strategy to repair the tissues are already identified. Furthermore, cell replacement can be combined with gene therapy by using genetically engineered progenitor and stem cells as vehicles for gene transfers. Such transgenic cells can increase the therapeutic potential by secreting proteins like antiinflammatory or immune-modulatory molecules, components of the extracellular matrix, proteases and signaling molecules.
At the moment, these therapeutic approaches are still in their infancies, because of two striking problems: First, the most suitable cell type for the different replacement therapies has to be identified (Lindvall and Kokaia, 2006; Srivastava and Ivey, 2006). Second, the stem cells have to be efficiently targeted and stably positioned in the diseased tissue/organ to enable their engraftment and restoring of function. The precise positioning of stem cells and progenitors in a target area of interest is a largely unexplored field. However, this is critical therapeutic requirement to enable efficient enrichment of cells at the lesion site.
The cardiovascular system is of major interest for systemically applied gene- and cellbased therapies. On the other hand it is particularly challenging to achieve guided application and positioning of gene delivery vehicles and/or stem and progenitor cells in the cardiovascular system, because of the blood stream.

Nano-sized drug delivery systems

Nanomedicine can be broadly defined as the application of nanotechnology to the
prevention, diagnosis and treatment of human diseases (Moghimi et al., 2005).Nanomedicine is a multidisciplinary scientific field devoted to the construction and use of therapeutically relevant structures in the nanometer scale size range (< 1000 nm). This sector of molecular medicine has great potential to provide tools for medical sciences and to improve health care in the 21st century. The use of nano- or micro-sized particles as drug delivery systems is of outstanding biomedical relevance, because two major pharmacological and therapeutic shortcomings of most established drugs can be addressed by nano-sized drug carriers (ref. in (Allen and Cullis, 2004)): (1) Lack of selectivity for target tissues and poor biodistribution, as well as (2) unfavorable pharmacokinetics.

A novel approach to nano-sized drug targeting is bio-physical targeting. Bio-physical targeting can be achieved by coupling pharmaceuticals to magnetic carriers, which is the basis for magnetic drug targeting (Lubbe et al., 2001; Plank et al., 2003b). This coupling may involve direct attachment of an active agent to the magnetic nanoparticles (MNPs) via chemical or physical linkage. Chemical linkage is usually based on standard coupling chemistry, by e.g. exploiting ester, amide, disulfide bonds or thioethers. Physical linkage comprises electrostatic, hydrophilic and hydrophobic interactions, as well as biological linkages such as biotin-streptavidin or antigen-antibody type linkages. The formulation may as well comprise indirect coupling of magnetic nanoparticles and active agent such as co-incorporation in magnetoliposomes, magnetic microbubbles (see below) or aerosol droplets. In any case, the magnetic nanoparticles must be synthesized in a manner to display tailored surface characteristics enabling a suitable interaction with other components of the pharmaceutical formulation. For this purpose, the crude iron oxide nanoparticles emerging from the synthesis are immediately coated with suitable compounds such as polycations or polyanions, dextrans or other carbohydrates, proteins, citric acid, synthetic polymers, lipids or detergents, just to name a few. For magnetic field-enhanced nucleic acid delivery with synthetic as well as viral gene vectors (Magnetofection), polycation and polyanion-coated MNPs have turned out particularly useful, but also biotin-streptavidin linkages have been used with great success.

The characteristic feature of MNPs is that these nanoparticles have superparamagnetic properties; i.e. an ensemble of MNPs shows a magnetic moment only in the presence of an external magnetic field (Rosensweig, 1985). Utilizing the superparamagnetism of the particles, they can be controlled from outside the living tissue by a magnetic field, while the magnetic action on the diamagnetic tissue around is negligible. If MNPs are placed in magnetic field gradients, physical force will act on the particles depending on their position within the field and in a direction to the highest field gradient. Appropriate systems  omposed of coils and electronic supply units producing time-dependent or mobile field gradients can direct particles and their cargo towards a defined location (Weyh et al., 2004). Through nanomagnetic targeting, accumulation and retention of drugs can be achieved at the target site non-invasively.

Importantly, nanomagnetic drug targeting can be extended to cell-based therapies: cells can be labeled by nanomagnetic particles. MNP-uptake by cells can be used for imaging purposes. In addition, MNP-labeled cells can be positioned by external magnetic fields. This aspect of nanomagnetic targeting is of high relevance for regenerative medicine.

In 2005, the NIH has launched a nanomedicine roadmap initiative to boost nanomedicine research in the United States. Central to this initiative are Nanomedicine Development Centers, multi- and interdisciplinary teams of scientists. Substantial funding (42 million $) to set-up four nanomedicine centers has already been allocated by the NIH in addition a 144 million $ program of the National Cancer Institute started 2004. In close analogy to these initiatives in the U.S., we propose to implement a DFG-funded Research Unit in Germany that focuses on nanomedicine.

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